**Meet the editor**

Thomas Rath is a doctor in Medicine and specialist in Internal Medicine, Nephrology and Infectious Diseases. He lives in Kaiserslautern, a city of 100,000 inhabitants in the southwest part of Germany. After completing his studies at the University of Mainz, he became a resident at the Westpfalz-Klinikum in Kaiserslautern, a tertiary care hospital with 1300 hospital beds. There, he is the

head of the Department of Nephrology and Transplantation Medicine and also for the outpatient clinic for patients with infectious diseases. He is an active member of many national and international societies. In his scientific career, he has published more than 25 papers in peer-reviewed journals and more than 150 abstracts and posters on national and international congresses. He gives lectures at the Technical University of Kaiserslautern on "artificial organ support".

Contents

**Preface IX**

**Section 1 Cardiovascular Aspects in CKD 1**

**Correction 43**

Usubalieva

Chapter 1 **Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic Kidney Disease 3**

Damir Rebić and Aida Hamzić-Mehmedbašić

Chapter 2 **Disorders in the System of Mineral and Bone Metabolism**

**Disease: Clinical Significance and Possibilities for**

Ludmila Y. Milovanova, Victor V. Fomin, Lidia V. Lysenko

Chapter 3 **Mechanisms and Clinical Implications of Vascular Calcifications**

Chapter 4 **Cardiovascular Risk Factors: The Old Ones and a Closer Look to**

Chapter 5 **Cardiovascular Aspects of Patients with Chronic Kidney Disease**

Ana Paula Silva, Anabela Malho Guedes and Pedro Leão Neves

Ali Osama Malik, Sumit Sehgal, Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and

**in Chronic Kidney Disease 61** Cristina Capusa and Daria Popescu

**the Mineral Metabolism 83**

Chowdhury Ahsan

**and End-Stage Renal Disease 105**

**Regulators—FGF-23, Klotho and Sclerostin—in Chronic Kidney**

(Kozlovskaya), Nikolay A. Mukhin, Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and Aigul Zh.

## Contents

## **Preface XIII**



(Kozlovskaya), Nikolay A. Mukhin, Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and Aigul Zh. Usubalieva


Chapter 5 **Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease 105** Ali Osama Malik, Sumit Sehgal, Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and Chowdhury Ahsan

## **Section 2 Inflammation and CKD 129**

Chapter 6 **Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances 131** Simona Mihai, Elena Codrici, Ionela Daniela Popescu, Ana-Maria Enciu, Laura Georgiana Necula, Gabriela Anton and Cristiana Tanase

**Section 5 Clinical Management in CKD 261**

Chapter 12 **Fluid Overload in Peritoneal Dialysis 263**

Chapter 13 **Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing Hemodialysis 281**

Guillermina Miranda-Diaz

Leonardo Pazarin-Villaseñor, Francisco Gerardo Yanowsky-Escatell, Jorge Andrade-Sierra, Luis Miguel Roman-Pintos and Alejandra

Contents **VII**

Luís Manuel Mota de Sousa, Ana Vanessa Antunes, Cristina Rosa Soares Lavareda Baixinho, Sandy Silva Pedro Severino, Cristina Maria Alves Marques-Vieira and Helena Maria Guerreiro José


## **Section 5 Clinical Management in CKD 261**

**Section 2 Inflammation and CKD 129**

Tanase

**VI** Contents

**Section 3 Nutrition in CKD 179**

W. Johnson

**and Recent Advances 131**

**Kidney Disease 153**

**Therapeutic Options 181**

**of Unknown Etiology 199**

Kalra and Ashok Kumar Tripathi

Lebedeva and Aigul Zh. Usubalieva

**Section 4 Genetic Aspects in CKD 237**

**Population 239**

Chapter 7 **Inflammation in Nonimmune-Mediated Chronic**

Camilla Fanelli, Ayman Noreddin and Ane Nunes

**with Chronic Kidney Disease: A Review of**

Chapter 10 **Nutritional Status Disorders in Chronic Kidney Disease: Practical Aspects (Systematic Review) 215**

Chapter 11 **Discovery of Single Nucleotide Polymorphism in Polycystic Kidney Disease among South Indian (Madurai)**

Pandiaraj Veeramuthumari and William Isabel

Chapter 8 **The Roles of Indoxyl Sulphate and p-Cresyl Sulphate in Patients**

Chapter 9 **Role of Organochlorine Pesticides in Chronic Kidney Diseases**

Ludmila Y. Milovanova, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Yuriy S. Milovanov, Nikolay A. Mukhin, Vasiliy V. Kozlov, Marina V. Taranova, Svetlana Y. Milovanova, Marina V.

Melissa Nataatmadja, Yeoungjee Cho, Katrina Campbell and David

Rishila Ghosh, Manushi Siddharth, Pawan Kuman Kare, Om Prakash

Chapter 6 **Inflammation and Chronic Kidney Disease: Current Approaches**

Simona Mihai, Elena Codrici, Ionela Daniela Popescu, Ana-Maria Enciu, Laura Georgiana Necula, Gabriela Anton and Cristiana

## Chapter 12 **Fluid Overload in Peritoneal Dialysis 263** Leonardo Pazarin-Villaseñor, Francisco Gerardo Yanowsky-Escatell, Jorge Andrade-Sierra, Luis Miguel Roman-Pintos and Alejandra Guillermina Miranda-Diaz

#### Chapter 13 **Subjective Wellbeing Assessment in People with Chronic Kidney Disease Undergoing Hemodialysis 281** Luís Manuel Mota de Sousa, Ana Vanessa Antunes, Cristina Rosa Soares Lavareda Baixinho, Sandy Silva Pedro Severino, Cristina Maria Alves Marques-Vieira and Helena Maria Guerreiro José

Preface

plantation; death overtakes dialysis.

and endothelial function.

disease and improve cardiovascular outcome.

Known worldwide, chronic kidney disease (CKD) is a disease that affects up to 4% of the population with increasing figures also in the developing countries. Life expectancy of pa‐ tients affected by CKD is shortened compared to the overall population, and only a minority of patients reach end-stage renal disease (ESRD) with the need for dialysis or renal trans‐

Most of the patients with CKD will die because of cardiovascular complications. Interesting‐ ly, the traditional risk factors for cardiovascular diseases (hypertension, diabetes mellitus, smoking, etc.) seem to have less influence on the fate of the patients. However, the role of uremic toxins in the development of cardiovascular complications is not fully understood. The progression of renal disease and the occurrence of complications are associated with alterations in inflammation processes. More and more data are added to shed light on the pathophysiological mechanisms involved in the progression of CKD and development of

One of the earliest changes related to CKD are the disorders of the phosphorus-calcium me‐ tabolism. There is a well-known link between high serum phosphate levels and the occur‐ rence of cardiovascular complications in patients on dialysis but also in the general population. New biological markers like fibroblast growth factor 23 (FGF-23) and Klotho give us insight into the interplay of hormones, functional aspects of the renal tubulus system

The interaction of the products of gut microbiota like indoxyl sulphate (IS) and p-cresyl sul‐ phate (PCS) with renal function and cardiovascular risk is very interesting. Both show in‐ creasing serum concentrations in patients with CKD. Therefore, a "gut-kidney-axis" is postulated, and IS and PCS are seen as therapeutic targets to slow the progression of kidney

Besides new pathophysiological insights and pharmacologically based therapies, established dietary restrictions, especially a low-protein diet, have beneficial effects on the progression of CKD. But also environmental aspects have gained more attention. Organochlorine pesticides used in farming and agriculture are suspected to increase the incidence and severity of CKD. All these fascinating aspects of scientific medicine are presented in this book. In addition, chap‐ ters dealing with the genetic aspects of polycystic kidney disease and also the clinical handling of patients with CKD and peritoneal dialysis will be beneficial for the open-minded reader. This book comprises a total of 13 chapters from authors and researches from different coun‐

complications leading to substantial clinical and socioeconomic effects.

tries and continents, thus reflecting worldwide importance of CKD.

## Preface

Known worldwide, chronic kidney disease (CKD) is a disease that affects up to 4% of the population with increasing figures also in the developing countries. Life expectancy of pa‐ tients affected by CKD is shortened compared to the overall population, and only a minority of patients reach end-stage renal disease (ESRD) with the need for dialysis or renal trans‐ plantation; death overtakes dialysis.

Most of the patients with CKD will die because of cardiovascular complications. Interesting‐ ly, the traditional risk factors for cardiovascular diseases (hypertension, diabetes mellitus, smoking, etc.) seem to have less influence on the fate of the patients. However, the role of uremic toxins in the development of cardiovascular complications is not fully understood.

The progression of renal disease and the occurrence of complications are associated with alterations in inflammation processes. More and more data are added to shed light on the pathophysiological mechanisms involved in the progression of CKD and development of complications leading to substantial clinical and socioeconomic effects.

One of the earliest changes related to CKD are the disorders of the phosphorus-calcium me‐ tabolism. There is a well-known link between high serum phosphate levels and the occur‐ rence of cardiovascular complications in patients on dialysis but also in the general population. New biological markers like fibroblast growth factor 23 (FGF-23) and Klotho give us insight into the interplay of hormones, functional aspects of the renal tubulus system and endothelial function.

The interaction of the products of gut microbiota like indoxyl sulphate (IS) and p-cresyl sul‐ phate (PCS) with renal function and cardiovascular risk is very interesting. Both show in‐ creasing serum concentrations in patients with CKD. Therefore, a "gut-kidney-axis" is postulated, and IS and PCS are seen as therapeutic targets to slow the progression of kidney disease and improve cardiovascular outcome.

Besides new pathophysiological insights and pharmacologically based therapies, established dietary restrictions, especially a low-protein diet, have beneficial effects on the progression of CKD. But also environmental aspects have gained more attention. Organochlorine pesticides used in farming and agriculture are suspected to increase the incidence and severity of CKD.

All these fascinating aspects of scientific medicine are presented in this book. In addition, chap‐ ters dealing with the genetic aspects of polycystic kidney disease and also the clinical handling of patients with CKD and peritoneal dialysis will be beneficial for the open-minded reader.

This book comprises a total of 13 chapters from authors and researches from different coun‐ tries and continents, thus reflecting worldwide importance of CKD.

We are grateful to all the contributors and experts for the preparation and submission of their stimulating manuscripts. And, last but not least, many thanks go to the team of InTech for giving us the opportunity to publish all these very interesting papers and thoughts in a peer-reviewed open access book.

> **Dr. Thomas Rath** Department of Nephrology and Transplantation Medicine Westpfalz-Klinikum Kaiserslautern, Germany

**Section 1**

**Cardiovascular Aspects in CKD**

**Section 1**

**Cardiovascular Aspects in CKD**

We are grateful to all the contributors and experts for the preparation and submission of their stimulating manuscripts. And, last but not least, many thanks go to the team of InTech for giving us the opportunity to publish all these very interesting papers and thoughts in a

**Dr. Thomas Rath**

Westpfalz-Klinikum Kaiserslautern, Germany

Department of Nephrology and Transplantation Medicine

peer-reviewed open access book.

X Preface

**Chapter 1**

**Provisional chapter**

**Traditional, Nontraditional, and Uremia-Related**

**Traditional, Nontraditional, and Uremia-Related** 

Damir Rebić and Aida Hamzić-Mehmedbašić

Damir Rebić and Aida Hamzić-Mehmedbašić

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69574

**Abstract**

renocardiac syndrome

**1. Introduction**

**Disease**

**Disease**

**Threats for Cardiovascular Disease in Chronic Kidney**

As many as 40–50% of all patients suffering from chronic kidney disease (CKD) die from reasons related to cardiovascular disease (CVD). The severity of the illness is directly connected to higher mortality caused by cardiovascular factors, with the cause of the CKD not as significant for the relationship. This risk of high cardiovascular mortality and morbidity is actually so high that it surpasses the risk of the patients reaching end-stage renal disease. Within the context of CKD, CVD has certain distinct characteristics. Left ventricular hypertrophy (LVH) is commonly used as a predictor of cardiovascular (CV) mortality. The striking cardiac interstitial fibrosis, a crucial part of uremic cardiomyopathy, and nonobstructive vascular diseases are highly prevalent CV pathology in CKD patients. Traditional risk factors appear to be of less importance in the CKD population compared to the general population but have been hypothesized as uremic toxins as a risk factor of cardiorenal syndrome. In this chapter, we discuss the importance of renal function in the pathophysiology of heart failure. We also elaborate on the novel understanding of chronic kidney disease and its role in cardiovascular disease progression. **Keywords:** chronic kidney disease, cardiovascular disease risk factors, traditional risk factors, nontraditional risk factors, uremia-related risk factors, cardiorenal syndrome,

**Threats for Cardiovascular Disease in Chronic Kidney** 

DOI: 10.5772/intechopen.69574

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Patients suffering from chronic kidney disease (CKD) have the higher risk of facing complications or mortality from causes related to cardiovascular disease (CVD) than reaching its end-stage renal disease (ESRD) [1]. In fact, 9 out of 10 patients face cardiovascular issues

**Provisional chapter**

## **Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic Kidney Disease Threats for Cardiovascular Disease in Chronic Kidney Disease**

**Traditional, Nontraditional, and Uremia-Related** 

DOI: 10.5772/intechopen.69574

Damir Rebić and Aida Hamzić-Mehmedbašić Damir Rebić and Aida Hamzić-Mehmedbašić Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69574

#### **Abstract**

As many as 40–50% of all patients suffering from chronic kidney disease (CKD) die from reasons related to cardiovascular disease (CVD). The severity of the illness is directly connected to higher mortality caused by cardiovascular factors, with the cause of the CKD not as significant for the relationship. This risk of high cardiovascular mortality and morbidity is actually so high that it surpasses the risk of the patients reaching end-stage renal disease. Within the context of CKD, CVD has certain distinct characteristics. Left ventricular hypertrophy (LVH) is commonly used as a predictor of cardiovascular (CV) mortality. The striking cardiac interstitial fibrosis, a crucial part of uremic cardiomyopathy, and nonobstructive vascular diseases are highly prevalent CV pathology in CKD patients. Traditional risk factors appear to be of less importance in the CKD population compared to the general population but have been hypothesized as uremic toxins as a risk factor of cardiorenal syndrome. In this chapter, we discuss the importance of renal function in the pathophysiology of heart failure. We also elaborate on the novel understanding of chronic kidney disease and its role in cardiovascular disease progression.

**Keywords:** chronic kidney disease, cardiovascular disease risk factors, traditional risk factors, nontraditional risk factors, uremia-related risk factors, cardiorenal syndrome, renocardiac syndrome

## **1. Introduction**

Patients suffering from chronic kidney disease (CKD) have the higher risk of facing complications or mortality from causes related to cardiovascular disease (CVD) than reaching its end-stage renal disease (ESRD) [1]. In fact, 9 out of 10 patients face cardiovascular issues

and/or die due to these causes before they ever progress to ESRD [2]. A number of epidemiologic studies and research concluded that a strong relationship exists between CKD and morbidity and mortality related to CVD. Taking better care of cardiovascular (CV) risk factors during the past 10 years has led to a drop of 40% in mortality caused by coronary artery disease [3]. This, however, has not spilled over to patients suffering from CKD or those that have progression to ESRD [4, 5]. This has an effect of increasing issues caused by CVD in CKD patients, as well as highlighting further those risk factors that go alongside old age, primarily arterial hypertension, vascular calcification, dyslipidemia, oxidative stress and inflammation [6]. An aging population and increasing incidence of hypertension, diabetes mellitus, obesity and other comorbid factors are associated with an increasing incidence of cardiorenal disorders [7]. Risk factors are usually intertwined, making it difficult to separate the traditional and newly discovered risk factors, which actually have very strong ties.

disease. Chronic kidney disease is already by nature a progressive kind of disease, which is further augmented through these factors, which, in turn, increase the risk for the "cardio-

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

5

Also, it has been hypothesized that uremic toxins as a risk factor of cardiorenal syndrome. Despite tremendous advances in the development of dialysis technology, CV mortality is still unacceptably high in dialysis patients. Rates of all-cause mortality for dialysis patients are 8.2 times greater than the general population. After CVD has started off, the probability of survival after a five-year period reduce to 18% and 47% for patients on dialysis and following transplantation, respectively. This is quite low compared to 64% survival chance of general population. Patients in long-term dialysis must take special care of their left ventricular hypertrophy development [11] that develops even if the blood pressure level is normalized and is no longer anemic. Three-quarters of patients on dialysis for more than 10 years have left ventricular hypertrophy (LVH). Cardiac fibrosis gets worse with time in these patients but its effect are reversed after transplantation has been performed [12]. An interesting finding is the negative correlation between duration of renal replacement therapy (RRT) prior to the transplantation and the recovery of cardiac functions after a successful procedure. Dialysis performed now fails to discard a large quantity of organic matter completely, which under normal conditions be excreted by the kidneys. This is because of its high molecular size and high protein affinity [12]. Due to pathophysiological actions of this matter, these uremic compounds can add to the overall CV risk in patients with chronic renal disease. According to their physicochemical determinants, there are three groups of uremic-retention compounds: small compounds soluble in water, middle molecules and small protein-bound compounds [13]. These uremic-retention solutes with negative biological effects are called

In the past few years, we have reached some understanding to their cardiovascular adverse effect, but we still need to reach conclusions regarding the mechanisms through which this

It is unclear as to what causes this high risk of cardiovascular disease in CKD patients. Uremia and ESRD-related risk factors, some of which are older age, hypertension, dyslipidemia, diabetes mellitus and LVH, are highly prevalent in CKD. However, these factors do not fully account for the extent of CVD in CKD. Several cross-sectional studies have suggested that other factors that are not included in the Framingham risk profile may play an independent and important role in promoting vascular disease in these patients. Unique risk factors related to ESRD and uremia such as hemodynamic and metabolic alterations, hyperhomocysteinaemia, oxidative stress, inflammation and anemia have been identified and also likely contribute to the excess CVD risk [14]. Several mechanisms are involved in the pathophysiology of CVD in CKD interrelated and complex ways. In CKD, several clinical pathologic entities underlie CVD, including endothelial dysfunction, accelerated atherosclerosis, arteriosclero-

renal syndrome".

uremic toxins.

occurs [13].

**2.2. Pathophysiologic mechanisms**

sis, and cardiomyopathy [15].

## **2. Main body**

#### **2.1. Reverse epidemiology**

Reverse epidemiology is the paradoxical observation that the well-documented associations in the general population between dyslipidemia, hypertension, obesity and poor outcomes does not exist or even may be reversed in dialysis patients. It should be mentioned that this phenomenon is not only observed in dialysis patients but also in geriatric populations and chronic heart failure (CHF). Studies have suggested that this confounded epidemiology is due to the overriding effect of malnutrition and persistent inflammation [8].

CVD in the setting of CKD has its own specific characteristics. First, despite the high incidence of accelerated atherosclerosis and high fatality following myocardial infarction (MI) in patients suffering from chronic kidney disease, a very small number of heart diseaserelated deaths are caused by ischemic heart disease—between 15 and 25% [9]. CVD-caused mortality is predicted by left ventricular hypertrophy (LVH), which is typically used as a forecaster. The mortality usually happens in the form of heart failure, myocardial infarction and sudden cardiac failure. Regardless of hypertension, a common cardiovascular pathology in patients with CKD is striking cardiac interstitial fibrosis, which occurs within uremic cardiomyopathy and nonobstructive vascular disease. Most common examples would be vascular stiffness, calcification and ossification [10]. These causes are predictive of negative cardiovascular events and can be used in explaining why sudden cardiac death and ischemic heart disease occur so often when there is no significant atherosclerosis. Importantly, traditional risk factors of CVD that we know are not as important in patients suffering from CKD as they are in the general population. Primarily, this is in reference to hypertension, diabetes mellitus, smoking and hyperlipidemia [9]. This can be seen through a stubbornly high CV mortality in CKD patients who control these factors. Evidence appearing right now indicates that uremic toxins and abnormal calcium-phosphate metabolism, which belong to novel CKD risk factors, directly add to the development and evolution of cardiovascular disease. Chronic kidney disease is already by nature a progressive kind of disease, which is further augmented through these factors, which, in turn, increase the risk for the "cardiorenal syndrome".

Also, it has been hypothesized that uremic toxins as a risk factor of cardiorenal syndrome. Despite tremendous advances in the development of dialysis technology, CV mortality is still unacceptably high in dialysis patients. Rates of all-cause mortality for dialysis patients are 8.2 times greater than the general population. After CVD has started off, the probability of survival after a five-year period reduce to 18% and 47% for patients on dialysis and following transplantation, respectively. This is quite low compared to 64% survival chance of general population. Patients in long-term dialysis must take special care of their left ventricular hypertrophy development [11] that develops even if the blood pressure level is normalized and is no longer anemic. Three-quarters of patients on dialysis for more than 10 years have left ventricular hypertrophy (LVH). Cardiac fibrosis gets worse with time in these patients but its effect are reversed after transplantation has been performed [12]. An interesting finding is the negative correlation between duration of renal replacement therapy (RRT) prior to the transplantation and the recovery of cardiac functions after a successful procedure. Dialysis performed now fails to discard a large quantity of organic matter completely, which under normal conditions be excreted by the kidneys. This is because of its high molecular size and high protein affinity [12]. Due to pathophysiological actions of this matter, these uremic compounds can add to the overall CV risk in patients with chronic renal disease. According to their physicochemical determinants, there are three groups of uremic-retention compounds: small compounds soluble in water, middle molecules and small protein-bound compounds [13]. These uremic-retention solutes with negative biological effects are called uremic toxins.

In the past few years, we have reached some understanding to their cardiovascular adverse effect, but we still need to reach conclusions regarding the mechanisms through which this occurs [13].

#### **2.2. Pathophysiologic mechanisms**

and/or die due to these causes before they ever progress to ESRD [2]. A number of epidemiologic studies and research concluded that a strong relationship exists between CKD and morbidity and mortality related to CVD. Taking better care of cardiovascular (CV) risk factors during the past 10 years has led to a drop of 40% in mortality caused by coronary artery disease [3]. This, however, has not spilled over to patients suffering from CKD or those that have progression to ESRD [4, 5]. This has an effect of increasing issues caused by CVD in CKD patients, as well as highlighting further those risk factors that go alongside old age, primarily arterial hypertension, vascular calcification, dyslipidemia, oxidative stress and inflammation [6]. An aging population and increasing incidence of hypertension, diabetes mellitus, obesity and other comorbid factors are associated with an increasing incidence of cardiorenal disorders [7]. Risk factors are usually intertwined, making it difficult to separate the traditional and newly discovered risk factors, which actually have very strong ties.

4 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Reverse epidemiology is the paradoxical observation that the well-documented associations in the general population between dyslipidemia, hypertension, obesity and poor outcomes does not exist or even may be reversed in dialysis patients. It should be mentioned that this phenomenon is not only observed in dialysis patients but also in geriatric populations and chronic heart failure (CHF). Studies have suggested that this confounded epidemiology is due

CVD in the setting of CKD has its own specific characteristics. First, despite the high incidence of accelerated atherosclerosis and high fatality following myocardial infarction (MI) in patients suffering from chronic kidney disease, a very small number of heart diseaserelated deaths are caused by ischemic heart disease—between 15 and 25% [9]. CVD-caused mortality is predicted by left ventricular hypertrophy (LVH), which is typically used as a forecaster. The mortality usually happens in the form of heart failure, myocardial infarction and sudden cardiac failure. Regardless of hypertension, a common cardiovascular pathology in patients with CKD is striking cardiac interstitial fibrosis, which occurs within uremic cardiomyopathy and nonobstructive vascular disease. Most common examples would be vascular stiffness, calcification and ossification [10]. These causes are predictive of negative cardiovascular events and can be used in explaining why sudden cardiac death and ischemic heart disease occur so often when there is no significant atherosclerosis. Importantly, traditional risk factors of CVD that we know are not as important in patients suffering from CKD as they are in the general population. Primarily, this is in reference to hypertension, diabetes mellitus, smoking and hyperlipidemia [9]. This can be seen through a stubbornly high CV mortality in CKD patients who control these factors. Evidence appearing right now indicates that uremic toxins and abnormal calcium-phosphate metabolism, which belong to novel CKD risk factors, directly add to the development and evolution of cardiovascular

to the overriding effect of malnutrition and persistent inflammation [8].

**2. Main body**

**2.1. Reverse epidemiology**

It is unclear as to what causes this high risk of cardiovascular disease in CKD patients. Uremia and ESRD-related risk factors, some of which are older age, hypertension, dyslipidemia, diabetes mellitus and LVH, are highly prevalent in CKD. However, these factors do not fully account for the extent of CVD in CKD. Several cross-sectional studies have suggested that other factors that are not included in the Framingham risk profile may play an independent and important role in promoting vascular disease in these patients. Unique risk factors related to ESRD and uremia such as hemodynamic and metabolic alterations, hyperhomocysteinaemia, oxidative stress, inflammation and anemia have been identified and also likely contribute to the excess CVD risk [14]. Several mechanisms are involved in the pathophysiology of CVD in CKD interrelated and complex ways. In CKD, several clinical pathologic entities underlie CVD, including endothelial dysfunction, accelerated atherosclerosis, arteriosclerosis, and cardiomyopathy [15].

#### **2.3. Neurohumoral activation and hemodynamic alterations**

Hemodynamic changes and neurohumoral factors such as renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activation play an important role in the interactions between the heart and the kidneys in patients with CKD and CVD (**Figure 1**). RAAS and SNS are both key regulatory systems for the maintenance of cardiovascular and renal function. Loss of renal mass in CKD leads to the accumulation of sodium and water resulting in hypertension and fluid overload in patients with Cardiorenal syndrome (CRS). In the setting of CKD, elevated concentration of angiotensin II increases sodium retention, regulates glomerular filtration rate (GFR), potentiates the renal effects of SNS stimulation and increases release of arginine vasopressin (AVP) from the posterior pituitary gland and aldosterone from the adrenal cortex [16].

both causes systemic arterial vasoconstriction and directly promote cardiac remodeling. AVP exerts its physiologic effects via activation of V1 and V2 receptors. Activation of V1a receptors on vascular smooth muscle cells results in vasoconstriction, while activation of V2 receptors on the collecting duct increases reabsorption of hypotonic water. Patients with CKD and CHF suffer from elevated afterload occurring after an increase in systemic vascular resistance, which arises from vasoconstriction mediated by the V1a receptor, as well as from increased preload due to water retention that occurs following the anti-diuretic effect mediated by the V2 receptor. AVP also has direct promoting effect of fibrosis and myocardial

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

7

Volume overload occurs, due to expansion of extracellular fluid arising from aldosterone, which is responsible for the rising reabsorption of sodium and water. Ventricular filling pressures increase, caused by retention of fluids, resulting in symptoms connected with HF such as dyspnea, jugular venous distension, hepatic congestion, peripheral edema and orthopnea. Preload, or higher ventricular filling pressures, increase the workload of heart and cause dilatation of the damaged ventricle. Other conditions along with chronic kidney disease increase the cardiac output demand, leading to volume overload; chronic anemia is one among them. It is the condition where the oxygen-transporting capacity of blood has gone down. Another is when the patient has an arteriovenous fistula for the hemodialysis (HD) access, which

Regulation of sodium balance is important for the maintenance of appropriate blood pressure and body fluid volume. Increased blood pressure resulting from a normal cardiac response to increasing fluid volume and pressure natriuresis and which is required for excretion of excess sodium and body fluid. Abnormal pressure natriuresis in heart failure due to low cardiac output has been described in low-flow theory. In patients with CKD who have insufficient sodium excretion because of reduced GFR due to reduced numbers of functional nephrons, there is an insufficient pressure natriuresis. Pressure natriuresis is also affected by neurohumoral factors such as RAAS and SNS. The combination of pump failure and low cardiac output leads to vascular congestion and edema that are worsened through a nonsensical renal reaction where water and sodium retention occurs, even though extracellular volume is expanded. Vascular congestion and edema become worse, under these conditions [20].

Low cardiac output and arterial underfilling are previously thought to be main causes of impaired renal function in heart failure. However, some evidence suggests that renal venous hypertension due to venous congestion, rather than arterial underfilling, may cause renal dysfunction. Central venous congestion is clinically evident as increased jugular venous pressure and peripheral edema. Increased central venous is transmitted downstream to the capillary beds of other organ systems including the kidneys. Recent clinical trials showed the relationship between increase in central venous pressure and decrease in estimated GFR [21]. GFR is considered to decrease in response to reduction in the net filtration pressure caused by increased hydrostatic pressure in Bowman's capsule secondary to increased interstitial pressure. These factors suggest that abnormal pressure natriuresis due to decreased GFR, exacerbation of venous congestion and worsening of heart failure due to low cardiac output

requires some cardiac output, leaving less to systemic circulation [19].

hypertrophy [18].

create a positive-feedback cycle [16].

Sympathetic stimulation results in several physiologic changes that under normal circumstances serve to maintain cardiac output and vascular integrity. In the setting of heart failure, overactivity of SNS worsens cardiac performance. Sympathetic hyperactivity is present in early and advanced stages of CKD, with levels that increase with worsening renal function [17]. Overdrive of renal adrenergic receptors promotes release of renin from juxtaglomerular cells and reabsorption of sodium from tubular cells. Angiotensin II and aldosterone

**Figure 1.** Neurohumoral activation and hemodynamic alterations in CKD and CHF. *Note*: CKD, chronic kidney disease; CHF, chronic heart failure; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system; LV, left ventricular; LVH, left ventricular hypertrophy.

both causes systemic arterial vasoconstriction and directly promote cardiac remodeling. AVP exerts its physiologic effects via activation of V1 and V2 receptors. Activation of V1a receptors on vascular smooth muscle cells results in vasoconstriction, while activation of V2 receptors on the collecting duct increases reabsorption of hypotonic water. Patients with CKD and CHF suffer from elevated afterload occurring after an increase in systemic vascular resistance, which arises from vasoconstriction mediated by the V1a receptor, as well as from increased preload due to water retention that occurs following the anti-diuretic effect mediated by the V2 receptor. AVP also has direct promoting effect of fibrosis and myocardial hypertrophy [18].

**2.3. Neurohumoral activation and hemodynamic alterations**

6 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

sterone from the adrenal cortex [16].

ventricular; LVH, left ventricular hypertrophy.

Hemodynamic changes and neurohumoral factors such as renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) activation play an important role in the interactions between the heart and the kidneys in patients with CKD and CVD (**Figure 1**). RAAS and SNS are both key regulatory systems for the maintenance of cardiovascular and renal function. Loss of renal mass in CKD leads to the accumulation of sodium and water resulting in hypertension and fluid overload in patients with Cardiorenal syndrome (CRS). In the setting of CKD, elevated concentration of angiotensin II increases sodium retention, regulates glomerular filtration rate (GFR), potentiates the renal effects of SNS stimulation and increases release of arginine vasopressin (AVP) from the posterior pituitary gland and aldo-

Sympathetic stimulation results in several physiologic changes that under normal circumstances serve to maintain cardiac output and vascular integrity. In the setting of heart failure, overactivity of SNS worsens cardiac performance. Sympathetic hyperactivity is present in early and advanced stages of CKD, with levels that increase with worsening renal function [17]. Overdrive of renal adrenergic receptors promotes release of renin from juxtaglomerular cells and reabsorption of sodium from tubular cells. Angiotensin II and aldosterone

**Figure 1.** Neurohumoral activation and hemodynamic alterations in CKD and CHF. *Note*: CKD, chronic kidney disease; CHF, chronic heart failure; SNS, sympathetic nervous system; RAAS, renin-angiotensin-aldosterone system; LV, left Volume overload occurs, due to expansion of extracellular fluid arising from aldosterone, which is responsible for the rising reabsorption of sodium and water. Ventricular filling pressures increase, caused by retention of fluids, resulting in symptoms connected with HF such as dyspnea, jugular venous distension, hepatic congestion, peripheral edema and orthopnea. Preload, or higher ventricular filling pressures, increase the workload of heart and cause dilatation of the damaged ventricle. Other conditions along with chronic kidney disease increase the cardiac output demand, leading to volume overload; chronic anemia is one among them. It is the condition where the oxygen-transporting capacity of blood has gone down. Another is when the patient has an arteriovenous fistula for the hemodialysis (HD) access, which requires some cardiac output, leaving less to systemic circulation [19].

Regulation of sodium balance is important for the maintenance of appropriate blood pressure and body fluid volume. Increased blood pressure resulting from a normal cardiac response to increasing fluid volume and pressure natriuresis and which is required for excretion of excess sodium and body fluid. Abnormal pressure natriuresis in heart failure due to low cardiac output has been described in low-flow theory. In patients with CKD who have insufficient sodium excretion because of reduced GFR due to reduced numbers of functional nephrons, there is an insufficient pressure natriuresis. Pressure natriuresis is also affected by neurohumoral factors such as RAAS and SNS. The combination of pump failure and low cardiac output leads to vascular congestion and edema that are worsened through a nonsensical renal reaction where water and sodium retention occurs, even though extracellular volume is expanded. Vascular congestion and edema become worse, under these conditions [20].

Low cardiac output and arterial underfilling are previously thought to be main causes of impaired renal function in heart failure. However, some evidence suggests that renal venous hypertension due to venous congestion, rather than arterial underfilling, may cause renal dysfunction. Central venous congestion is clinically evident as increased jugular venous pressure and peripheral edema. Increased central venous is transmitted downstream to the capillary beds of other organ systems including the kidneys. Recent clinical trials showed the relationship between increase in central venous pressure and decrease in estimated GFR [21]. GFR is considered to decrease in response to reduction in the net filtration pressure caused by increased hydrostatic pressure in Bowman's capsule secondary to increased interstitial pressure. These factors suggest that abnormal pressure natriuresis due to decreased GFR, exacerbation of venous congestion and worsening of heart failure due to low cardiac output create a positive-feedback cycle [16].

#### **2.4. Uremic cardiomyopathy**

In the general population, pathological LVH is connected to poor survival prognosis, the development of diastolic dysfunction, arrhythmias and cardiac failure progression. A similar state is present with predialysis, as well as dialysis patients. Although the terms used to describe this condition overlap, uremic cardiomyopathy marks the influence of reduced renal function on functional cardiac capability [22]. Epidemiological studies show that the primary manifestation of uremic cardiomyopathy is LVH. Reduced renal function in different stages of arrest, combined with cardiac diseases, most often causes the development of uremic cardiomyopathy. Go et al. in a study on a large number of examinees determined that the reduction of GFR by 50%, increases the overall risk of death by five times [23]. The treatment of ESRD by kidney transplantation severely reduces the risk of cardiovascular death, but with persistence of some mortality risks. The study conducted by Zoccali et al. shows that short-term dialysis patients have a better prognosis and survival concerning cardiovascular diseases post kidney transplantation. The same authors determined that LVH is an independent factor of cardiovascular risk, connected to significant survival rate reduction [24]. LVH pathogenesis in uremic cardiomyopathy remains uncertain. Taking into account the high frequency of hypertension in patients with a difficult chronic renal disease, one of the hypotheses is that LVH occurs as a product of blood pressure encumbrance. In patients with diabetic nephropathy, blood pressure, as an independent risk factor, leads to the increase of left ventricular mass (LVM), as well as the LV mass index (LVMI). The application of blood pressure drugs, as well as dialysis treatment successfully reduces ventricular mass [25], and so, this treatment is used in normotensive patients. The application of angiotensin-converting enzyme (ACE) inhibitors reduces LVM in dialysis patients, previously normotensive. Larsen et al. have shown that left ventricular wall size is reduced in patients on intensive, continuous and daily dialysis, over the course of a year, unlike those patients who had intermittent dialysis three times a week, despite similar systolic blood pressure values. Another potential cause of uremic cardiomyopathy is volume encumbrance, which can cause the development of eccentric LVH, by increasing left ventricular end diastolic diameter (LVEDD). The reduction of interdialytic mass correlates with LVMI reduction, but LVH can persist, irrelevant of LVMI normalization. Another hypothesis on the etiology of uremic cardiomyopathy is that the accumulation of hypertrophic growth factor, connecter to ESRD, initiates signal activation independent of mechanical stress, which leads to cardiac pathology progression. Several matters can modulate cardiac growth and function, which are accumulated in ESRD patients, primarily endothelin-1, parathyroid hormone (PTH), tumor necrosis factor alpha (TNF-α), leptin, interleukin1 alpha (IL-1α) and interleukin 6 (IL-6) [26].

a result of volume encumbrance, the increase of LV wall thickening, and the combination of characteristics of both eccentric and concentric LVH. The precise distinction of LVH between eccentric and concentric is sometimes difficult in hemodialysis patients, because of cyclical variations of extracellular fluid and humoral balance. The internal dimensions of LV are under the influence of the volume status, and the decrease of blood volume during dialysis reduces LV diameter, causing "acute" changes in the relative thickness of the left ventricular wall. In stable patients with compensated hypertrophy, the systolic function remains within normal boundaries, while diastolic charging often varies. The LVH is an adaptive response to increased heart rate. LVH is both damaging and beneficial at the same time. The benefits are tied to the number of sarcomeres and the increase of heart function capability, which allows for energy conservation. Such an effect sustains normal systolic function during the initial, compensated, or "adaptive" phase of LVH development. Continued stress gradually leads to an "inappropriate" hypertrophic response. In this phase of LVH, a loss of balance between energy consumption and production occurs in the activated myocardial cells, which eventually results in chronic energy deficiency and accelerated myocyte death [28]. The increase of extracellular matrix and collagen content makes the functional competence of heart contractions sustainable, however, at the expense of weakened diastolic charging. LVH usually occurs as a response to initiated mechanical stress. Pressure encumbrance results in the parallel addition of new sarcomeres, with a disproportionate increase in LV wall thickness and a normal ventricular diameter (concentric hypertrophy). Volume encumbrance primarily results in the addition of new sarcomeres in series, and a secondary order of new sarcomeres parallel, which again leads to the increase of LV diameter, with an increase of wall thickness (eccentric hypertrophy). The development and markings of LVH are under the influence of several factors such as age, gender and race, a co-existing disease such as diabetes, systemic

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9

The changes in the vascular system of uremic patients are attributed to a synergistic effect of numerous factors such as dyslipidemia, prothrombotic factors, anemia, hypertension, increased oxidative stress, hyperparathyroidism, synthesis disorder homocysteine and nitric oxide, endothelial dysfunction as well as LV remodeling, which leads to the modification of

Accelerated atherosclerosis and more frequent and generally higher intensity cardiovascular events go alongside CKD. Atherosclerosis is an intimal disease where vascular lesions and plaques develop. A specific morphology can be noticed in lesions in patients with CKD. They can be calcified, with media thickness. In contrast, the atherosclerotic lesions are fibro athero-

In CKD, as in the general population, the accumulation of conventional risk factors initiates the atherosclerotic process. Among these risk factors, dyslipidemia is a major determinant.

More than one CKD uremia-related factor leads to renal function which is substantially reduced. Despite multiple pathobiological factors being involved, vascular disease is aggravated by the

disease or kidney failure [29] (**Figure 3**).

structural and functional cardiac and vascular characteristics.

**2.6. Vascular remodeling and CKD**

matous in the general population.

#### **2.5. Left ventricular hypertrophy**

The prevalence of LVH is high among patients suffering from ESRD. Structural changes appear in the early stages of kidney function damage. In prospective research, just prior to the start of RRT, 74% of patients had LVH, with a high LVMI, as an independent mortality predictor after 2 years of dialysis treatment. Up to 80% of dialysis patients have increased LVM [27]. The increase of LVM in ESRD patients can be caused by an increase of LVEDD as a result of volume encumbrance, the increase of LV wall thickening, and the combination of characteristics of both eccentric and concentric LVH. The precise distinction of LVH between eccentric and concentric is sometimes difficult in hemodialysis patients, because of cyclical variations of extracellular fluid and humoral balance. The internal dimensions of LV are under the influence of the volume status, and the decrease of blood volume during dialysis reduces LV diameter, causing "acute" changes in the relative thickness of the left ventricular wall. In stable patients with compensated hypertrophy, the systolic function remains within normal boundaries, while diastolic charging often varies. The LVH is an adaptive response to increased heart rate. LVH is both damaging and beneficial at the same time. The benefits are tied to the number of sarcomeres and the increase of heart function capability, which allows for energy conservation. Such an effect sustains normal systolic function during the initial, compensated, or "adaptive" phase of LVH development. Continued stress gradually leads to an "inappropriate" hypertrophic response. In this phase of LVH, a loss of balance between energy consumption and production occurs in the activated myocardial cells, which eventually results in chronic energy deficiency and accelerated myocyte death [28]. The increase of extracellular matrix and collagen content makes the functional competence of heart contractions sustainable, however, at the expense of weakened diastolic charging. LVH usually occurs as a response to initiated mechanical stress. Pressure encumbrance results in the parallel addition of new sarcomeres, with a disproportionate increase in LV wall thickness and a normal ventricular diameter (concentric hypertrophy). Volume encumbrance primarily results in the addition of new sarcomeres in series, and a secondary order of new sarcomeres parallel, which again leads to the increase of LV diameter, with an increase of wall thickness (eccentric hypertrophy). The development and markings of LVH are under the influence of several factors such as age, gender and race, a co-existing disease such as diabetes, systemic disease or kidney failure [29] (**Figure 3**).

#### **2.6. Vascular remodeling and CKD**

**2.4. Uremic cardiomyopathy**

8 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

In the general population, pathological LVH is connected to poor survival prognosis, the development of diastolic dysfunction, arrhythmias and cardiac failure progression. A similar state is present with predialysis, as well as dialysis patients. Although the terms used to describe this condition overlap, uremic cardiomyopathy marks the influence of reduced renal function on functional cardiac capability [22]. Epidemiological studies show that the primary manifestation of uremic cardiomyopathy is LVH. Reduced renal function in different stages of arrest, combined with cardiac diseases, most often causes the development of uremic cardiomyopathy. Go et al. in a study on a large number of examinees determined that the reduction of GFR by 50%, increases the overall risk of death by five times [23]. The treatment of ESRD by kidney transplantation severely reduces the risk of cardiovascular death, but with persistence of some mortality risks. The study conducted by Zoccali et al. shows that short-term dialysis patients have a better prognosis and survival concerning cardiovascular diseases post kidney transplantation. The same authors determined that LVH is an independent factor of cardiovascular risk, connected to significant survival rate reduction [24]. LVH pathogenesis in uremic cardiomyopathy remains uncertain. Taking into account the high frequency of hypertension in patients with a difficult chronic renal disease, one of the hypotheses is that LVH occurs as a product of blood pressure encumbrance. In patients with diabetic nephropathy, blood pressure, as an independent risk factor, leads to the increase of left ventricular mass (LVM), as well as the LV mass index (LVMI). The application of blood pressure drugs, as well as dialysis treatment successfully reduces ventricular mass [25], and so, this treatment is used in normotensive patients. The application of angiotensin-converting enzyme (ACE) inhibitors reduces LVM in dialysis patients, previously normotensive. Larsen et al. have shown that left ventricular wall size is reduced in patients on intensive, continuous and daily dialysis, over the course of a year, unlike those patients who had intermittent dialysis three times a week, despite similar systolic blood pressure values. Another potential cause of uremic cardiomyopathy is volume encumbrance, which can cause the development of eccentric LVH, by increasing left ventricular end diastolic diameter (LVEDD). The reduction of interdialytic mass correlates with LVMI reduction, but LVH can persist, irrelevant of LVMI normalization. Another hypothesis on the etiology of uremic cardiomyopathy is that the accumulation of hypertrophic growth factor, connecter to ESRD, initiates signal activation independent of mechanical stress, which leads to cardiac pathology progression. Several matters can modulate cardiac growth and function, which are accumulated in ESRD patients, primarily endothelin-1, parathyroid hormone (PTH), tumor necrosis factor alpha (TNF-α),

leptin, interleukin1 alpha (IL-1α) and interleukin 6 (IL-6) [26].

The prevalence of LVH is high among patients suffering from ESRD. Structural changes appear in the early stages of kidney function damage. In prospective research, just prior to the start of RRT, 74% of patients had LVH, with a high LVMI, as an independent mortality predictor after 2 years of dialysis treatment. Up to 80% of dialysis patients have increased LVM [27]. The increase of LVM in ESRD patients can be caused by an increase of LVEDD as

**2.5. Left ventricular hypertrophy**

The changes in the vascular system of uremic patients are attributed to a synergistic effect of numerous factors such as dyslipidemia, prothrombotic factors, anemia, hypertension, increased oxidative stress, hyperparathyroidism, synthesis disorder homocysteine and nitric oxide, endothelial dysfunction as well as LV remodeling, which leads to the modification of structural and functional cardiac and vascular characteristics.

Accelerated atherosclerosis and more frequent and generally higher intensity cardiovascular events go alongside CKD. Atherosclerosis is an intimal disease where vascular lesions and plaques develop. A specific morphology can be noticed in lesions in patients with CKD. They can be calcified, with media thickness. In contrast, the atherosclerotic lesions are fibro atheromatous in the general population.

In CKD, as in the general population, the accumulation of conventional risk factors initiates the atherosclerotic process. Among these risk factors, dyslipidemia is a major determinant.

More than one CKD uremia-related factor leads to renal function which is substantially reduced. Despite multiple pathobiological factors being involved, vascular disease is aggravated by the calcification of the intimal atheromatous lesions and vascular wall media, which are representations of mineral metabolism disturbances.

Older populations suffering from CKD have a higher prevalence of occlusive atherosclerotic disease. Clinically, this is mirrored as ischemic heart disease (myocardial infarction, angina and sudden cardiac death), heart failure, peripheral and cerebrovascular vascular disease [30].

Arteriosclerosis must be taken into consideration when discussing CKD patients with CV risk. It is a process of remodeling, diffuse and nonocclusive by nature, involving the central arteries. Its determinants are an increased luminal diameter, medial calcification, destruction of the elastic lamellae, and an extracellular matrix increase. The arterial wall shows signs of stiffness due to these changes, meaning it is not as elastic. We still do not exactly know the link between this arterial stiffness and CKD. Altered mineral homeostasis is a suspect in this connection, due to the high medial calcification. In the ESRD, hyperphosphatemia, a higher level of calcium-phosphate product, hyperparathyroidism and lower 1.25-dyhydroxyvitamin D levels are characteristics of mineral imbalance metabolism [31].

synthase (e-NOS) inhibitor asymmetric dimethylarginine (ADMA), which leads to reduced bioavailability of endothelial NO; (2) activation of angiotensin II, which induces oxidative stress; (3) high levels of homocysteine; (4) chronic inflammation; (5) dyslipidemia and (6) endothelial progenitor cell deficiency [32]. Endothelial dysfunction contributes significantly to the initiation and progression of CVD in CKD. It exacerbates arterial luminal narrowing and arterial wall stiffening by allowing development of intima-media thickening, medial

Middle Age/Elderly + CKD Tradional CV Risk factros

Young Adults + CKDrelated CV risk factors

Arteriosclerosis

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**Cardiovascular disease**

11

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Atherosclerosis

A significant number of patients with uremia that are in the late stage of their renal disease show the following: (1) symptoms of myocardial ischemia without coronary artery disease by coronary angiography and (2) difficult or impossible to treat congestive heart failure. Functional and morphological characteristics of uremia are to blame for the existence of these clinical conditions [33]. As they are expected to enter ESRD, and as their kidney function is worsened, patients suffering from uremia generally have hypertension, anemia, hyperactive circulation caused by arteriovenous fistulae, increased stiffness of the arteries, and LVH and cardiac dilatation caused by overload of pressure and volume and a metabolic profile that does not fit normal characteristics. The myocardium structure is also changed due to intramyocardial thickening of the coronary artery, reduced density of myocardial capillary and higher levels of interstitial myocardial fibrosis. These factors put together lead to cardiomyopathy. Chemical anomalies in patients suffering from CKD or ESRD, including hyperkalemia, uremia, acidosis and calcium/phosphorus dysregulation, lead to higher rates of cardiac arrhythmia [33]. Primary cardiac arrhythmias account for 50% of CV deaths in patients with ESRD. Structural heart disease secondary to CKD/ESRD such as LVH, valvular abnormalities, conduction system calcification and heart failure can independently worsen the outcome of

CVD progression in CKD a higher and burden is undoubtedly connected with the late stages of CKD. In comparison with individuals of the same gender and age from the general population, ESRD patients face 100 times higher morbidity and mortality rates. Accelerated CVD is promoted by chronic kidney disease, which is one of its most significant risk factors. The relationship is an exponential one between CKD and CVD. It is already in the first stages of kidney damage that the risk starts growing and continues all the way through to the late stage disease, where ESRD patients face 20–30 times higher risk than the general population. The

hypertrophy and calcification [30].

**Figure 3.** Pathogenesis of atherosclerosis and arteriosclerosis.

arrhythmias in this population [34].

**2.7. Uremia-related CVD**

**Chronic kidney disease**

Diffuse nonocclusive medial calcification and increased arterial stiffnesses are the more dominant forms of vascular pathology in adolescents and young adults with CKD. These morphologic changes are associated with systolic hypertension, wide pulse pressure, LVH, coronary hypoperfusion, further renal damage, congestive heart failure and sudden death (**Figure 2**).

Impaired endothelial function is a characteristic of early stages of chronic kidney disease, and multiple possible causes have been identified: (1) reduced clearance of endothelial NO

**Figure 2.** Mechanisms left ventricular remodeling.

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ... http://dx.doi.org/10.5772/intechopen.69574 11

**Figure 3.** Pathogenesis of atherosclerosis and arteriosclerosis.

synthase (e-NOS) inhibitor asymmetric dimethylarginine (ADMA), which leads to reduced bioavailability of endothelial NO; (2) activation of angiotensin II, which induces oxidative stress; (3) high levels of homocysteine; (4) chronic inflammation; (5) dyslipidemia and (6) endothelial progenitor cell deficiency [32]. Endothelial dysfunction contributes significantly to the initiation and progression of CVD in CKD. It exacerbates arterial luminal narrowing and arterial wall stiffening by allowing development of intima-media thickening, medial hypertrophy and calcification [30].

#### **2.7. Uremia-related CVD**

**Figure 2.** Mechanisms left ventricular remodeling.

calcification of the intimal atheromatous lesions and vascular wall media, which are representa-

Older populations suffering from CKD have a higher prevalence of occlusive atherosclerotic disease. Clinically, this is mirrored as ischemic heart disease (myocardial infarction, angina and sudden cardiac death), heart failure, peripheral and cerebrovascular vascular disease [30]. Arteriosclerosis must be taken into consideration when discussing CKD patients with CV risk. It is a process of remodeling, diffuse and nonocclusive by nature, involving the central arteries. Its determinants are an increased luminal diameter, medial calcification, destruction of the elastic lamellae, and an extracellular matrix increase. The arterial wall shows signs of stiffness due to these changes, meaning it is not as elastic. We still do not exactly know the link between this arterial stiffness and CKD. Altered mineral homeostasis is a suspect in this connection, due to the high medial calcification. In the ESRD, hyperphosphatemia, a higher level of calcium-phosphate product, hyperparathyroidism and lower 1.25-dyhydroxyvitamin

Diffuse nonocclusive medial calcification and increased arterial stiffnesses are the more dominant forms of vascular pathology in adolescents and young adults with CKD. These morphologic changes are associated with systolic hypertension, wide pulse pressure, LVH, coronary hypoperfusion, further renal damage, congestive heart failure and sudden death (**Figure 2**). Impaired endothelial function is a characteristic of early stages of chronic kidney disease, and multiple possible causes have been identified: (1) reduced clearance of endothelial NO

tions of mineral metabolism disturbances.

10 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

D levels are characteristics of mineral imbalance metabolism [31].

A significant number of patients with uremia that are in the late stage of their renal disease show the following: (1) symptoms of myocardial ischemia without coronary artery disease by coronary angiography and (2) difficult or impossible to treat congestive heart failure. Functional and morphological characteristics of uremia are to blame for the existence of these clinical conditions [33]. As they are expected to enter ESRD, and as their kidney function is worsened, patients suffering from uremia generally have hypertension, anemia, hyperactive circulation caused by arteriovenous fistulae, increased stiffness of the arteries, and LVH and cardiac dilatation caused by overload of pressure and volume and a metabolic profile that does not fit normal characteristics. The myocardium structure is also changed due to intramyocardial thickening of the coronary artery, reduced density of myocardial capillary and higher levels of interstitial myocardial fibrosis. These factors put together lead to cardiomyopathy. Chemical anomalies in patients suffering from CKD or ESRD, including hyperkalemia, uremia, acidosis and calcium/phosphorus dysregulation, lead to higher rates of cardiac arrhythmia [33]. Primary cardiac arrhythmias account for 50% of CV deaths in patients with ESRD. Structural heart disease secondary to CKD/ESRD such as LVH, valvular abnormalities, conduction system calcification and heart failure can independently worsen the outcome of arrhythmias in this population [34].

CVD progression in CKD a higher and burden is undoubtedly connected with the late stages of CKD. In comparison with individuals of the same gender and age from the general population, ESRD patients face 100 times higher morbidity and mortality rates. Accelerated CVD is promoted by chronic kidney disease, which is one of its most significant risk factors. The relationship is an exponential one between CKD and CVD. It is already in the first stages of kidney damage that the risk starts growing and continues all the way through to the late stage disease, where ESRD patients face 20–30 times higher risk than the general population. The risk can be seen when eGFR levels are below 50–60 ml/min/1.73 m<sup>2</sup> , and it becomes extremely high once eGFR drops <45 ml/min/1.73 m<sup>2</sup> [33].

**3.3. Diabetes mellitus**

**3.4. Arterial hypertension**

North-American registry data show that the number of diabetic patients annually admitted to RRT more than doubled from 1995 to 2000. Diabetes mellitus has become the single most important cause of ESRD. Renal replacement therapy continues showing unsatisfactory results for diabetic patients, as survival rates are low. Compared to dialysis patients with other underlying kidney conditions, those with diabetes have the lowest chance of survival. The main cause of death is coronary heart disease—myocardial infarction (MI), angina, history of bypass surgery, PTCA and pathology on coronary angiography. Cardiovascular issues, primarily coronary atheroma, add up before the diabetic patient enters renal replacement therapy programs. Therefore, it is crucial to improving care for the patient with diabetes before he enters the end-stage of the disease. Diabetic patients with underlying CKD face an increased cardiac risk after developing acute MI, which is mirrored through atrial and ventricular arrhythmia, atrioventricular (AV) block, asystole, pulmonary congestion and cardiogenic shock [40].

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13

Arterial hypertension is very common in CKD patients and is connected to increased risk of CV death [41]. Hypertension is often present in dialysis patients. According to the results of an Italian multicentric study, 88% of 504 patients treated with RRT suffer from arterial hypertension, with anti-hypertensive therapy included. Arterial hypertension in dialysis patients is usually connected to volume encumbrance. In a report by the UK renal registry in 2008, it is stated that in a larger number of patients treated with HD the targeted blood pressure was achieved, as opposed to peritoneal dialysis (PD) patients (45–33%) [42]. However, unlike the general population of dialysis-treated patients, the connection between high blood pressure and mortality is not so pronounced. Hypertension strongly correlates with LVH, which is often found in CKD. Almost 70% of patients at the beginning of dialysis therapy suffer from an echocardiography recognizable LVH. According to research done by Coen et al., LVH is more potent in long-term dialysis patients than in HD patients, most likely because of inadequate volume control [43].

Low blood pressure has a negative effect on the rates of survival of dialysis patients. However, hypertension is used as a predictor of mortality in patients with CKD before or at the initiation of dialysis. To be able to comprehend this paradox, a separation of blood pressure must be made into systolic, diastolic, mean arterial pressure (MAP) and pulse pressure. Isolated systolic hypertension combined with a high pulse pressure is the most common anomaly regarding blood pressure in patients on dialysis. This occurs due to medial sclerosis of arteries with secondary arterial stiffening. This, in turn, leads to higher pulse-wave velocity, creating an increased peak systolic pressure thanks to a pulse wave reflected too early. LV dysfunction and congestive heart failure occur as a result. A consequence, afterward, could be a lower MAP and diastolic pressure, combined with high CVD risk. Altogether, this points to a U-shaped relationship between blood pressure and mortality: isolated systolic hypertension and increased pulse pressure probably point to high risk, in the long-run, in dialysis patients, whereas low mean and diastolic blood pressure predict a high change of early death. The danger that is not obvious, when it comes to hypertension, is that a large percentage of CKD patients are "nondippers", that is, do not have their blood pressure levels drop during the night. Sleep apnea has been shown to be a condition in CKD which has not attracted as

## **2.8. CVD in kidney transplant recipients**

Although kidney transplant recipients recover adequate renal function, CVD remains an important cause of morbidity and mortality: mortality rates are twice as high as in mortality rates are twice as high as in the general population, adjusted for age and gender. The most likely explanation is the high prevalence of conventional risk factors such as hypertension, diabetes mellitus, LVH, and dyslipidemia, as well as risk factors that do not belong to the traditional spectrum, that are connected to transplantation such as the effect of immunosuppressive medication or organ rejection. In comparison with the population in dialysis, patients that conducted a kidney transplant have a lower rate of CVD mortality. This is most likely caused by the removal of kidney-specific risk factors following the transplantation [35].

## **3. Traditional risk factors**

Hypertension, smoking, hyperlipidemia, obesity and diabetes are all risk factors which are connected to CVD in general populations, but also in PD patients, and are categorized into so-called traditional risk factors.

## **3.1. Age and gender**

Male gender is another well-known risk factor for CVD in the general population, and the frequency of acute myocardial infarction is as much as 2.5 times higher than in the female population suffering from CKD, adjusted for age. However, due to menopause caused by age or comorbidity, the senior female population will also be at higher risk of CVD. Research has shown that about 70% of women on hemodialysis (HD) were menopausal before or after starting RRT, and the incidence of Acute Myocardial Infarction (AMI) was 3–5 times higher in female patients suffering from chronic kidney disease, compared to the age-adjusted general population [36, 37].

#### **3.2. Tobacco smoking**

Smoking is not only a risk factor for the development of CVD but is also connected to the risk of developing CKD, defined as the reduction GFR at <45 ml/min/1.73 m<sup>2</sup> . In a large study from Norway, long-term smoking of over 20 cigarettes a day is connected to 1.52 times increased the relative risk of CKD occurrence [38]. However, it is relatively unknown whether smoking increases the risk of CV death in dialysis patients. A small study on diabetic dialysis patients found no effects of smoking on the risk of CV death, although a series of studies showed that smoking, or a history of smoking, is an independent risk factor for increased morbidity and mortality [39]. These apparent differences can be framed through the presence of other risk factors in some populations, which can supersede the effects of smoking in various multivariable analyses.

## **3.3. Diabetes mellitus**

risk can be seen when eGFR levels are below 50–60 ml/min/1.73 m<sup>2</sup>

[33].

Although kidney transplant recipients recover adequate renal function, CVD remains an important cause of morbidity and mortality: mortality rates are twice as high as in mortality rates are twice as high as in the general population, adjusted for age and gender. The most likely explanation is the high prevalence of conventional risk factors such as hypertension, diabetes mellitus, LVH, and dyslipidemia, as well as risk factors that do not belong to the traditional spectrum, that are connected to transplantation such as the effect of immunosuppressive medication or organ rejection. In comparison with the population in dialysis, patients that conducted a kidney transplant have a lower rate of CVD mortality. This is most likely caused by the removal of kidney-specific risk factors following the

Hypertension, smoking, hyperlipidemia, obesity and diabetes are all risk factors which are connected to CVD in general populations, but also in PD patients, and are categorized into

Male gender is another well-known risk factor for CVD in the general population, and the frequency of acute myocardial infarction is as much as 2.5 times higher than in the female population suffering from CKD, adjusted for age. However, due to menopause caused by age or comorbidity, the senior female population will also be at higher risk of CVD. Research has shown that about 70% of women on hemodialysis (HD) were menopausal before or after starting RRT, and the incidence of Acute Myocardial Infarction (AMI) was 3–5 times higher in female patients suffering from chronic kidney disease, compared to the age-adjusted general

Smoking is not only a risk factor for the development of CVD but is also connected to the risk

Norway, long-term smoking of over 20 cigarettes a day is connected to 1.52 times increased the relative risk of CKD occurrence [38]. However, it is relatively unknown whether smoking increases the risk of CV death in dialysis patients. A small study on diabetic dialysis patients found no effects of smoking on the risk of CV death, although a series of studies showed that smoking, or a history of smoking, is an independent risk factor for increased morbidity and mortality [39]. These apparent differences can be framed through the presence of other risk factors in some populations, which can supersede the effects of smoking in various multivariable analyses.

of developing CKD, defined as the reduction GFR at <45 ml/min/1.73 m<sup>2</sup>

high once eGFR drops <45 ml/min/1.73 m<sup>2</sup>

12 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**2.8. CVD in kidney transplant recipients**

transplantation [35].

**3.1. Age and gender**

population [36, 37].

**3.2. Tobacco smoking**

**3. Traditional risk factors**

so-called traditional risk factors.

, and it becomes extremely

. In a large study from

North-American registry data show that the number of diabetic patients annually admitted to RRT more than doubled from 1995 to 2000. Diabetes mellitus has become the single most important cause of ESRD. Renal replacement therapy continues showing unsatisfactory results for diabetic patients, as survival rates are low. Compared to dialysis patients with other underlying kidney conditions, those with diabetes have the lowest chance of survival. The main cause of death is coronary heart disease—myocardial infarction (MI), angina, history of bypass surgery, PTCA and pathology on coronary angiography. Cardiovascular issues, primarily coronary atheroma, add up before the diabetic patient enters renal replacement therapy programs. Therefore, it is crucial to improving care for the patient with diabetes before he enters the end-stage of the disease. Diabetic patients with underlying CKD face an increased cardiac risk after developing acute MI, which is mirrored through atrial and ventricular arrhythmia, atrioventricular (AV) block, asystole, pulmonary congestion and cardiogenic shock [40].

### **3.4. Arterial hypertension**

Arterial hypertension is very common in CKD patients and is connected to increased risk of CV death [41]. Hypertension is often present in dialysis patients. According to the results of an Italian multicentric study, 88% of 504 patients treated with RRT suffer from arterial hypertension, with anti-hypertensive therapy included. Arterial hypertension in dialysis patients is usually connected to volume encumbrance. In a report by the UK renal registry in 2008, it is stated that in a larger number of patients treated with HD the targeted blood pressure was achieved, as opposed to peritoneal dialysis (PD) patients (45–33%) [42]. However, unlike the general population of dialysis-treated patients, the connection between high blood pressure and mortality is not so pronounced. Hypertension strongly correlates with LVH, which is often found in CKD. Almost 70% of patients at the beginning of dialysis therapy suffer from an echocardiography recognizable LVH. According to research done by Coen et al., LVH is more potent in long-term dialysis patients than in HD patients, most likely because of inadequate volume control [43].

Low blood pressure has a negative effect on the rates of survival of dialysis patients. However, hypertension is used as a predictor of mortality in patients with CKD before or at the initiation of dialysis. To be able to comprehend this paradox, a separation of blood pressure must be made into systolic, diastolic, mean arterial pressure (MAP) and pulse pressure. Isolated systolic hypertension combined with a high pulse pressure is the most common anomaly regarding blood pressure in patients on dialysis. This occurs due to medial sclerosis of arteries with secondary arterial stiffening. This, in turn, leads to higher pulse-wave velocity, creating an increased peak systolic pressure thanks to a pulse wave reflected too early. LV dysfunction and congestive heart failure occur as a result. A consequence, afterward, could be a lower MAP and diastolic pressure, combined with high CVD risk. Altogether, this points to a U-shaped relationship between blood pressure and mortality: isolated systolic hypertension and increased pulse pressure probably point to high risk, in the long-run, in dialysis patients, whereas low mean and diastolic blood pressure predict a high change of early death. The danger that is not obvious, when it comes to hypertension, is that a large percentage of CKD patients are "nondippers", that is, do not have their blood pressure levels drop during the night. Sleep apnea has been shown to be a condition in CKD which has not attracted as much attention as necessary, considering it is associated with no dipping blood pressure, SNS activation and increased CVD risk [44].

**3.8. Insulin resistance (IR)**

A number of issues found in metabolic syndrome patients such as insulin resistance (IR), can be found in chronic kidney disease as well, a so-called uremic-metabolic syndrome. The etiology of resistance to insulin in CKD is multifactorial, with factors such as fat accumulation, lack of vitamin D, metabolic acidosis, inflammation, and uremic toxins accumulation all contributing. These factors create adverse changes in the pathway for the insulin receptor signal. Available data shows that IR is present in CKD patients starting from the early stages of renal failure. The potential of IR to promote blood vessel damage, regardless of the coexistence of other vascular risk factors, is large [49]. In several studies, the role of IR in patients on dialysis was analyzed, and a connection between IR and a disturbed fatty acid metabolism has been discovered, which further contributed to left ventricular dysfunction. Also, more and more evidence points to the fact that the application of ACE inhibitors (ACEIs) can modulate IR. In PD, IR of the tissue can be worsened by the intake of glucose through dialysis solutions. However, these studies are controversial as well: in patients on cycler PD, IR is greater than HD patients, while in PD patients, IR is normalized, similar to HD patients. By using icodextrin dialysis solutions, insu-

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

15

lin levels in serum could potentially be reduced, and insulin sensitivity increased [50].

to CKD and uremia, as well as the development of CV morbidity, includes inflammation, malnutrition, endothelial dysfunction, oxidative stress, vascular calcifications, vitamin D defi-

Newly acquired evidence points to a strong, independent relationship between low eGFR and mortality risk, CV events and hospitalization [52]. The mechanisms behind the process of progressive renal function deterioration's acceleration of the atherogenic process are not well known. However, the presence and severity of multiple novel CKD risk factors, including inflammation, oxidative stress, vascular calcification and accumulation of advanced glycation end products (AGEs) increases. Many other accumulating solutes for uremic retention, for example, ADMA, guanidine, homocysteine, indoxyl sulfate and p-cresol, could have a proatherogenic effect. Kidneys may also produce substances like renalase which should control and limit CVD, but a renal function deterioration leads to vascular disease through separate

Chronic inflammation is characterized by the persistent effect of a causative stimulus, destroying cells and tissue and having a deteriorating effect on the body. In later stages of CKD, the systemic concentrations of both pro- and anti-inflammatory cytokines are significantly higher

. A further drop

, increases the risk of CV death. Potential factors tied

**4. Nontraditional and/or uremia-specific risk factors**

in GFR values, below 45 ml/min/1.73 m<sup>2</sup>

ciency and hyperhomocysteinemia [51].

**4.1. Renal failure per se**

mechanisms and not retention.

**4.2. Inflammation**

A known risk factor for the genesis of CV disease is GFR < 60 ml/min/1.73 m<sup>2</sup>

#### **3.5. Atherosclerosis**

It has been proven that arterial rigidity, which is usually estimated by pulse-wave velocity on the aorta, the quantity of common carotid artery (CCA) intima-media thickness (IMT), and also by peak systolic velocity in the systole on the CCA, is a useful predictor of CV morbidity and mortality in the general population, and as such, in patients suffering from CKD.

Zoccali et al. [38], through their research, have determined that in a large group of patients suffering from CKD, the rigidity of large arteries was independently connected with age, blood pressure, as well as other risk factors for the development of CVD. The presence of vascular calcifications has shown itself to be one of the most prominent factors connected to arterial rigidity. However, relevant studies in dialysis patients are relatively small and have numerous limitations [45].

#### **3.6. Obesity**

Obesity is a risk factor for the development of CV diseases in the general population but is also connected to an increased risk factor for the development of CKD. The results of studies performed on dialysis patients have not been consistent about the influence of obesity on survival rates. The results of some studies showed that obesity is connected to better survival rates, while other studies have discovered that there is a connection between obesity and increased mortality risk. A prospective, time limited analysis in 688 dialysis patients showed that only those with a BMI <18.5 have an increased risk of CV death. High BMI had no protective effective but was also not connected to reduced survival risk [46].

## **3.7. Dyslipidemia**

Dyslipidemia is known as a traditional risk factor for CVD in the general population, as well as in dialysis patients. Several observational studies have shown that the values of cholesterol and low-density lipoprotein (LDL) are among the most significant independent CV morbidity and mortality factors. Patients with damaged renal function suffer from significant changes in lipoprotein metabolism, which has a precise role in atherosclerotic pathogenesis. This is still controversial [47]. Renal dyslipidemia is characterized by an atherogenic apolipoprotein profile. This means there are lower levels of apolipoprotein A (apoA)-containing lipoproteins and higher levels of apoB-containing lipoproteins. CKD, as a progressive disease, is connected with high levels of apoCIII. Whereas total serum cholesterol levels, in general, are normal, or even low, high-density lipoprotein (HDL)-cholesterol is reduced; and low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL)-cholesterol, plasma triglycerides, and lipoprotein(a) (Lp(a)) levels are increased. Compared to HD patients, patients treated with PD more often have both hypercholesterolemia and hypertriglyceridemia. Elevated Lp(a) levels have been reported to be associated with increased CVD mortality both in HD and PD patients. Two randomized controlled trials showed no benefit of statin treatment in dialysis patients [48].

#### **3.8. Insulin resistance (IR)**

much attention as necessary, considering it is associated with no dipping blood pressure, SNS

It has been proven that arterial rigidity, which is usually estimated by pulse-wave velocity on the aorta, the quantity of common carotid artery (CCA) intima-media thickness (IMT), and also by peak systolic velocity in the systole on the CCA, is a useful predictor of CV morbidity

Zoccali et al. [38], through their research, have determined that in a large group of patients suffering from CKD, the rigidity of large arteries was independently connected with age, blood pressure, as well as other risk factors for the development of CVD. The presence of vascular calcifications has shown itself to be one of the most prominent factors connected to arterial rigidity. However, relevant studies in dialysis patients are relatively small and have

Obesity is a risk factor for the development of CV diseases in the general population but is also connected to an increased risk factor for the development of CKD. The results of studies performed on dialysis patients have not been consistent about the influence of obesity on survival rates. The results of some studies showed that obesity is connected to better survival rates, while other studies have discovered that there is a connection between obesity and increased mortality risk. A prospective, time limited analysis in 688 dialysis patients showed that only those with a BMI <18.5 have an increased risk of CV death. High BMI had no protec-

Dyslipidemia is known as a traditional risk factor for CVD in the general population, as well as in dialysis patients. Several observational studies have shown that the values of cholesterol and low-density lipoprotein (LDL) are among the most significant independent CV morbidity and mortality factors. Patients with damaged renal function suffer from significant changes in lipoprotein metabolism, which has a precise role in atherosclerotic pathogenesis. This is still controversial [47]. Renal dyslipidemia is characterized by an atherogenic apolipoprotein profile. This means there are lower levels of apolipoprotein A (apoA)-containing lipoproteins and higher levels of apoB-containing lipoproteins. CKD, as a progressive disease, is connected with high levels of apoCIII. Whereas total serum cholesterol levels, in general, are normal, or even low, high-density lipoprotein (HDL)-cholesterol is reduced; and low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL)-cholesterol, plasma triglycerides, and lipoprotein(a) (Lp(a)) levels are increased. Compared to HD patients, patients treated with PD more often have both hypercholesterolemia and hypertriglyceridemia. Elevated Lp(a) levels have been reported to be associated with increased CVD mortality both in HD and PD patients. Two randomized controlled trials showed no benefit of statin treatment in dialysis patients [48].

tive effective but was also not connected to reduced survival risk [46].

and mortality in the general population, and as such, in patients suffering from CKD.

activation and increased CVD risk [44].

14 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**3.5. Atherosclerosis**

numerous limitations [45].

**3.6. Obesity**

**3.7. Dyslipidemia**

A number of issues found in metabolic syndrome patients such as insulin resistance (IR), can be found in chronic kidney disease as well, a so-called uremic-metabolic syndrome. The etiology of resistance to insulin in CKD is multifactorial, with factors such as fat accumulation, lack of vitamin D, metabolic acidosis, inflammation, and uremic toxins accumulation all contributing. These factors create adverse changes in the pathway for the insulin receptor signal. Available data shows that IR is present in CKD patients starting from the early stages of renal failure. The potential of IR to promote blood vessel damage, regardless of the coexistence of other vascular risk factors, is large [49]. In several studies, the role of IR in patients on dialysis was analyzed, and a connection between IR and a disturbed fatty acid metabolism has been discovered, which further contributed to left ventricular dysfunction. Also, more and more evidence points to the fact that the application of ACE inhibitors (ACEIs) can modulate IR. In PD, IR of the tissue can be worsened by the intake of glucose through dialysis solutions. However, these studies are controversial as well: in patients on cycler PD, IR is greater than HD patients, while in PD patients, IR is normalized, similar to HD patients. By using icodextrin dialysis solutions, insulin levels in serum could potentially be reduced, and insulin sensitivity increased [50].

## **4. Nontraditional and/or uremia-specific risk factors**

A known risk factor for the genesis of CV disease is GFR < 60 ml/min/1.73 m<sup>2</sup> . A further drop in GFR values, below 45 ml/min/1.73 m<sup>2</sup> , increases the risk of CV death. Potential factors tied to CKD and uremia, as well as the development of CV morbidity, includes inflammation, malnutrition, endothelial dysfunction, oxidative stress, vascular calcifications, vitamin D deficiency and hyperhomocysteinemia [51].

## **4.1. Renal failure per se**

Newly acquired evidence points to a strong, independent relationship between low eGFR and mortality risk, CV events and hospitalization [52]. The mechanisms behind the process of progressive renal function deterioration's acceleration of the atherogenic process are not well known. However, the presence and severity of multiple novel CKD risk factors, including inflammation, oxidative stress, vascular calcification and accumulation of advanced glycation end products (AGEs) increases. Many other accumulating solutes for uremic retention, for example, ADMA, guanidine, homocysteine, indoxyl sulfate and p-cresol, could have a proatherogenic effect. Kidneys may also produce substances like renalase which should control and limit CVD, but a renal function deterioration leads to vascular disease through separate mechanisms and not retention.

#### **4.2. Inflammation**

Chronic inflammation is characterized by the persistent effect of a causative stimulus, destroying cells and tissue and having a deteriorating effect on the body. In later stages of CKD, the systemic concentrations of both pro- and anti-inflammatory cytokines are significantly higher as production has increased, coupled with decreased renal clearance. Aside from this, there are plenty of dialysis-related issues (such as membrane biocompatibility and thrombosed AV fistula) and nondialysis factors (e.g. infection, comorbidity, poor oral health, failed kidney transplants, genetic factors, diet) that may contribute to a continuous inflammation.

functional impairment of EPC due to inflammation and/or toxic effects of retained uremic solutes, there seems to be a disparity between EPC and CEC, which could eventually cause

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

17

A marked connection between malnutrition, increased levels of CRP and atherosclerosis is well known, although the precise mechanisms of their synergistic effects on the organism are not known. This relationship was first described by Stenvinkel et al. in a study on CKD patients [57]. Patients with CRP levels >10 mg/L have significantly lesser values of serum albumin and a higher prevalence of atherosclerosis than patients with a lower CKD level. The combination of malnutrition, inflammation and atherosclerosis presence has been described by Stenvinkel as MIA (Malnutrition Inflammation Atherosclerosis) syndrome. A 2008 study has shown that MIA syndrome is connected to increased mortality risks [58]. In a Korean study, comorbidity cardiovascular diseases were present in 78% of patients on dialysis with signs of malnutrition. These patients have a 3.3 times greater risk of mortality than patients suffering from malnutrition with no comorbidity conditions [59]. Taking malnutrition, protein deficits, and inflammation into account, the recommendation for the description of this entity in CKD patients is protein-energy wasting (PEW). PEW is characterized by reduced protein and initiation energy accumulation. Several studies have shown that there are two types of malnutrition: the first is connected to poor food intake, and the second to inflammation and present comorbidity. Low levels of serum albumin can only be found in the second type of malnutrition, but the exact contribution of malnutrition or inflammation in the development of risk of CV mortality in dialysis patients remains uncertain [58]. A large number of studies have dealt in hypoalbuminemia and the outcome of treating patients on dialysis. It has been determined that serum albumin levels below 40 g/L are combined with 4–20 times increased mortality. In addition, 45% of PD patients die during the first year of dialysis treatment in cases where albumin levels drop below 25 g/L. A CANUSA study has shown an 8%

endothelial dysfunction in CKD patients.

**4.4. Malnutrition and protein-energy wasting (PEW)**

survival rate increase in cases of serum albumin growth of only 1% [60].

Oxidative stress is defined as the damage of tissue which stems from the disturbed balance between excessive oxidation compound production and insufficient anti-oxidant defensive function. CKD patients have a deficiency in the anti-oxidant defensive mechanism (because of e.g., reduced vitamin levels, or hypoalbuminemia) and increased pro-oxidant compound activity (e.g. accumulation of solvent materials such as AGEs and β2-microglobulin). Oxidative stress leads to the production of free radicals, highly reactive compounds that can oxidize proteins lipids and nucleic acids. High concentrations of these molecules are present in CKD patients. Oxidation products of proteins and oxidized DNA have been discovered in leukocytes with residual renal function (RRF). The underlying connection between increased levels of oxidation stress and the risk of CV death in ESRD patients is still unknown, even though the results of several prospective studies point to the conclusion that oxidation stress can be a risk factor for CV morbidity and mortality in ESRD patients [14]. Four pathways of

**4.5. Oxidative stress**

Inflammation, the effects of local inflammatory stimuli such as oxidation products, end advanced glycosylation products and chronic infective processes modify blood vessels in the sense of atherosclerosis development. These changes benefit proatherogenic adhesion molecule production, for example, intercellular adhesion molecule1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), growth factor, as well as chemokine (such as IL-6, long pentraxin 3 (PTX3), S-albumin, TNF and white blood cell count). Such inflammatory intermediates encourage the synthesis of acute phase proteins such as C-reactive protein (CRP), reduction of albumin synthesis in the liver of dialysis-treated patients [53], which leads to endothelial dysfunction, which is usually defined as reduced vasodilatation capability, which again creates early atherosclerosis occurrence predisposition. However, the question, whether inflammation is a reflection of vascular damage, or actually supports factors that cause vascular injury, remains unanswered. The precise link between inflammation, endothelial dysfunction, oxidative stress, CVD and mortality in dialysis patients remains unknown. In a prospective study of dialysis patients, CRP level of >6 mg/L was an independent predictive mark of possible myocardial infarction. Aside from that, the proinflammatory IL-6 mark is increased in ESRD patients but is also an independent mortality predictor in patients on dialysis [54].

However, as many features are known to mediate atherosclerosis such as endothelial dysfunction, vascular calcification, IR, and increased oxidative stress, all are more or less associated with inflammation biomarkers, the association between chronic inflammation and CVD may also be indirect.

## **4.3. Endothelial dysfunction**

In dialysis patients, endothelial function is reduced, the same as in hemodialysis patients, most likely because of a reduced bioavailability of NO. In a study conducted in 2009, flowmediated vasodilatation is significantly lower in PD patients than in the healthy population, which negatively correlates with inflammation markers such as CRP or IL-6 [55]. There is evidence that suggests that the endogenic inhibitor of NO, ADMA, has a significant role in the origin and occurrence of CVD and mortality in dialysis patients. NO deficit and ADMA accumulation promote endothelial dysfunction, vasoconstriction, and arterial thrombosis. The remaining factors of endothelial dysfunction such as soluble adhesive molecules are predictors of all causes of CV in ESRD patients. The levels of VCAM-1 negatively correlate with LVH in patients undergoing RRT.

Evidence from newer studies shows that detached circulating endothelial cells (CEC) are suitable markers for endothelial damage [56]. They can be used for predicting purposes in order to prevent future CV events in HD patients. As a feedback to ischemic insult and cytokine stimulation, endothelial progenitor cells (EPC) are mobilized from the bone marrow to act as "repair" cells in response to the endothelial injury. As to reduced numbers of and/or a functional impairment of EPC due to inflammation and/or toxic effects of retained uremic solutes, there seems to be a disparity between EPC and CEC, which could eventually cause endothelial dysfunction in CKD patients.

#### **4.4. Malnutrition and protein-energy wasting (PEW)**

A marked connection between malnutrition, increased levels of CRP and atherosclerosis is well known, although the precise mechanisms of their synergistic effects on the organism are not known. This relationship was first described by Stenvinkel et al. in a study on CKD patients [57]. Patients with CRP levels >10 mg/L have significantly lesser values of serum albumin and a higher prevalence of atherosclerosis than patients with a lower CKD level. The combination of malnutrition, inflammation and atherosclerosis presence has been described by Stenvinkel as MIA (Malnutrition Inflammation Atherosclerosis) syndrome. A 2008 study has shown that MIA syndrome is connected to increased mortality risks [58]. In a Korean study, comorbidity cardiovascular diseases were present in 78% of patients on dialysis with signs of malnutrition. These patients have a 3.3 times greater risk of mortality than patients suffering from malnutrition with no comorbidity conditions [59]. Taking malnutrition, protein deficits, and inflammation into account, the recommendation for the description of this entity in CKD patients is protein-energy wasting (PEW). PEW is characterized by reduced protein and initiation energy accumulation. Several studies have shown that there are two types of malnutrition: the first is connected to poor food intake, and the second to inflammation and present comorbidity. Low levels of serum albumin can only be found in the second type of malnutrition, but the exact contribution of malnutrition or inflammation in the development of risk of CV mortality in dialysis patients remains uncertain [58]. A large number of studies have dealt in hypoalbuminemia and the outcome of treating patients on dialysis. It has been determined that serum albumin levels below 40 g/L are combined with 4–20 times increased mortality. In addition, 45% of PD patients die during the first year of dialysis treatment in cases where albumin levels drop below 25 g/L. A CANUSA study has shown an 8% survival rate increase in cases of serum albumin growth of only 1% [60].

#### **4.5. Oxidative stress**

as production has increased, coupled with decreased renal clearance. Aside from this, there are plenty of dialysis-related issues (such as membrane biocompatibility and thrombosed AV fistula) and nondialysis factors (e.g. infection, comorbidity, poor oral health, failed kidney

Inflammation, the effects of local inflammatory stimuli such as oxidation products, end advanced glycosylation products and chronic infective processes modify blood vessels in the sense of atherosclerosis development. These changes benefit proatherogenic adhesion molecule production, for example, intercellular adhesion molecule1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), growth factor, as well as chemokine (such as IL-6, long pentraxin 3 (PTX3), S-albumin, TNF and white blood cell count). Such inflammatory intermediates encourage the synthesis of acute phase proteins such as C-reactive protein (CRP), reduction of albumin synthesis in the liver of dialysis-treated patients [53], which leads to endothelial dysfunction, which is usually defined as reduced vasodilatation capability, which again creates early atherosclerosis occurrence predisposition. However, the question, whether inflammation is a reflection of vascular damage, or actually supports factors that cause vascular injury, remains unanswered. The precise link between inflammation, endothelial dysfunction, oxidative stress, CVD and mortality in dialysis patients remains unknown. In a prospective study of dialysis patients, CRP level of >6 mg/L was an independent predictive mark of possible myocardial infarction. Aside from that, the proinflammatory IL-6 mark is increased in ESRD

transplants, genetic factors, diet) that may contribute to a continuous inflammation.

16 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

patients but is also an independent mortality predictor in patients on dialysis [54].

may also be indirect.

**4.3. Endothelial dysfunction**

LVH in patients undergoing RRT.

However, as many features are known to mediate atherosclerosis such as endothelial dysfunction, vascular calcification, IR, and increased oxidative stress, all are more or less associated with inflammation biomarkers, the association between chronic inflammation and CVD

In dialysis patients, endothelial function is reduced, the same as in hemodialysis patients, most likely because of a reduced bioavailability of NO. In a study conducted in 2009, flowmediated vasodilatation is significantly lower in PD patients than in the healthy population, which negatively correlates with inflammation markers such as CRP or IL-6 [55]. There is evidence that suggests that the endogenic inhibitor of NO, ADMA, has a significant role in the origin and occurrence of CVD and mortality in dialysis patients. NO deficit and ADMA accumulation promote endothelial dysfunction, vasoconstriction, and arterial thrombosis. The remaining factors of endothelial dysfunction such as soluble adhesive molecules are predictors of all causes of CV in ESRD patients. The levels of VCAM-1 negatively correlate with

Evidence from newer studies shows that detached circulating endothelial cells (CEC) are suitable markers for endothelial damage [56]. They can be used for predicting purposes in order to prevent future CV events in HD patients. As a feedback to ischemic insult and cytokine stimulation, endothelial progenitor cells (EPC) are mobilized from the bone marrow to act as "repair" cells in response to the endothelial injury. As to reduced numbers of and/or a Oxidative stress is defined as the damage of tissue which stems from the disturbed balance between excessive oxidation compound production and insufficient anti-oxidant defensive function. CKD patients have a deficiency in the anti-oxidant defensive mechanism (because of e.g., reduced vitamin levels, or hypoalbuminemia) and increased pro-oxidant compound activity (e.g. accumulation of solvent materials such as AGEs and β2-microglobulin). Oxidative stress leads to the production of free radicals, highly reactive compounds that can oxidize proteins lipids and nucleic acids. High concentrations of these molecules are present in CKD patients. Oxidation products of proteins and oxidized DNA have been discovered in leukocytes with residual renal function (RRF). The underlying connection between increased levels of oxidation stress and the risk of CV death in ESRD patients is still unknown, even though the results of several prospective studies point to the conclusion that oxidation stress can be a risk factor for CV morbidity and mortality in ESRD patients [14]. Four pathways of oxidative stress exist in CKD (carbonyl stress, nitrosative stress, chlorinated stress and classical oxidative stress). Evidence suggests that oxidative stress plays a major role. The relation between accumulation of AGE and the cardiovascular disease's outcome is not as transparent and obvious. Studies focusing on Chronic Myelogenous Leukemia (CML) and pentosidine found no significant effect on mortality. However, one study pointed to the conclusion that skin autofluorescence predicted death in HD patients [61].

In the general population, coronary artery calcification is infrequently observed in younger age groups. It is a phenomenon that increases with age, and the majority of people affected by vascular calcification are >65 years. In ESRD patients, on the other hand, extensive vascular calcification can be commonly observed in much younger age groups as well. The calcification process frequently starts before the initiation of dialysis treatment. The prevalence and extent of vascular calcification, arterial media calcification and arterial stiffness have recently been

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

19

Besides diabetes mellitus, CV calcification can, with the presence of uremia, be caused by abnormal calcium and phosphate metabolism and an enduring inflammation as it may by

Fetuin-A, an important inhibitor of vascular calcification, is down-regulated during the inflammation process, and low levels are linked to poor survival in dialysis patients. However, fetuin-A is certainly not the only modifier of extraosseous calcification. Phosphate, calcium and some proinflammatory mediators have the capacity to induce osteogenic differentiation, which is a transition of vascular smooth muscle cells toward osteoblast behavior. A system of calcification inhibitors (and inducers) is of major importance, as the extracellular calcium and phosphate environment must be formally considered as being "supersaturated" regarding the chemical solubility product of these ions in an aqueous solution. Among them, leptin, matrix GLA protein, TNF-α, pyrophosphates, bone morphogenetic proteins and osteoprote-

shown to be strong predictors of CVD and all-cause mortality in dialysis patients.

gerin, may be related to a process of accelerated vascular calcification in ESRD [64].

Homocysteine (Hcy) is a nonprotein sulfur-containing amino acid that has attracted considerable interest by vascular researchers, as it may by several mechanisms mediate premature atherosclerosis and CVD. The prevalence of hyperhomocysteinemia in patients with advanced CKD is >90%. In contrast to the well-documented association between total Hcy (tHcy) and vascular disease in the general population, the relationship between tHcy and CVD is not that clear and strong assuming renal function is reduced, with studies and reports demonstrating low levels of tHcy in patients with chronic kidney disease with CVD [13]. Although there are several reasons that may explain this paradoxical relationship, one of the most significant relationships is the strong association between tHcy and hypoalbuminemia, PEW and inflammation. S-albumin and tHcy have an established strong positive correlation, and hypoalbuminemia is an established predictor of adverse outcomes that this relationship may confound

Decreased baroreflex sensitivity is significant for CKD and one of its main attributes, which can, together with inflammation and wasting, lead to an increased risk of sudden death. Increased sympathetic nerve activity can be seen in CKD patients quite frequently, and it is a predictor of an adverse result [66]. Sympathetic overactivity is probably partial due to sleep apnea, which is considered a contributor to the condition in patients with moderate and

**4.8. Hyperhomocysteinemia**

the impact of tHcy on vascular disease [65].

**4.9. Autonomic dysfunction**

severe-stage CKD.

several mechanisms mediate untimely atherosclerosis and premature CVD.

One of the most important toxins connected to the uremic environment and connected to oxidative stress and inflammation stage and the presence of inflammation biomarkers is β2-microglobulin. Increased levels of β2-microglobulin in plasma are a known marker of chronic renal function failure and are among the most important toxins tied to uremia. In PD patients, the level of β2-microglobulin is primarily tied to amyloidosis. In recent times it has been suggested that β2-microglobulin could be a new biomarker of peripheral arterial disease and an independent predictor of aortic rigidity in the atherosclerotic process, in both the general population and ESRD patients [62]. Additionally, increased levels of β2-microglobulin present a new marker for differentiating the levels of acute cardiac arrest creation risk in patients with creatinine levels ≤265 μmol/L [54]. All of these results point to an important role of β2-microglobulin in CV risk prediction in dialysis patients.

#### **4.6. Hyperparathyroidism**

In ESRD patients, the ability of the diseased kidney to produce 1.25-dihydroxycalciferol is reduced, which significantly contributes to the development of osteodystrophy, secondary hyperparathyroidism and the disturbed metabolism of divalent ions. PTH is considered a potent uremic toxin that harmfully affects myocardial cells. The improvement of left ventricular dysfunction after parathyroidectomy in uremic patients with increased PTH points to a connection between left ventricular function and hyperparathyroidism. All this confirms the assumption about the role of parathormone as a risk factor in the development of uremic cardiomyopathy. Significant research results point to the conclusion that a small level of vitamin D is connected to CVD in the general population, and that a greater concentration of that vitamin can have a positive influence on survival. Similar results were discovered in predialysis patients. Wang et al. have determined that low concentrations of serum 25-hydroxyvitamin D in dialysis patients are connected to increased risk of fatal or nonfatal CV incidents. It seems that the effects of vitamin D on the CV system are connected to residual renal function, LVH and cardiac dysfunction [54].

## **4.7. Cardiovascular calcification**

The arterial media, atherosclerotic plaques and heart valves are affected through this cardiovascular process. One of the main signs of medial calcification is arterial stiffness, which is shown clinically through an increased pulse pressure. The pathophysiological role of plaque calcification is less clear, as it is mostly soft plaques, which rupture and cause AMI. It is now evident that the burden caused by atherosclerotic calcification is a suitable risk marker for cardiovascular events. In patients in dialysis, valvular calcification leads to a developing stenosis and morbidity that goes with it, after targeting and affecting the aortic and mitral valves [63].

In the general population, coronary artery calcification is infrequently observed in younger age groups. It is a phenomenon that increases with age, and the majority of people affected by vascular calcification are >65 years. In ESRD patients, on the other hand, extensive vascular calcification can be commonly observed in much younger age groups as well. The calcification process frequently starts before the initiation of dialysis treatment. The prevalence and extent of vascular calcification, arterial media calcification and arterial stiffness have recently been shown to be strong predictors of CVD and all-cause mortality in dialysis patients.

Besides diabetes mellitus, CV calcification can, with the presence of uremia, be caused by abnormal calcium and phosphate metabolism and an enduring inflammation as it may by several mechanisms mediate untimely atherosclerosis and premature CVD.

Fetuin-A, an important inhibitor of vascular calcification, is down-regulated during the inflammation process, and low levels are linked to poor survival in dialysis patients. However, fetuin-A is certainly not the only modifier of extraosseous calcification. Phosphate, calcium and some proinflammatory mediators have the capacity to induce osteogenic differentiation, which is a transition of vascular smooth muscle cells toward osteoblast behavior. A system of calcification inhibitors (and inducers) is of major importance, as the extracellular calcium and phosphate environment must be formally considered as being "supersaturated" regarding the chemical solubility product of these ions in an aqueous solution. Among them, leptin, matrix GLA protein, TNF-α, pyrophosphates, bone morphogenetic proteins and osteoprotegerin, may be related to a process of accelerated vascular calcification in ESRD [64].

## **4.8. Hyperhomocysteinemia**

oxidative stress exist in CKD (carbonyl stress, nitrosative stress, chlorinated stress and classical oxidative stress). Evidence suggests that oxidative stress plays a major role. The relation between accumulation of AGE and the cardiovascular disease's outcome is not as transparent and obvious. Studies focusing on Chronic Myelogenous Leukemia (CML) and pentosidine found no significant effect on mortality. However, one study pointed to the conclusion that

One of the most important toxins connected to the uremic environment and connected to oxidative stress and inflammation stage and the presence of inflammation biomarkers is β2-microglobulin. Increased levels of β2-microglobulin in plasma are a known marker of chronic renal function failure and are among the most important toxins tied to uremia. In PD patients, the level of β2-microglobulin is primarily tied to amyloidosis. In recent times it has been suggested that β2-microglobulin could be a new biomarker of peripheral arterial disease and an independent predictor of aortic rigidity in the atherosclerotic process, in both the general population and ESRD patients [62]. Additionally, increased levels of β2-microglobulin present a new marker for differentiating the levels of acute cardiac arrest creation risk in patients with creatinine levels ≤265 μmol/L [54]. All of these results point to an important role

In ESRD patients, the ability of the diseased kidney to produce 1.25-dihydroxycalciferol is reduced, which significantly contributes to the development of osteodystrophy, secondary hyperparathyroidism and the disturbed metabolism of divalent ions. PTH is considered a potent uremic toxin that harmfully affects myocardial cells. The improvement of left ventricular dysfunction after parathyroidectomy in uremic patients with increased PTH points to a connection between left ventricular function and hyperparathyroidism. All this confirms the assumption about the role of parathormone as a risk factor in the development of uremic cardiomyopathy. Significant research results point to the conclusion that a small level of vitamin D is connected to CVD in the general population, and that a greater concentration of that vitamin can have a positive influence on survival. Similar results were discovered in predialysis patients. Wang et al. have determined that low concentrations of serum 25-hydroxyvitamin D in dialysis patients are connected to increased risk of fatal or nonfatal CV incidents. It seems that the effects of vitamin D on the CV system are connected to residual renal function, LVH

The arterial media, atherosclerotic plaques and heart valves are affected through this cardiovascular process. One of the main signs of medial calcification is arterial stiffness, which is shown clinically through an increased pulse pressure. The pathophysiological role of plaque calcification is less clear, as it is mostly soft plaques, which rupture and cause AMI. It is now evident that the burden caused by atherosclerotic calcification is a suitable risk marker for cardiovascular events. In patients in dialysis, valvular calcification leads to a developing stenosis and morbidity that goes with it, after targeting and affecting the aortic and mitral valves [63].

skin autofluorescence predicted death in HD patients [61].

18 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

of β2-microglobulin in CV risk prediction in dialysis patients.

**4.6. Hyperparathyroidism**

and cardiac dysfunction [54].

**4.7. Cardiovascular calcification**

Homocysteine (Hcy) is a nonprotein sulfur-containing amino acid that has attracted considerable interest by vascular researchers, as it may by several mechanisms mediate premature atherosclerosis and CVD. The prevalence of hyperhomocysteinemia in patients with advanced CKD is >90%. In contrast to the well-documented association between total Hcy (tHcy) and vascular disease in the general population, the relationship between tHcy and CVD is not that clear and strong assuming renal function is reduced, with studies and reports demonstrating low levels of tHcy in patients with chronic kidney disease with CVD [13]. Although there are several reasons that may explain this paradoxical relationship, one of the most significant relationships is the strong association between tHcy and hypoalbuminemia, PEW and inflammation. S-albumin and tHcy have an established strong positive correlation, and hypoalbuminemia is an established predictor of adverse outcomes that this relationship may confound the impact of tHcy on vascular disease [65].

## **4.9. Autonomic dysfunction**

Decreased baroreflex sensitivity is significant for CKD and one of its main attributes, which can, together with inflammation and wasting, lead to an increased risk of sudden death. Increased sympathetic nerve activity can be seen in CKD patients quite frequently, and it is a predictor of an adverse result [66]. Sympathetic overactivity is probably partial due to sleep apnea, which is considered a contributor to the condition in patients with moderate and severe-stage CKD.

## **4.10. Anemia**

In ESRD, the condition causes LVH and LV dilatation. Normalizing hemoglobin has not shown any CV outcome improvement, despite a partial correction of anemia using erythropoietin causing a regression in LVH. The appropriate target hematocrit to minimize LVH or other CVD has not been defined. However, briefly summarizing guideline recommendations favors target hemoglobin of about 11 g/dl [66].

of LVH and leads to increased serum concentrations of natriuretic peptide, because of their increased myocardial production. These peptides are used as a prognostic marker for the

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21

The connection between the lack of peritoneal ultrafiltration and mortality has been proven in anuric patients. When fluid intake is not adjusted to peritoneal ultrafiltration, the patient will

Genetic factors can influence the appearance and frequency of vascular complications in dialysis patients. Thus, polymorphism of a single nucleotide in the IL-6 gene is connected to increased levels of IL-6 in plasma, and comorbidity in HD patients, greater diastolic pressure values and left ventricular mass [70]. Polymorphism of the enzyme, which transforms angiotensin I to angiotensin II, can determine the degree of the function of recombined human erythropoietin in PD patients, which presents a significant prescreening for the assessment of erythropoietin resistance. Polymorphism on the human receptor of vitamin D is combined with an increased risk of the development of hypercalcemia, modulation of NO activity via the polymorphism of endothelial NOS, as well as functionally relevant polymorphism of the IL-6, which together can have a significant effect on basic peritoneal permeability [71]. In the future, research in this field could enable a more precise approach for the identification of risk groups of patients treated by PD, and the development of personalized treatment strategies. A new approach in the research of atherosclerosis focuses on the role of epigenetics, which change studies in gene expression that are not coded in the DNA sequence itself but are instead a consequence of post-translatory changes in the DNA-protein. These epigenetic changes can be lost in several sequential cellular generations. Changes in the genome methylation of DNA have important regulatory functions in normal and pathological cellular processes. A persistent inflammatory reaction is most likely connected to DNA hypermethylation [72]. Further research is necessary to determine whether epigenetic DNA changes are connected to acceler-

**5. Chronic cardiorenal and renocardiac syndrome interaction**

The interplay between cardiac and renal disease is complex and the term CRS has been introduced recently as an attempt to describe the close interaction between CV and renal systems, especially in the chronic disease settings. Division of CRS into five categories is proposed by Ronco et al. [73]. This classification is based on etiologic and chronologic factors [74]. The temporal relationship between the heart and kidney disease as well as the coexistence of CVD and CKD represent important aspects of chronic cardiorenal and renocardiac syndromes definition. CRS type 2, or chronic cardiorenal syndrome, is characterized by chronic abnormalities in cardiac function leading to kidney injury or dysfunction. CHF causally underlies the occurrence and progression of CKD [75]. CRS type 4, or chronic renocardiac syndrome, has been defined as "chronic abnormalities in renal function leading to cardiac disease" and recognizes the extreme burden of CVD in patients with CKD such as chronic glomerular disease and autosomal dominant polycystic kidney disease (ADPKD). This is the condition where

general mortality of ESRD patients [69].

**4.14. Genetic and epigenetic factors**

ated atherosclerosis in uremia.

develop volume overload, which increases the risk of CVD.

## **4.11. Hormonal disorder**

The loss of kidney function and the altered metabolic milieu in CKD affects hormone secretion and response of target tissues, causing a number of endocrine dysfunctions that may affect both PEW prevalence and future CVD risk. Changes in the GH-IGF-1 axis lead to many important CKD complications such as growth retardation, PEW, atherosclerosis and disease progression. Other common hormonal disturbances in chronic kidney disease are subclinical hypothyroidism and the low-T3 syndrome, which occurs in one-fifth of CKD patients. However, chance of CV events increases in the general population with thyroid changes, and thyroid production is substantially reduced by inflammation. Therefore, the hypothesis exists saying these factors create a connection between stress caused by inflammation and a negative cardiovascular event in CKD patients [66]. Finally, during the chronic kidney disease, the sex hormone profile does not stay the same. In as many as 50–70% of males in ESRD, male hypogonadism occurs. Testosterone decline occurs for multiple reasons such as low synthesis of muscle protein and hemoglobin, as well as atherosclerosis development and arterial vasoconstriction and/or hardening. This relationship between male hypogonadism and increased risk of death caused by CV factors in dialysis patients has been brought to attention, which will hopefully put some focus on this issue. New studies conducted on nonCKD patients using low testosterone dosage showed satisfactory outcomes such as muscle gain and improved metabolism (no studies have been conducted regarding interventions targeting the adverse outcomes of CV) [67].

## **4.12. Residual renal function (RRF)**

The residual renal function is important for dialysis patients because it contributes to total daily clearance of 20% or more. It is thought that a dialysis patient has preserved RRF if his clearance of creatinine is greater than 1.5 mL/min. In PD and HD patients, RRF is connected to all causes of mortality, and so it is connected with the risk of CV death. The vital role of RRF in the survival of PD patients was determined in large prospective studies such as the CANUSA and ADEMEX studies. In the ADEMEX study, by a prospective, randomized examination of 965 dialysis patients with a weekly diuresis of 10 L/m<sup>2</sup> , a relative mortality risk drop of 11% was noted [68]. These results were also confirmed by the NECOSAD study, where the rate of reduction of RRF was a stronger predictor of mortality and technical insufficiency of longterm PD treatment, in relation to basic RRF [58].

#### **4.13. Volume overload and ultrafiltration insufficiency**

Ultrafiltration insufficiency occurs in around a third of dialysis patients and can lead to arterial hypertension and volume encumbrance. Volume overload promoted the development of LVH and leads to increased serum concentrations of natriuretic peptide, because of their increased myocardial production. These peptides are used as a prognostic marker for the general mortality of ESRD patients [69].

The connection between the lack of peritoneal ultrafiltration and mortality has been proven in anuric patients. When fluid intake is not adjusted to peritoneal ultrafiltration, the patient will develop volume overload, which increases the risk of CVD.

## **4.14. Genetic and epigenetic factors**

**4.10. Anemia**

**4.11. Hormonal disorder**

favors target hemoglobin of about 11 g/dl [66].

20 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

tions targeting the adverse outcomes of CV) [67].

965 dialysis patients with a weekly diuresis of 10 L/m<sup>2</sup>

**4.13. Volume overload and ultrafiltration insufficiency**

term PD treatment, in relation to basic RRF [58].

**4.12. Residual renal function (RRF)**

In ESRD, the condition causes LVH and LV dilatation. Normalizing hemoglobin has not shown any CV outcome improvement, despite a partial correction of anemia using erythropoietin causing a regression in LVH. The appropriate target hematocrit to minimize LVH or other CVD has not been defined. However, briefly summarizing guideline recommendations

The loss of kidney function and the altered metabolic milieu in CKD affects hormone secretion and response of target tissues, causing a number of endocrine dysfunctions that may affect both PEW prevalence and future CVD risk. Changes in the GH-IGF-1 axis lead to many important CKD complications such as growth retardation, PEW, atherosclerosis and disease progression. Other common hormonal disturbances in chronic kidney disease are subclinical hypothyroidism and the low-T3 syndrome, which occurs in one-fifth of CKD patients. However, chance of CV events increases in the general population with thyroid changes, and thyroid production is substantially reduced by inflammation. Therefore, the hypothesis exists saying these factors create a connection between stress caused by inflammation and a negative cardiovascular event in CKD patients [66]. Finally, during the chronic kidney disease, the sex hormone profile does not stay the same. In as many as 50–70% of males in ESRD, male hypogonadism occurs. Testosterone decline occurs for multiple reasons such as low synthesis of muscle protein and hemoglobin, as well as atherosclerosis development and arterial vasoconstriction and/or hardening. This relationship between male hypogonadism and increased risk of death caused by CV factors in dialysis patients has been brought to attention, which will hopefully put some focus on this issue. New studies conducted on nonCKD patients using low testosterone dosage showed satisfactory outcomes such as muscle gain and improved metabolism (no studies have been conducted regarding interven-

The residual renal function is important for dialysis patients because it contributes to total daily clearance of 20% or more. It is thought that a dialysis patient has preserved RRF if his clearance of creatinine is greater than 1.5 mL/min. In PD and HD patients, RRF is connected to all causes of mortality, and so it is connected with the risk of CV death. The vital role of RRF in the survival of PD patients was determined in large prospective studies such as the CANUSA and ADEMEX studies. In the ADEMEX study, by a prospective, randomized examination of

was noted [68]. These results were also confirmed by the NECOSAD study, where the rate of reduction of RRF was a stronger predictor of mortality and technical insufficiency of long-

Ultrafiltration insufficiency occurs in around a third of dialysis patients and can lead to arterial hypertension and volume encumbrance. Volume overload promoted the development

, a relative mortality risk drop of 11%

Genetic factors can influence the appearance and frequency of vascular complications in dialysis patients. Thus, polymorphism of a single nucleotide in the IL-6 gene is connected to increased levels of IL-6 in plasma, and comorbidity in HD patients, greater diastolic pressure values and left ventricular mass [70]. Polymorphism of the enzyme, which transforms angiotensin I to angiotensin II, can determine the degree of the function of recombined human erythropoietin in PD patients, which presents a significant prescreening for the assessment of erythropoietin resistance. Polymorphism on the human receptor of vitamin D is combined with an increased risk of the development of hypercalcemia, modulation of NO activity via the polymorphism of endothelial NOS, as well as functionally relevant polymorphism of the IL-6, which together can have a significant effect on basic peritoneal permeability [71]. In the future, research in this field could enable a more precise approach for the identification of risk groups of patients treated by PD, and the development of personalized treatment strategies.

A new approach in the research of atherosclerosis focuses on the role of epigenetics, which change studies in gene expression that are not coded in the DNA sequence itself but are instead a consequence of post-translatory changes in the DNA-protein. These epigenetic changes can be lost in several sequential cellular generations. Changes in the genome methylation of DNA have important regulatory functions in normal and pathological cellular processes. A persistent inflammatory reaction is most likely connected to DNA hypermethylation [72]. Further research is necessary to determine whether epigenetic DNA changes are connected to accelerated atherosclerosis in uremia.

## **5. Chronic cardiorenal and renocardiac syndrome interaction**

The interplay between cardiac and renal disease is complex and the term CRS has been introduced recently as an attempt to describe the close interaction between CV and renal systems, especially in the chronic disease settings. Division of CRS into five categories is proposed by Ronco et al. [73]. This classification is based on etiologic and chronologic factors [74]. The temporal relationship between the heart and kidney disease as well as the coexistence of CVD and CKD represent important aspects of chronic cardiorenal and renocardiac syndromes definition. CRS type 2, or chronic cardiorenal syndrome, is characterized by chronic abnormalities in cardiac function leading to kidney injury or dysfunction. CHF causally underlies the occurrence and progression of CKD [75]. CRS type 4, or chronic renocardiac syndrome, has been defined as "chronic abnormalities in renal function leading to cardiac disease" and recognizes the extreme burden of CVD in patients with CKD such as chronic glomerular disease and autosomal dominant polycystic kidney disease (ADPKD). This is the condition where primary CKD contributes a reduction in cardiac function such as cardiac remodeling, left ventricular diastolic dysfunction or hypertrophy, and/or an increased risk for CV events such as MI, heart failure or stroke [76].

Coexistence of the chronic heart and kidney disease was clearly described in large observational studies. However, this type of data cannot establish whether the primary process is the kidney disease (CRS type 4) or the heart disease (CRS type 2). For these situations, it has been suggested to use term CRS "type 2/4". For example, large database studies have shown the prevalence of CKD of 26–63% in the population of CHF patients. Likewise, retrospective and/ or secondary post hoc analyses from large clinical registries have evaluated the CV event rates and outcomes in selected CKD-specific populations [77]. The severity of CKD in those studies ranged from near normal kidney function to End stage kidney disease (ESKD). Furthermore, in a secondary analysis of the HEMO Study, cardiac disease was found in 80% of ESKD patients at enrollment [78]. During 12 months follow-up, 39.8% patients had cardiac-related hospitalizations with angina and acute myocardial infarction accounting for 42.7% of these hospitalizations. There were 39.4% of cardiac deaths. Baseline cardiac disease was highly predictive of cardiac-related death during follow-up (relative risk 2.57). Moreover, other authors have suggested that chronic maintenance hemodialysis induces repetitive myocardial injury and can accelerate systolic dysfunction [79].

B-type natiuretic peptide (BNP) produced by ventricular myocardium in response to ventricular stretching, and its inactive fragment N-terminal proBNP (NT-proBNP) are well-known diagnostic and prognostic markers in patients with heart failure. BNP and NT-proBNP are also useful markers of adverse CV events and overall mortality in CKD patients. They correlate with severity of heart failure and left ventricular dysfunction and can be used in guiding the management of heart failure in CKD patients. Some evidence suggests that NT-proBNP and high-sensitivity CRP (hs-CRP) are independent predictors of overall mortality in a nondialysis CKD population and their role in risk stratification can be useful in this specific patient population [82]. Similar results were found in the dialysis-dependent ESKD patients. High levels of NT-proBNP and cardiac troponin T showed to be strongly associated with adverse CV morbidity and mortality in HD patients [83]. In chronic PD patients, NT-pro-BNP is prognostic marker of congestive heart failure, mortality or combined end point including death

Troponins Neutrophil gelatinase-associated lipocalin (NGAL)

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C-reactive protein (CRP) N-acetyl-beta-d-glucosaminidase (NAG) Homocysteine Kidney injury molecule-1 (KIM-1)

Asymmetric dimethylarginine (ADMA) Fibroblast growth factor-23 (FGF23) Adiponectin (APN) Matrix metalloproteinases (MMPs)

**Cardiac biomarkers Renal biomarkers** Natriuretic peptides Cystatin C

Plasminogen activator inhibitor 1(PAI-1) Interleukin-18 (IL-18)

**Table 1.** Biomarkers of adverse cardiovascular events in chronic kidney disease.

Plasminogen activator inhibitor 1 (PAI-1), a specific inhibitor of tissue-type and urokinasetype plasminogen activators (t-PA and u-PA), plays a critical role in regulating the fibrinolysis. PAI-1 is classified as an endothelial dysfunction marker. The activated or injured endothelial cells synthesize higher rates of PAI-1 and endothelial dysfunction was recognized as an initial event of atherosclerosis. Elevated PAI-1 levels are associated with increased CV risk in the general population. Plasma levels of PAI-1 are also associated with the occurrence of a first AMI in a population with high prevalence of coronary heart disease. In addition, high plasma PAI-1 concentration was found to be independent predictor of CV in patients ongoing PD [85]. Adiponectin (APN) is a protein secreted by adipocytes with activities focusing on anti-inflammatory and anti-atherogenic goals. It also increases the body's insulin sensitivity. The way it assumed its functions are by suppressing proinflammatory cytokines such as TNF-a and IL-6 from being released and promoting the release of anti-inflammatory cytokines such as IL-10, as well as through increasing sensitivity to insulin. Through these roles, it controls antiatherosclerotic activities. Low levels of APN can be seen in obese patients, those with metabolic syndrome, diabetes mellitus, coronary artery disease and essential hypertension. On the other hand, APN plasma levels are three times higher than regular levels in patients with

and other adverse CV outcomes [84].

Advanced glycation end products (AGEs)

## **6. Biomarkers of adverse cardiovascular events in CKD patients**

Biomarkers must be determined in situations where we have renal and cardiac issues and dysfunctions, as it is crucial to know if any functional and structural damage occurred in the beginning stages of the disease. They are then used to separate the patients according to the risk level by considering established renal and cardiac parameters, in order to establish individual treatment and prognosis. These biomarkers may help with early diagnosis, prognosis, treatment and monitoring of CRS. There can be any measurable parameter, like components of serum or urine. In patients with CRS, a group of multiple biomarkers, rather than a single test, may improve diagnosis and better define prognosis [80].

Recent studies have evaluated the utility of biomarkers in the assessment of the CV risk in CKD population. Several cardiac biomarkers such as natriuretic peptides, troponins, CRP, homocysteine, plasminogen activator inhibitor 1 (PAI-1), ADMA, adiponectin (APN) and AGEs have been demonstrated to correlate with CV outcomes in CKD patients. Renal biomarkers such as cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), fibroblast growth factor-23 (FGF23), matrix metalloproteinases (MMPs) and interleukin-18 (IL-18) have been recently found to be diagnostic and prognostic markers of CV outcomes in CKD (**Table 1**) [81].

#### **6.1. Cardiac biomarkers**

The natriuretic peptides are family of hormones that share a common 17 amino acid ring structure and have actions targeted to protect the CV system from the effects of volume overload.


**Table 1.** Biomarkers of adverse cardiovascular events in chronic kidney disease.

primary CKD contributes a reduction in cardiac function such as cardiac remodeling, left ventricular diastolic dysfunction or hypertrophy, and/or an increased risk for CV events such

Coexistence of the chronic heart and kidney disease was clearly described in large observational studies. However, this type of data cannot establish whether the primary process is the kidney disease (CRS type 4) or the heart disease (CRS type 2). For these situations, it has been suggested to use term CRS "type 2/4". For example, large database studies have shown the prevalence of CKD of 26–63% in the population of CHF patients. Likewise, retrospective and/ or secondary post hoc analyses from large clinical registries have evaluated the CV event rates and outcomes in selected CKD-specific populations [77]. The severity of CKD in those studies ranged from near normal kidney function to End stage kidney disease (ESKD). Furthermore, in a secondary analysis of the HEMO Study, cardiac disease was found in 80% of ESKD patients at enrollment [78]. During 12 months follow-up, 39.8% patients had cardiac-related hospitalizations with angina and acute myocardial infarction accounting for 42.7% of these hospitalizations. There were 39.4% of cardiac deaths. Baseline cardiac disease was highly predictive of cardiac-related death during follow-up (relative risk 2.57). Moreover, other authors have suggested that chronic maintenance hemodialysis induces repetitive myocardial injury and can

**6. Biomarkers of adverse cardiovascular events in CKD patients**

test, may improve diagnosis and better define prognosis [80].

Biomarkers must be determined in situations where we have renal and cardiac issues and dysfunctions, as it is crucial to know if any functional and structural damage occurred in the beginning stages of the disease. They are then used to separate the patients according to the risk level by considering established renal and cardiac parameters, in order to establish individual treatment and prognosis. These biomarkers may help with early diagnosis, prognosis, treatment and monitoring of CRS. There can be any measurable parameter, like components of serum or urine. In patients with CRS, a group of multiple biomarkers, rather than a single

Recent studies have evaluated the utility of biomarkers in the assessment of the CV risk in CKD population. Several cardiac biomarkers such as natriuretic peptides, troponins, CRP, homocysteine, plasminogen activator inhibitor 1 (PAI-1), ADMA, adiponectin (APN) and AGEs have been demonstrated to correlate with CV outcomes in CKD patients. Renal biomarkers such as cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), fibroblast growth factor-23 (FGF23), matrix metalloproteinases (MMPs) and interleukin-18 (IL-18) have been recently

found to be diagnostic and prognostic markers of CV outcomes in CKD (**Table 1**) [81].

The natriuretic peptides are family of hormones that share a common 17 amino acid ring structure and have actions targeted to protect the CV system from the effects of volume overload.

as MI, heart failure or stroke [76].

22 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

accelerate systolic dysfunction [79].

**6.1. Cardiac biomarkers**

B-type natiuretic peptide (BNP) produced by ventricular myocardium in response to ventricular stretching, and its inactive fragment N-terminal proBNP (NT-proBNP) are well-known diagnostic and prognostic markers in patients with heart failure. BNP and NT-proBNP are also useful markers of adverse CV events and overall mortality in CKD patients. They correlate with severity of heart failure and left ventricular dysfunction and can be used in guiding the management of heart failure in CKD patients. Some evidence suggests that NT-proBNP and high-sensitivity CRP (hs-CRP) are independent predictors of overall mortality in a nondialysis CKD population and their role in risk stratification can be useful in this specific patient population [82]. Similar results were found in the dialysis-dependent ESKD patients. High levels of NT-proBNP and cardiac troponin T showed to be strongly associated with adverse CV morbidity and mortality in HD patients [83]. In chronic PD patients, NT-pro-BNP is prognostic marker of congestive heart failure, mortality or combined end point including death and other adverse CV outcomes [84].

Plasminogen activator inhibitor 1 (PAI-1), a specific inhibitor of tissue-type and urokinasetype plasminogen activators (t-PA and u-PA), plays a critical role in regulating the fibrinolysis. PAI-1 is classified as an endothelial dysfunction marker. The activated or injured endothelial cells synthesize higher rates of PAI-1 and endothelial dysfunction was recognized as an initial event of atherosclerosis. Elevated PAI-1 levels are associated with increased CV risk in the general population. Plasma levels of PAI-1 are also associated with the occurrence of a first AMI in a population with high prevalence of coronary heart disease. In addition, high plasma PAI-1 concentration was found to be independent predictor of CV in patients ongoing PD [85].

Adiponectin (APN) is a protein secreted by adipocytes with activities focusing on anti-inflammatory and anti-atherogenic goals. It also increases the body's insulin sensitivity. The way it assumed its functions are by suppressing proinflammatory cytokines such as TNF-a and IL-6 from being released and promoting the release of anti-inflammatory cytokines such as IL-10, as well as through increasing sensitivity to insulin. Through these roles, it controls antiatherosclerotic activities. Low levels of APN can be seen in obese patients, those with metabolic syndrome, diabetes mellitus, coronary artery disease and essential hypertension. On the other hand, APN plasma levels are three times higher than regular levels in patients with CKD, probably due to catabolism or reduced clearance. Some observational studies linked APN to adverse CV outcomes in patients with CKD. Low plasma APN levels were predictive of CV events among nondiabetic patients with mild to moderate CKD. Furthermore, low APN levels were found among the dialysis patients who developed CV complications [86].

NAG is an enzyme of hydrolase class that is abundant in the kidney, predominantly in the lysosomes of proximal tubular cells. The increased excretion of NAG is thought to be a specific marker of functional tubular impairment in many renal pathologies. Likewise KIM-1, NAG has been a useful marker of acute kidney injury (AKI) [97]. A recent study in type 1 diabetes mellitus found that lower levels of urinary NAG were associated with the regression of microalbuminuria [98]. It has not been assessed longitudinally in CKD [95]. In patients with CHF, urinary NAG was associated with an increased risk of death, heart failure hospitaliza-

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IL-18 is a proinflammatory cytokine that is released by the epithelial cells of the proximal tubule within hours of renal injury. It is significantly increased in AKI in comparison to urinary tract infection and nephrotic syndrome [96]. The destabilization of human coronary plaques can be connected to IL-18, which was originally thought to be a factor that promotes interferon-γ synthesis. In addition, in one study it was confirmed that young and middleaged patients with a recent AMI have higher IL-18 concentration in serum than age- and sex-matched control subjects, showing that concentration of this cytokine is associated with severity of coronary atherosclerosis [100]. In addition, recent evidence suggests that serum IL-18 is an important indicator and predictor of CV death in two-year follow-up among non-

diabetic patients suffering from CKD, with history of AMI in the previous year [101].

Fibroblast growth factor-23 (FGF23) is a newly discovered hormone produced in the bone that regulates phosphate and vitamin D metabolism by the kidneys. The main physiological functions of FGF23 are mediated by FGF receptors, generally in the presence of Klotho coreceptors. Decreased phosphorus excretion triggers FGF23 production, which in turn stimulates Klotho coreceptors in the kidneys [102]. CKD progression leads to compensatory elevation of FGF23 levels, resulting in typical CKD manifestations such as hyperphosphatemia, secondary hyperparathyroidism and bone disease, and progression to ESRD [80]. Elevated FGF23 has been associated with LVH, and it has been suggested that FGF23 may induce myocardial hypertrophy through a direct effect on cardiac myocytes [102]. FGF-23 has been independently associated with risk of all-cause death in dialysis and CKD patients, heart failure, CV

Matrix metalloproteinases (MMPs) are a large family of endopeptidases capable of degrading all components of the extracellular matrix and are therefore responsible for controlling the pathophysiological remodeling of tissues, including CV and renal systems. MMPs are classified according to their structure and substrate specificity, so MMP-2 and MMP-9 belong to the family of gelatinases that can cleave denatured collagen (gelatin), elastin and type IV collagen. Traditionally, MMPs were conceived of as exclusively anti-fibrotic tissue components; however, in the last few years, new paradigms have emerged in which inadequate extracellular matrix turnover governed by MMPs is also the hallmark of many pathological and generalized states such as inflammation, deleterious remodeling, oxidative stress and apoptosis [103]. Previous studies have demonstrated that increase in circulating levels of MMP-2 or MMP-9 are associated with arterial stiffness, hypertension and kidney disease progression in diabetic nephropathy. Recent data have proposed an important role of MMPs as markers of deleterious remodeling in the progression of renal disease and CVD [104]. Deleterious remodeling at the glomerular basement membrane, governed by pathological MMP activity, could contribute to

tions and heart transplantation, independent of GFR [99].

events and death in the general population [86].

## **6.2. Renal biomarkers**

Cystatin C is 13-kDa protein synthesized at a constant rate in all nucleated cells. It is freely filtered by the glomerulus and is reabsorbed and catabolized completely in the proximal tubule with a lack of tubular secretion. It is considered to be a better marker of early kidney dysfunction and more reliable marker of kidney function than serum creatinine. Cystatin C is very useful biomarker in CKD and used for CVD assessment. Cystatin C seems to be better predictor of mortality and CV events than serum creatinine [87]. High cystatin C concentrations predict substantial increased risks of all-cause mortality, CV events and incident heart failure [88] and are associated with increased LVM and a concentric LVH phenotype independent of renal function [89].

Across the CVD spectrum, including peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure and coronary artery disease, a connection has been established between high plasma levels of cystatin C and negative outcomes and risk stratification, without any particular explanations behind the mechanisms of the connection. Possible ties between negative CV outcomes and high cystatin C levels could stem from deteriorated renal function, atherogenesis and inflammatory mediators, myocardial tissue remodeling as well as other factors such as genetic determinants, age and aging and social habits [90].

NGAL is 25-kDa protein with 178 amino acids belonging to the lipocalin family [91]. It is highly expressed in kidney following ischemic and nephrotoxic injury. Plasma/serum and urine NGAL is used as an early marker of acute kidney injury (AKI) in several renal diseases. NGAL has also been investigated as a prognostic marker in CKD patients. Plasma and urine NGAL levels predict progression of CKD and reflected the severity of renal disease in the study performed by Bolignano et al. [92]. However, although urine NGAL was an independent risk factor for progression among patients with established CKD of diverse etiology in Chronic Renal Insufficiency Cohort (CRIC) study, it did not substantially improve prediction of outcome events in this patient population [93]. Nevertheless, NGAL has also shown promising results as a marker of CV risk in dialysis patients. In the study by Furuya et al., elevated levels of serum NGAL were independent risk factors for de novo CVD in HD patients [94]. Furthermore, hemodialysis patients with high NGAL levels in combination with high BNP levels had the greatest risk of CVD [86].

KIM-1 is a transmembrane glycoprotein with immunoglobulin-like features. Within 24–48 h after kidney injury, KIM-1 expression is dramatically increased in proximal tubular epithelial cells. It is increased in the urine in AKI. Experimental studies suggest that KIM-1 may be an indicator of AKI to CKD transition. In the setting of patients with CHF, urinary KIM-1 outperformed NGAL and NAG in predicting a combined CV outcome of death, heart transplantation, MI, coronary angioplasty or heart failure hospitalization. However, when compared to patients with heart failure without CKD, urinary KIM-1 levels were not statistically elevated in heart failure patients with CKD [95, 96].

NAG is an enzyme of hydrolase class that is abundant in the kidney, predominantly in the lysosomes of proximal tubular cells. The increased excretion of NAG is thought to be a specific marker of functional tubular impairment in many renal pathologies. Likewise KIM-1, NAG has been a useful marker of acute kidney injury (AKI) [97]. A recent study in type 1 diabetes mellitus found that lower levels of urinary NAG were associated with the regression of microalbuminuria [98]. It has not been assessed longitudinally in CKD [95]. In patients with CHF, urinary NAG was associated with an increased risk of death, heart failure hospitalizations and heart transplantation, independent of GFR [99].

CKD, probably due to catabolism or reduced clearance. Some observational studies linked APN to adverse CV outcomes in patients with CKD. Low plasma APN levels were predictive of CV events among nondiabetic patients with mild to moderate CKD. Furthermore, low APN levels were found among the dialysis patients who developed CV complications [86].

Cystatin C is 13-kDa protein synthesized at a constant rate in all nucleated cells. It is freely filtered by the glomerulus and is reabsorbed and catabolized completely in the proximal tubule with a lack of tubular secretion. It is considered to be a better marker of early kidney dysfunction and more reliable marker of kidney function than serum creatinine. Cystatin C is very useful biomarker in CKD and used for CVD assessment. Cystatin C seems to be better predictor of mortality and CV events than serum creatinine [87]. High cystatin C concentrations predict substantial increased risks of all-cause mortality, CV events and incident heart failure [88] and are associated with increased LVM and a concentric LVH phenotype independent of renal function [89]. Across the CVD spectrum, including peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure and coronary artery disease, a connection has been established between high plasma levels of cystatin C and negative outcomes and risk stratification, without any particular explanations behind the mechanisms of the connection. Possible ties between negative CV outcomes and high cystatin C levels could stem from deteriorated renal function, atherogenesis and inflammatory mediators, myocardial tissue remodeling as well as

other factors such as genetic determinants, age and aging and social habits [90].

NGAL is 25-kDa protein with 178 amino acids belonging to the lipocalin family [91]. It is highly expressed in kidney following ischemic and nephrotoxic injury. Plasma/serum and urine NGAL is used as an early marker of acute kidney injury (AKI) in several renal diseases. NGAL has also been investigated as a prognostic marker in CKD patients. Plasma and urine NGAL levels predict progression of CKD and reflected the severity of renal disease in the study performed by Bolignano et al. [92]. However, although urine NGAL was an independent risk factor for progression among patients with established CKD of diverse etiology in Chronic Renal Insufficiency Cohort (CRIC) study, it did not substantially improve prediction of outcome events in this patient population [93]. Nevertheless, NGAL has also shown promising results as a marker of CV risk in dialysis patients. In the study by Furuya et al., elevated levels of serum NGAL were independent risk factors for de novo CVD in HD patients [94]. Furthermore, hemodialysis patients with high NGAL levels in combination with high BNP

KIM-1 is a transmembrane glycoprotein with immunoglobulin-like features. Within 24–48 h after kidney injury, KIM-1 expression is dramatically increased in proximal tubular epithelial cells. It is increased in the urine in AKI. Experimental studies suggest that KIM-1 may be an indicator of AKI to CKD transition. In the setting of patients with CHF, urinary KIM-1 outperformed NGAL and NAG in predicting a combined CV outcome of death, heart transplantation, MI, coronary angioplasty or heart failure hospitalization. However, when compared to patients with heart failure without CKD, urinary KIM-1 levels were not statistically elevated

**6.2. Renal biomarkers**

24 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

levels had the greatest risk of CVD [86].

in heart failure patients with CKD [95, 96].

IL-18 is a proinflammatory cytokine that is released by the epithelial cells of the proximal tubule within hours of renal injury. It is significantly increased in AKI in comparison to urinary tract infection and nephrotic syndrome [96]. The destabilization of human coronary plaques can be connected to IL-18, which was originally thought to be a factor that promotes interferon-γ synthesis. In addition, in one study it was confirmed that young and middleaged patients with a recent AMI have higher IL-18 concentration in serum than age- and sex-matched control subjects, showing that concentration of this cytokine is associated with severity of coronary atherosclerosis [100]. In addition, recent evidence suggests that serum IL-18 is an important indicator and predictor of CV death in two-year follow-up among nondiabetic patients suffering from CKD, with history of AMI in the previous year [101].

Fibroblast growth factor-23 (FGF23) is a newly discovered hormone produced in the bone that regulates phosphate and vitamin D metabolism by the kidneys. The main physiological functions of FGF23 are mediated by FGF receptors, generally in the presence of Klotho coreceptors. Decreased phosphorus excretion triggers FGF23 production, which in turn stimulates Klotho coreceptors in the kidneys [102]. CKD progression leads to compensatory elevation of FGF23 levels, resulting in typical CKD manifestations such as hyperphosphatemia, secondary hyperparathyroidism and bone disease, and progression to ESRD [80]. Elevated FGF23 has been associated with LVH, and it has been suggested that FGF23 may induce myocardial hypertrophy through a direct effect on cardiac myocytes [102]. FGF-23 has been independently associated with risk of all-cause death in dialysis and CKD patients, heart failure, CV events and death in the general population [86].

Matrix metalloproteinases (MMPs) are a large family of endopeptidases capable of degrading all components of the extracellular matrix and are therefore responsible for controlling the pathophysiological remodeling of tissues, including CV and renal systems. MMPs are classified according to their structure and substrate specificity, so MMP-2 and MMP-9 belong to the family of gelatinases that can cleave denatured collagen (gelatin), elastin and type IV collagen. Traditionally, MMPs were conceived of as exclusively anti-fibrotic tissue components; however, in the last few years, new paradigms have emerged in which inadequate extracellular matrix turnover governed by MMPs is also the hallmark of many pathological and generalized states such as inflammation, deleterious remodeling, oxidative stress and apoptosis [103]. Previous studies have demonstrated that increase in circulating levels of MMP-2 or MMP-9 are associated with arterial stiffness, hypertension and kidney disease progression in diabetic nephropathy. Recent data have proposed an important role of MMPs as markers of deleterious remodeling in the progression of renal disease and CVD [104]. Deleterious remodeling at the glomerular basement membrane, governed by pathological MMP activity, could contribute to glomerular hyperfiltration, albuminuria and loss of renal function [103]. The vascular changes observed in CKD patients not only consist of atherosclerosis but also arteriosclerosis associated with both medial and intimal vascular calcifications. The degree of arterial stiffening and the extent of calcification are closely related, and both of these variables are strong and independent prognostic markers of all-cause and CV mortality in patients on HD. Over the last few years, matrix metalloproteinases (MMPs) have been increasingly implicated in connective tissue remodeling during atherogenesis. MMPs are involved in plaque rupture, which is the main pathological cause of myocardial infarction. Interstitial collagenase (MMP-1) is the only MMP that can cleave native collagen types I and III, which are major structural components of the fibrous plaque cap. MMP-1 might play a significant role in fibrous plaque disruption by contributing to the degradation of interstitial collagens and thinning of the fibrous cap [105].

a strong suggestion of benefit to anemia management in observational studies, a number of studies in predialysis patients yielded disappointing results. The TREAT study involved diabetic CKD patients with moderate anemia treated with darbepoetin alfa [108]. Correction of anemia to hemoglobin level of 13 g/dL was associated with increased risk of stroke. Recent systematization and meta-analysis of erythropoiesis-stimulating agent therapy showed that this type of therapy has 1.5 times higher risk of stroke, as well as promotes hypertension and even increases the mortality risk, risk of severe CV events and ESRD with higher hemoglobin targets [109]. These studies have not been in vain, as they have led to changes in the usage of the medication for the purpose of correction of anemia in CKD patients to a target quantity of 11–12 g/dL [107]. Increased homocysteine has been associated with adverse CV outcomes CKD population. Folic acid, vitamin B6 and vitamin B12 in combination are an effective and inexpensive strategy to decrease homocysteine in most populations. However, trials of multivitamins in ESRD patients have been disappointing with negative results from a number of well-conducted clinical trials. This could be explained partly by the fact that vitamins fail to normalize homocysteine in ESRD patients, and toxicity from the vitamins themselves poten-

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

27

CKD-mineral and bone disorder (CKD-MBD) has been linked to the progression of cardiac disease, and investigators have shown a link between even mild degrees of renal injury and vascular calcification. Therefore, strategies to control phosphate, control PTH and vitamin D analogs have been mainstays of therapy in this regard [111]. In terms of phosphate binding, a Cochrane systematic review discovered that the effect of sevelamer hydrochloride and lanthanum carbonate were not as beneficial as calcium salts for the purpose of phosphate control. Some of the studies appeared to show improvements in the surrogate outcome of vascular calcification, which subsequently did not add to any reduction in CV morbidity or

Statins play a central role in the primary and secondary management of the CVD risk. Results of SHARP (Study of Heart and Renal Protection) study showed a significant benefit of the combination of simvastatin and ezetimibe in lowering the risk of major atherosclerotic events. This study included both ESRD patients and CKD patients not on dialysis. However, the subgroup of ESRD patients in SHARP seemed to experience less benefit compared to lesser degrees of CKD, and all-cause mortality was unaffected. Consistent with this negative findings, the initiation of treatment with rosuvastatin in the AURORA study had no significant effect on the composite primary end point of death from CV causes, nonfatal MI or nonfatal stroke in ESRD patient undergoing HD. It seems that CKD patients could benefit from statins but pragmatic approach is to recommend therapy with statins in CKD stages I–IV with

Dialytic strategies are used to improve cardiovascular outcome. Dialysis technology improvements should lead to improvements in hemodynamic stability, oxidative and inflammatory stress and increase the efficiency of removing low and middle toxins, which leads to 'cardioprotective dialysis'. Both the use of modern machines that fit safety, quality of therapy,

tially could offset any theoretical benefit [110].

mortality [111].

increased risk of CVD [107].

**7.2. Dialytic strategies to improve cardiovascular outcome**

## **7. Strategies to improve cardiovascular outcome in CKD**

#### **7.1. Medical therapies to improve cardiovascular outcome**

Risk modification is very important in CKD patient in order to improve outcomes. Strategies to reduce CV risk in CKD patients should target traditional, nontraditional and uremia-related factors. Recent opinions suggest a potential benefit from a more individualized perspective, that takes into account patient-specific trends and distinctive dynamic features of the actual clinical situation [106].

Blood pressure management has been advocated for both reducing cardiovascular risk and for slowing the renal progression of CKD. In all CKD patients, blood pressure should be <140/90 mm Hg and in patients with CKD and diabetes or those with significant proteinuria, target values should be <130/80 mm Hg. Agents acting via the RAAS, including ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are often recommended as firstline treatment particularly in patients with diabetes and/or proteinuria. ACEIs have positive effects on neurohormonal activity and ventricular remodeling, while ARBs seem to reduce oxidative stress and inflammation [107]. In a randomized trial performed on ESKD patients, fosinopril was found to reduce CV death, heart failure, myocardial infarction and nonfatal stroke. Beta-blockers were found to reduce the cardiac risk in coronary artery disease patients with or without CKD in the Bezafibrate Infarction Prevention study. A significant reduction of CV mortality and occurrence of sudden death was demonstrated in dialysis patients treated with carvedilol. However, new dialysis patients not previously treated with beta-blockers were more likely to develop new-onset heart failure [107].

One most neglected aspect is the effect of sodium intake on blood pressure. Only a minority of renal patients reduce sodium chloride intake to the recommended target of 7 g/day. Apart from reduced salt intake, co-administration of diuretics is mandatory (in early stages, mostly thiazides). Loop diuretics are required in advanced stages of CKD.

Anemia is considered to be one of the most important factors along with hypertension for the development of LVH in CKD patients. In terms of erythropoiesis-stimulating agents, despite a strong suggestion of benefit to anemia management in observational studies, a number of studies in predialysis patients yielded disappointing results. The TREAT study involved diabetic CKD patients with moderate anemia treated with darbepoetin alfa [108]. Correction of anemia to hemoglobin level of 13 g/dL was associated with increased risk of stroke. Recent systematization and meta-analysis of erythropoiesis-stimulating agent therapy showed that this type of therapy has 1.5 times higher risk of stroke, as well as promotes hypertension and even increases the mortality risk, risk of severe CV events and ESRD with higher hemoglobin targets [109]. These studies have not been in vain, as they have led to changes in the usage of the medication for the purpose of correction of anemia in CKD patients to a target quantity of 11–12 g/dL [107]. Increased homocysteine has been associated with adverse CV outcomes CKD population. Folic acid, vitamin B6 and vitamin B12 in combination are an effective and inexpensive strategy to decrease homocysteine in most populations. However, trials of multivitamins in ESRD patients have been disappointing with negative results from a number of well-conducted clinical trials. This could be explained partly by the fact that vitamins fail to normalize homocysteine in ESRD patients, and toxicity from the vitamins themselves potentially could offset any theoretical benefit [110].

glomerular hyperfiltration, albuminuria and loss of renal function [103]. The vascular changes observed in CKD patients not only consist of atherosclerosis but also arteriosclerosis associated with both medial and intimal vascular calcifications. The degree of arterial stiffening and the extent of calcification are closely related, and both of these variables are strong and independent prognostic markers of all-cause and CV mortality in patients on HD. Over the last few years, matrix metalloproteinases (MMPs) have been increasingly implicated in connective tissue remodeling during atherogenesis. MMPs are involved in plaque rupture, which is the main pathological cause of myocardial infarction. Interstitial collagenase (MMP-1) is the only MMP that can cleave native collagen types I and III, which are major structural components of the fibrous plaque cap. MMP-1 might play a significant role in fibrous plaque disruption by contributing to the degradation of interstitial collagens and thinning of the fibrous cap [105].

Risk modification is very important in CKD patient in order to improve outcomes. Strategies to reduce CV risk in CKD patients should target traditional, nontraditional and uremia-related factors. Recent opinions suggest a potential benefit from a more individualized perspective, that takes into account patient-specific trends and distinctive dynamic features of the actual

Blood pressure management has been advocated for both reducing cardiovascular risk and for slowing the renal progression of CKD. In all CKD patients, blood pressure should be <140/90 mm Hg and in patients with CKD and diabetes or those with significant proteinuria, target values should be <130/80 mm Hg. Agents acting via the RAAS, including ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are often recommended as firstline treatment particularly in patients with diabetes and/or proteinuria. ACEIs have positive effects on neurohormonal activity and ventricular remodeling, while ARBs seem to reduce oxidative stress and inflammation [107]. In a randomized trial performed on ESKD patients, fosinopril was found to reduce CV death, heart failure, myocardial infarction and nonfatal stroke. Beta-blockers were found to reduce the cardiac risk in coronary artery disease patients with or without CKD in the Bezafibrate Infarction Prevention study. A significant reduction of CV mortality and occurrence of sudden death was demonstrated in dialysis patients treated with carvedilol. However, new dialysis patients not previously treated with beta-blockers

One most neglected aspect is the effect of sodium intake on blood pressure. Only a minority of renal patients reduce sodium chloride intake to the recommended target of 7 g/day. Apart from reduced salt intake, co-administration of diuretics is mandatory (in early stages, mostly

Anemia is considered to be one of the most important factors along with hypertension for the development of LVH in CKD patients. In terms of erythropoiesis-stimulating agents, despite

**7. Strategies to improve cardiovascular outcome in CKD**

**7.1. Medical therapies to improve cardiovascular outcome**

26 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

were more likely to develop new-onset heart failure [107].

thiazides). Loop diuretics are required in advanced stages of CKD.

clinical situation [106].

CKD-mineral and bone disorder (CKD-MBD) has been linked to the progression of cardiac disease, and investigators have shown a link between even mild degrees of renal injury and vascular calcification. Therefore, strategies to control phosphate, control PTH and vitamin D analogs have been mainstays of therapy in this regard [111]. In terms of phosphate binding, a Cochrane systematic review discovered that the effect of sevelamer hydrochloride and lanthanum carbonate were not as beneficial as calcium salts for the purpose of phosphate control. Some of the studies appeared to show improvements in the surrogate outcome of vascular calcification, which subsequently did not add to any reduction in CV morbidity or mortality [111].

Statins play a central role in the primary and secondary management of the CVD risk. Results of SHARP (Study of Heart and Renal Protection) study showed a significant benefit of the combination of simvastatin and ezetimibe in lowering the risk of major atherosclerotic events. This study included both ESRD patients and CKD patients not on dialysis. However, the subgroup of ESRD patients in SHARP seemed to experience less benefit compared to lesser degrees of CKD, and all-cause mortality was unaffected. Consistent with this negative findings, the initiation of treatment with rosuvastatin in the AURORA study had no significant effect on the composite primary end point of death from CV causes, nonfatal MI or nonfatal stroke in ESRD patient undergoing HD. It seems that CKD patients could benefit from statins but pragmatic approach is to recommend therapy with statins in CKD stages I–IV with increased risk of CVD [107].

#### **7.2. Dialytic strategies to improve cardiovascular outcome**

Dialytic strategies are used to improve cardiovascular outcome. Dialysis technology improvements should lead to improvements in hemodynamic stability, oxidative and inflammatory stress and increase the efficiency of removing low and middle toxins, which leads to 'cardioprotective dialysis'. Both the use of modern machines that fit safety, quality of therapy, performance and monitoring standards and the use of new biomaterials designed to mitigate inflammation and enhance membrane performance represent the application of new technologies [81]. In HD synthetic membranes are regarded as being more "biocompatible" in that they incite less of an immune response than cellulose-based membranes. However, Cochrane metaanalysis found no evidence of benefit when synthetic (high-flux) membranes were compared to cellulose/modified cellulose membranes in terms of reduced mortality in HD patients. This meta-analysis also showed that synthetic membranes achieved significantly higher Kt/V values when compared to modified cellulose membranes [112]. Results that are shown in the study of House et al. were compared the use of high-flux and low-flux hemodialysis on homocysteine and lipid profiles. The larger intradialytic effect of high-flux dialysis on homocysteine did not significantly affect predialysis levels after 3 months of study [113]. In contrast to this finding, high-flux membranes were associated with improved 2-year survival in the study of Chauveau et al. [114]. Other authors have reported that 'hemofiltration' or 'hemodiafiltration' treatment was associated with better blood pressure control, lower incidence of intradialytic hypotension or arrhythmia, better β2-microglobulin, phosphate clearance, reduced inflammation and oxidative stress as well as reduced hospitalization rate [81]. Ultrapure dialysate might also contribute to improvements in the morbidity and mortality of HD patients. Honda et al. found that serum myeloperoxidase and hs-CRP levels were significantly decreased in the patients treated with ultrapure dialysate compared to the patients undergoing HD using conventional dialysate. Ultrapure dialysate can improve the chronic inflammatory status, oxidative stress, and lipid abnormalities, suggesting a possible contribution to reduced CVD risk [115].

from thiocyanate by myeloperoxidase in atheroma plates [118]. As kidney function declines, metabolic substances such as urea and its derivates, cyanate and ammonia, dramatically increase thus leading to a significant amount of carbamylated proteins. Carbamylation of caeruloplasmin increases oxidative stress by decreasing the ferroxidase activity; carbamylated HDL reduces the lecithin-cholesterol acyltransferase thus inducing cholesterol accumulation; carbamylated LDL induces endothelial apoptosis and proliferation [76]. Amino acid therapy is applicable for reduction of protein carbonylation in CKD patients. The United States Food and Drug Administration (FDA) recently approved intravenous amino acid solution for this purpose (clinical trials.gov Identifier: NCT01612429). It was reported that uremic patients are deficient of free amino acids so that an infusion of free amino acids protects the proteins from carbamoylation due to the fact that both free amino acids and proteins compete with

Traditional, Nontraditional, and Uremia-Related Threats for Cardiovascular Disease in Chronic ...

http://dx.doi.org/10.5772/intechopen.69574

29

Glycation is a nonenzymatic reaction of reducing sugars with the amino group of amino acids, nucleic acids, lipids and proteins. AGEs are considered extremely significant in determining the development of CVD in diabetic patients by changing the structure, function and characteristics of tissue through crosslinking inter- and extracellular matrix proteins and modulation of cellular processes through binding to receptors located on the cell's surface [119]. As CKD develops, the kidney is unable to successfully excrete AGE, leading to high concentrations. AGEs can be considered as uremic toxins, as they increase CV morbidity in patients suffering from CKD by altering their vascular matrix, thus increasing arterial stiffening, vascular calcifications and left ventricular hypertrophy. The pathophysiological effects of AGEs can be blocked by using inhibitors of AGE synthesis (aminoguanidine, pyridoxamine, benfotiamine, ALT-946, OBP-9195 and pimagedine); AGE cross-link breakers (alagebrium, N-phenacetyl thiazollium, TRC4186 and C-36) and anti-RAGE, which serve as a receptor blocker [120].

Oxidation generally refers to the loss of electrons or gain of oxygen or loss of hydrogen by a molecule. The addition of reactive carbonyl functional groups on proteins is generally termed as protein carbonylation. Oxidation mechanism is also involved in carbonylation. There is a close relationship between oxidative stress and carbonyl stress and these are enhanced in correlation with the progression of CKD among predialysis CKD patients. Proteins are the major targets for these reactive oxygen and nitrogen species, leading to peptide-bound cleavage or oxidation of side chains of amino acids resulting in the structural and functional changes of oxidized proteins. Almost all amino acids are vulnerable to radical attacks of reactive oxygen and nitrogen species. Oxidized forms of phenylalanine and tyrosine, markers for the oxidative damage, are all together termed as advanced oxidation protein products (AOPP). Clinical studies revealed that LDL oxidation, AOPP and protein carbonyls can be used as biomarkers of oxidative stress in CKD patients. AOPP levels independently predict atherosclerotic CV events in patients with CKD in the predialysis phase and might directly contribute to the uremia-associated accelerated atherogenesis [117]. Oxidized LDL could be involved in

cyanate [117].

**8.2. Glycation**

**8.3. Oxidation/carbonylation**

PD might circumvent the hemodynamic instability of frequent and rapid ultrafiltration associated with conventional HD. Previous randomized controlled trials and many other observational studies have produced conflicting results as to which therapy may have a CV advantage. Some registry data suggests PD is associated with a lower mortality than HD in the first 1–2 years but thereafter may be higher on PD than HD. Other registry data do not support this. The decision to undergo either PD or HD is based on many factors which include the differential damage the RRT may have on the CV system [116].

## **8. Post-translational modifications (PTMs) in CKD and CVD**

Post-translational modifications (PTMs) of proteins and peptides have recently gained much attention, as they are involved in the pathogenesis of CVD and also play a role in the progression of CKD. PTMs are covalent changes of proteins or peptides that are altered either by proteolytic cleavage or by adding moieties to one or more amino acids. The most commonly reported PTMs are carbamoylation, glycation and oxidation [117].

#### **8.1. Carbamylation**

Carbamylation is a nonenzymatic spontaneous reaction of a primary amine or a free sulfhydryl group of proteins with isocyanate. This process is increased during CKD because of hyperuricemia, and in other pathologies like atherosclerosis, where isocyanic may be formed from thiocyanate by myeloperoxidase in atheroma plates [118]. As kidney function declines, metabolic substances such as urea and its derivates, cyanate and ammonia, dramatically increase thus leading to a significant amount of carbamylated proteins. Carbamylation of caeruloplasmin increases oxidative stress by decreasing the ferroxidase activity; carbamylated HDL reduces the lecithin-cholesterol acyltransferase thus inducing cholesterol accumulation; carbamylated LDL induces endothelial apoptosis and proliferation [76]. Amino acid therapy is applicable for reduction of protein carbonylation in CKD patients. The United States Food and Drug Administration (FDA) recently approved intravenous amino acid solution for this purpose (clinical trials.gov Identifier: NCT01612429). It was reported that uremic patients are deficient of free amino acids so that an infusion of free amino acids protects the proteins from carbamoylation due to the fact that both free amino acids and proteins compete with cyanate [117].

## **8.2. Glycation**

performance and monitoring standards and the use of new biomaterials designed to mitigate inflammation and enhance membrane performance represent the application of new technologies [81]. In HD synthetic membranes are regarded as being more "biocompatible" in that they incite less of an immune response than cellulose-based membranes. However, Cochrane metaanalysis found no evidence of benefit when synthetic (high-flux) membranes were compared to cellulose/modified cellulose membranes in terms of reduced mortality in HD patients. This meta-analysis also showed that synthetic membranes achieved significantly higher Kt/V values when compared to modified cellulose membranes [112]. Results that are shown in the study of House et al. were compared the use of high-flux and low-flux hemodialysis on homocysteine and lipid profiles. The larger intradialytic effect of high-flux dialysis on homocysteine did not significantly affect predialysis levels after 3 months of study [113]. In contrast to this finding, high-flux membranes were associated with improved 2-year survival in the study of Chauveau et al. [114]. Other authors have reported that 'hemofiltration' or 'hemodiafiltration' treatment was associated with better blood pressure control, lower incidence of intradialytic hypotension or arrhythmia, better β2-microglobulin, phosphate clearance, reduced inflammation and oxidative stress as well as reduced hospitalization rate [81]. Ultrapure dialysate might also contribute to improvements in the morbidity and mortality of HD patients. Honda et al. found that serum myeloperoxidase and hs-CRP levels were significantly decreased in the patients treated with ultrapure dialysate compared to the patients undergoing HD using conventional dialysate. Ultrapure dialysate can improve the chronic inflammatory status, oxidative stress,

28 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

and lipid abnormalities, suggesting a possible contribution to reduced CVD risk [115].

include the differential damage the RRT may have on the CV system [116].

**8. Post-translational modifications (PTMs) in CKD and CVD**

reported PTMs are carbamoylation, glycation and oxidation [117].

**8.1. Carbamylation**

PD might circumvent the hemodynamic instability of frequent and rapid ultrafiltration associated with conventional HD. Previous randomized controlled trials and many other observational studies have produced conflicting results as to which therapy may have a CV advantage. Some registry data suggests PD is associated with a lower mortality than HD in the first 1–2 years but thereafter may be higher on PD than HD. Other registry data do not support this. The decision to undergo either PD or HD is based on many factors which

Post-translational modifications (PTMs) of proteins and peptides have recently gained much attention, as they are involved in the pathogenesis of CVD and also play a role in the progression of CKD. PTMs are covalent changes of proteins or peptides that are altered either by proteolytic cleavage or by adding moieties to one or more amino acids. The most commonly

Carbamylation is a nonenzymatic spontaneous reaction of a primary amine or a free sulfhydryl group of proteins with isocyanate. This process is increased during CKD because of hyperuricemia, and in other pathologies like atherosclerosis, where isocyanic may be formed Glycation is a nonenzymatic reaction of reducing sugars with the amino group of amino acids, nucleic acids, lipids and proteins. AGEs are considered extremely significant in determining the development of CVD in diabetic patients by changing the structure, function and characteristics of tissue through crosslinking inter- and extracellular matrix proteins and modulation of cellular processes through binding to receptors located on the cell's surface [119]. As CKD develops, the kidney is unable to successfully excrete AGE, leading to high concentrations. AGEs can be considered as uremic toxins, as they increase CV morbidity in patients suffering from CKD by altering their vascular matrix, thus increasing arterial stiffening, vascular calcifications and left ventricular hypertrophy. The pathophysiological effects of AGEs can be blocked by using inhibitors of AGE synthesis (aminoguanidine, pyridoxamine, benfotiamine, ALT-946, OBP-9195 and pimagedine); AGE cross-link breakers (alagebrium, N-phenacetyl thiazollium, TRC4186 and C-36) and anti-RAGE, which serve as a receptor blocker [120].

## **8.3. Oxidation/carbonylation**

Oxidation generally refers to the loss of electrons or gain of oxygen or loss of hydrogen by a molecule. The addition of reactive carbonyl functional groups on proteins is generally termed as protein carbonylation. Oxidation mechanism is also involved in carbonylation. There is a close relationship between oxidative stress and carbonyl stress and these are enhanced in correlation with the progression of CKD among predialysis CKD patients. Proteins are the major targets for these reactive oxygen and nitrogen species, leading to peptide-bound cleavage or oxidation of side chains of amino acids resulting in the structural and functional changes of oxidized proteins. Almost all amino acids are vulnerable to radical attacks of reactive oxygen and nitrogen species. Oxidized forms of phenylalanine and tyrosine, markers for the oxidative damage, are all together termed as advanced oxidation protein products (AOPP). Clinical studies revealed that LDL oxidation, AOPP and protein carbonyls can be used as biomarkers of oxidative stress in CKD patients. AOPP levels independently predict atherosclerotic CV events in patients with CKD in the predialysis phase and might directly contribute to the uremia-associated accelerated atherogenesis [117]. Oxidized LDL could be involved in the stiffening of vascular wall which contributes to structural changes in the artery that may lead to CVD [121]. Anti-oxidant therapy could be beneficial in uremic patients with oxidative stress since the oxidative metabolites accumulate in CKD. Treatment with N-acetylcysteine in dialysis patients reduced the levels of oxidized LDL and partly improved anemia [122]. Vitamin E and C as well as ACEIs reduce ROS production, thereby decreasing oxidative stress in CKD patients [123]. Coenzyme Q10 (CoQ10) administration was effective in protecting against oxidative stress in dialysis patients in a phase IV clinical trial (ClinicalTrials.gov Identifier: NCT00307996).

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31

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## **Author details**

Damir Rebić\* and Aida Hamzić-Mehmedbašić†

\*Address all correspondence to: damir.rebic@gmail.com

Clinic for Nephrology, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina

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\*Address all correspondence to: damir.rebic@gmail.com

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[88] Ix JH, Shlipak MG, Chertow GM, Whooley MA. Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart

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[90] Angelidis C, Deftereos S, Giannopoulos G, Anatoliotakis N, Bouras G, Hatzis G, Panagopoulou V, Pyrgakis V, Cleman MW. Cystatin C: An emerging biomarker in car-

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[93] Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, Hamano T, He J, Lash J, Lustigova E, Rosas SE, Simonson MS, Tao K, Hsu CY; Chronic Renal Insufficiency Cohort (CRIC) study investigators. Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. Kidney

[94] Furuya F, Shimura H, Yokomichi H, Takahashi K, Akiyama D, Asakawa C, Okamura A, Motosugi A, Haraguchi K, Yamagata Z, Kobayashi T. Neutrophil gelatinase-associated lipocalin levels associated with cardiovascular disease in chronic kidney disease patients. Clinical and Experimental Nephrology. 2014;**18**(5):778-783. DOI: 10.1007/s10157-013-0923-4

[95] Fassett RG, Venuthurupalli SK, Gobe GC, Coombes JS, Cooper MA, Hoy WE. Biomarkers in chronic kidney disease: A review. Kidney International. 2011;**80**(8):806-

[96] Comnick M, Ishani A. Renal biomarkers of kidney injury in cardiorenal syndrome. Current Heart Failure Reports. 2011;**8**(2):99-105. DOI: 10.1007/s11897-011-0052-x

[97] Doi K, Katagiri D, Negishi K, Hasegawa S, Hamasaki Y, Fujita T, Matsubara T, Ishii T, Yahagi N, Sugaya T, Noiri E. Mild elevation of urinary biomarkers in prerenal acute kidney injury. Kidney International. 2012;**82**(10):1114-1120. DOI: 10.1038/ki.2012.266

[98] Vaidya VS, Niewczas MA, Ficociello LH, Johnson AC, Collings FB, Warram JH, Bonventre JV. Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-β-d-glucosaminidase. Kidney International. 2011);**79**(4):464-470. DOI: 10.1038/

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**Chapter 2**

**Provisional chapter**

**Disorders in the System of Mineral and Bone**

**Significance and Possibilities for Correction**

**Metabolism Regulators—FGF-23, Klotho and** 

**Sclerostin—in Chronic Kidney Disease: Clinical** 

**Disorders in the System of Mineral and Bone** 

**Possibilities for Correction**

Ludmila Y. Milovanova, Victor V. Fomin,

Ludmila Y. Milovanova, Victor V. Fomin,

Yuriy S. Milovanov, Vasiliy V. Kozlov and

http://dx.doi.org/10.5772/intechopen.69298

Aigul Zh. Usubalieva

**Abstract**

cardiac remodelling

Aigul Zh. Usubalieva

Lidia V. Lysenko (Kozlovskaya), Nikolay A. Mukhin,

of CV events, as the major cause of death in CKD patients.

Lidia V. Lysenko (Kozlovskaya), Nikolay A. Mukhin,

Svetlana Y. Milovanova, Marina V. Taranova,

Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Metabolism Regulators—FGF-23, Klotho and Sclerostin**

DOI: 10.5772/intechopen.69298

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Keywords:** chronic kidney disease, FGF-23, Klotho, sclerostin, vascular calcification,

The chapter discusses the current understanding of the system of mineral and bone metabolism regulators—FGF-23, Klotho and sclerostin—disturbances in chronic kidney disease (CKD). In the chapter we presented the date, including our own results, which allow to suggest the change in the ratio of FGF-23-Klotho-sclerostin in CKD as an early biomarker not only for the chronic kidney damage but also for high cardiovascular (CV) risk. Results of studies show that disorders in FGF-23-Klotho-sclerostin ratio correlate with the frequency and severity of hypertension, vascular calcification, cardiac remodelling, anaemia, malnutrition, inflammation and strong aggravate CV risk in CKD. It was found independent from blood pressure (BP) action of increased serum FGF-23 on the myocardium as well as the correlation of serum high-sensitive troponin I with increased serum FGF-23 and low Klotho levels in CKD patients. At the same time, it was shown that renoprotective therapy, including renin-angiotensin blockers, low-protein diet with amino/keto acid supplementation and phosphate binders, erythropoiesis stimulators, vitamin D metabolites used to get the target levels of BP, serum phosphorus, haemoglobin, parathyroid hormone and nutritional status disorders correction can reduce the risk

**—in Chronic Kidney Disease: Clinical Significance and**

**Provisional chapter**

**Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho and Sclerostin —in Chronic Kidney Disease: Clinical Significance and Possibilities for Correction Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho and Sclerostin—in Chronic Kidney Disease: Clinical Significance and Possibilities for Correction**

DOI: 10.5772/intechopen.69298

Ludmila Y. Milovanova, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Nikolay A. Mukhin, Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and Aigul Zh. Usubalieva Lidia V. Lysenko (Kozlovskaya), Nikolay A. Mukhin, Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and Aigul Zh. Usubalieva Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Ludmila Y. Milovanova, Victor V. Fomin,

http://dx.doi.org/10.5772/intechopen.69298

#### **Abstract**

The chapter discusses the current understanding of the system of mineral and bone metabolism regulators—FGF-23, Klotho and sclerostin—disturbances in chronic kidney disease (CKD). In the chapter we presented the date, including our own results, which allow to suggest the change in the ratio of FGF-23-Klotho-sclerostin in CKD as an early biomarker not only for the chronic kidney damage but also for high cardiovascular (CV) risk. Results of studies show that disorders in FGF-23-Klotho-sclerostin ratio correlate with the frequency and severity of hypertension, vascular calcification, cardiac remodelling, anaemia, malnutrition, inflammation and strong aggravate CV risk in CKD. It was found independent from blood pressure (BP) action of increased serum FGF-23 on the myocardium as well as the correlation of serum high-sensitive troponin I with increased serum FGF-23 and low Klotho levels in CKD patients. At the same time, it was shown that renoprotective therapy, including renin-angiotensin blockers, low-protein diet with amino/keto acid supplementation and phosphate binders, erythropoiesis stimulators, vitamin D metabolites used to get the target levels of BP, serum phosphorus, haemoglobin, parathyroid hormone and nutritional status disorders correction can reduce the risk of CV events, as the major cause of death in CKD patients.

**Keywords:** chronic kidney disease, FGF-23, Klotho, sclerostin, vascular calcification, cardiac remodelling

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **1. Introduction**

Chronic kidney disease (CKD) is a global problem that has not only medical but also great social and economic importance, due to a significant prevalence in the population (10–15%), high mortality rate from cardiovascular complications (CVC), as well as the need for high-cost treatment for the end CKD stage (dialysis, transplantation). As compared with general population, mortality rate due to CVC in patients with chronic renal failure is 10 times higher, and in young people, this risk is higher by 100 or more time. Many patients with CKD die from CVC on pre-dialysis stages, not reaching the end stage of CKD [1, 2].

than PTH [8, 9], that allows to reconsider the traditional concept of secondary hyperparathy-

FGF-23, produced by osteocytes, is a phosphaturic hormone that maintains a normal serum phosphorus concentration by increasing excretion of phosphorus in the urine and reducing its absorption from the gastrointestinal tract by inhibiting synthesis of 1,25-dihydroxyvitamin D in kidneys. Physiological stimuli for FGF-23 secretion are both a diet with an excess of phos-

D3

D3

D3

FGF-23 suppresses the expression of the sodium-phosphorus co-transporters of both types (IIa and IIc) located on the apical surface of the epithelial cells of the proximal renal tubules;

At the same time, a date on the direct blocking effect of FGF-23 on PTH secretion was obtained [11]. It was found that FGF-23 stimulates mitogen-activated protein kinase (PKA) pathway, and so it inhibits the expression of PTH mRNA and PTH secretion both in vivo in rats and in

caemia occurs, which stimulates PTH overproduction [12]. Thus, normal levels of calcium

Initially, at the early CKD, the increase in FGF-23 is a compensatory response aimed at normalizing phosphorus serum levels while decreasing the functioning nephron number [8, 12]. The serum FGF-23 level increases in parallel with the progressive decrease in kidney function, and the serum phosphorus does not increase significantly until GFR falls <30 mL/min/1.73 m<sup>2</sup> [5, 8]. When this stage of CKD is reached, the above compensation mechanism becomes ineffective, and constant hyperphosphatemia occurs that stimulates the increasing secretion of FGF-23 and PTH [8]. By the time when patients reach the end stage of CKD, FGF-23 level

To realize its effects in the kidneys, FGF-23 needs a co-receptor which is a transmembrane form of Klotho protein [5, 10]. Klotho was originally identified as an "ageing suppressor" [13]. The Klotho gene encodes a transmembrane protein, which is expressed predominantly in the epithelial cells of distal tubules in the kidneys, in parathyroid glands (PTG) and in the cerebral vascular plexus. Two forms of Klotho protein were found: transmembrane and secreted forms, each of which has different functions. The membrane Klotho form acts as an obligate co-receptor for FGF-23, inducing the excretion of phosphate in the urine. Secreted Klotho form (sKlotho) is detected in human serum and cerebrospinal fluid. It was found that it is formed as a result of Klotho protein cleavage from the cell membrane of the distal tubules of the kidneys [5, 10]. The decrease of Klotho protein expression in the kidneys due to CKD advancement allows to consider it as an early diagnostic marker of kidney damage [5, 14].

levels in circulation [5, 8]. In the kidneys, FGF-

http://dx.doi.org/10.5772/intechopen.69298

, as well as FGF-23 stimulates the formation of

into its inactive metabolites. At the same time,

D3

D3

gene expression,

, thereby

45

D3

is decreased, hypocal-

formation by inhibiting 1α-hydroxylase enzyme activity, which

Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho...

roidism (SGPT) pathogenesis.

23 suppresses 1,25(OH)<sup>2</sup>

converts 25(OH)D<sup>3</sup>

phorus content and an increase in 1,25(OH)<sup>2</sup>

24-hydroxylase, which converts 1,25(OH)<sup>2</sup>

D3

transition to 1,25(OH)<sup>2</sup>

as a result, renal excretion of phosphorus increases [5, 8, 10].

closing the negative feedback of vitamin D homeostasis.

exceeds its normal range by 100 or more times [8].

vitro in parathyroid cell culture [11]. Since PTH is the inducer of 1,25(OH)<sup>2</sup>

As the renal 1α-hydroxylase is inhibited and secretion of 1,25(OH)<sup>2</sup>

the suppression of PTH, caused by FGF-23, reduces the serum level of 1,25(OH)<sup>2</sup>

and phosphorus in serum are maintained that is successful at the early CKD stages.

Among cardiovascular damage in CKD, the progressive both cardiac remodelling and vascular calcification have leading contribution, which together lead to an urgently high cardiovascular mortality in patients with CKD [3, 4]. Understanding of the early mechanisms of arterial calcification as well as left ventricular hypertrophy (LVH) is important for the development of new therapeutic strategies aimed for cardiovascular morbidity reducing, pre-dialysis period prolonging and overall survival of CKD patients improving.

Clarification of CKD progression mechanisms and possible early markers of CVC has led to interest in studying of the identified in recent years factors such as morphogenetic proteins fibroblast growth factor-23 (FGF-23), Klotho protein and sclerostin glycoprotein—which were estimated initially only as bone-mineral metabolism regulators in CKD [5].

Nowadays, the broader functional role of FGF-23, Klotho and sclerostin in organism has become understandable, including them significance as humoral factors involved in the processes of remodelling and calcification of the heart and vessels in CKD [6, 7]. Furthermore, the accumulated recently data allow to consider these factors as a possible therapeutic option for reducing mortality in CKD patients, but new randomized trials are still needed to clarify the individual mechanisms of their influence on remodelling and calcification of the heart and blood vessels as well as the optimal therapeutic modalities for correction of these disturbances.

The aim of the review was to systematize accumulated information and to establish the significance of the changes in serum levels of morphogenetic proteins (FGF-23, Klotho) and sclerostin glycoprotein, based on available literature data, including the results of our own studies, to assess renal and cardiac prognosis and possibilities for improving of cardio-renoprotective strategy in CKD.

## **2. FGF-23, Klotho and sclerostin in mineral bone disorders (MBD) in CKD**

Disorders of phosphorus-calcium metabolism begin to be detected already on the 3A stage of CKD, when serum phosphorus starts to increase in serum due to glomerular filtration rate (GFR) decreasing [8]. PTH and vitamin D (calcitriol) were considered as main phosphor-regulating hormones for a long time. However, in recent years, it has been established, including our data, that FGF-23 begins to increase in serum in response to phosphorus retention, earlier than PTH [8, 9], that allows to reconsider the traditional concept of secondary hyperparathyroidism (SGPT) pathogenesis.

**1. Introduction**

strategy in CKD.

**in CKD**

Chronic kidney disease (CKD) is a global problem that has not only medical but also great social and economic importance, due to a significant prevalence in the population (10–15%), high mortality rate from cardiovascular complications (CVC), as well as the need for high-cost treatment for the end CKD stage (dialysis, transplantation). As compared with general population, mortality rate due to CVC in patients with chronic renal failure is 10 times higher, and in young people, this risk is higher by 100 or more time. Many patients with CKD die from

Among cardiovascular damage in CKD, the progressive both cardiac remodelling and vascular calcification have leading contribution, which together lead to an urgently high cardiovascular mortality in patients with CKD [3, 4]. Understanding of the early mechanisms of arterial calcification as well as left ventricular hypertrophy (LVH) is important for the development of new therapeutic strategies aimed for cardiovascular morbidity reducing, pre-dialysis period

Clarification of CKD progression mechanisms and possible early markers of CVC has led to interest in studying of the identified in recent years factors such as morphogenetic proteins fibroblast growth factor-23 (FGF-23), Klotho protein and sclerostin glycoprotein—which were

Nowadays, the broader functional role of FGF-23, Klotho and sclerostin in organism has become understandable, including them significance as humoral factors involved in the processes of remodelling and calcification of the heart and vessels in CKD [6, 7]. Furthermore, the accumulated recently data allow to consider these factors as a possible therapeutic option for reducing mortality in CKD patients, but new randomized trials are still needed to clarify the individual mechanisms of their influence on remodelling and calcification of the heart and blood vessels as well as the optimal therapeutic modalities for correction of these disturbances. The aim of the review was to systematize accumulated information and to establish the significance of the changes in serum levels of morphogenetic proteins (FGF-23, Klotho) and sclerostin glycoprotein, based on available literature data, including the results of our own studies, to assess renal and cardiac prognosis and possibilities for improving of cardio-renoprotective

**2. FGF-23, Klotho and sclerostin in mineral bone disorders (MBD)** 

Disorders of phosphorus-calcium metabolism begin to be detected already on the 3A stage of CKD, when serum phosphorus starts to increase in serum due to glomerular filtration rate (GFR) decreasing [8]. PTH and vitamin D (calcitriol) were considered as main phosphor-regulating hormones for a long time. However, in recent years, it has been established, including our data, that FGF-23 begins to increase in serum in response to phosphorus retention, earlier

CVC on pre-dialysis stages, not reaching the end stage of CKD [1, 2].

estimated initially only as bone-mineral metabolism regulators in CKD [5].

prolonging and overall survival of CKD patients improving.

44 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

FGF-23, produced by osteocytes, is a phosphaturic hormone that maintains a normal serum phosphorus concentration by increasing excretion of phosphorus in the urine and reducing its absorption from the gastrointestinal tract by inhibiting synthesis of 1,25-dihydroxyvitamin D in kidneys. Physiological stimuli for FGF-23 secretion are both a diet with an excess of phosphorus content and an increase in 1,25(OH)<sup>2</sup> D3 levels in circulation [5, 8]. In the kidneys, FGF-23 suppresses 1,25(OH)<sup>2</sup> D3 formation by inhibiting 1α-hydroxylase enzyme activity, which converts 25(OH)D<sup>3</sup> transition to 1,25(OH)<sup>2</sup> D3 , as well as FGF-23 stimulates the formation of 24-hydroxylase, which converts 1,25(OH)<sup>2</sup> D3 into its inactive metabolites. At the same time, FGF-23 suppresses the expression of the sodium-phosphorus co-transporters of both types (IIa and IIc) located on the apical surface of the epithelial cells of the proximal renal tubules; as a result, renal excretion of phosphorus increases [5, 8, 10].

At the same time, a date on the direct blocking effect of FGF-23 on PTH secretion was obtained [11]. It was found that FGF-23 stimulates mitogen-activated protein kinase (PKA) pathway, and so it inhibits the expression of PTH mRNA and PTH secretion both in vivo in rats and in vitro in parathyroid cell culture [11]. Since PTH is the inducer of 1,25(OH)<sup>2</sup> D3 gene expression, the suppression of PTH, caused by FGF-23, reduces the serum level of 1,25(OH)<sup>2</sup> D3 , thereby closing the negative feedback of vitamin D homeostasis.

As the renal 1α-hydroxylase is inhibited and secretion of 1,25(OH)<sup>2</sup> D3 is decreased, hypocalcaemia occurs, which stimulates PTH overproduction [12]. Thus, normal levels of calcium and phosphorus in serum are maintained that is successful at the early CKD stages.

Initially, at the early CKD, the increase in FGF-23 is a compensatory response aimed at normalizing phosphorus serum levels while decreasing the functioning nephron number [8, 12]. The serum FGF-23 level increases in parallel with the progressive decrease in kidney function, and the serum phosphorus does not increase significantly until GFR falls <30 mL/min/1.73 m<sup>2</sup> [5, 8]. When this stage of CKD is reached, the above compensation mechanism becomes ineffective, and constant hyperphosphatemia occurs that stimulates the increasing secretion of FGF-23 and PTH [8]. By the time when patients reach the end stage of CKD, FGF-23 level exceeds its normal range by 100 or more times [8].

To realize its effects in the kidneys, FGF-23 needs a co-receptor which is a transmembrane form of Klotho protein [5, 10]. Klotho was originally identified as an "ageing suppressor" [13]. The Klotho gene encodes a transmembrane protein, which is expressed predominantly in the epithelial cells of distal tubules in the kidneys, in parathyroid glands (PTG) and in the cerebral vascular plexus. Two forms of Klotho protein were found: transmembrane and secreted forms, each of which has different functions. The membrane Klotho form acts as an obligate co-receptor for FGF-23, inducing the excretion of phosphate in the urine. Secreted Klotho form (sKlotho) is detected in human serum and cerebrospinal fluid. It was found that it is formed as a result of Klotho protein cleavage from the cell membrane of the distal tubules of the kidneys [5, 10]. The decrease of Klotho protein expression in the kidneys due to CKD advancement allows to consider it as an early diagnostic marker of kidney damage [5, 14].

Unlike the membrane form, the secreted form of Klotho has systemic effects: it regulates endothelial production of NO [15], maintains the integrity and permeability of the endothelium [16] and calcium homeostasis in the kidneys [17] and suppresses intracellular signals of insulin and insulin-like growth factor-1 as mechanisms evolutionarily associated with life expectancy [18]. The low serum level of sKlotho is associated with an increase of CVC [6] and all causes mortality [19].

According to the results of recent studies, a disorder of the FGF-23-Klotho-sclerostin ratio in CKD is an early biomarker of the degree of chronic renal damage, preceded to the changes in other established markers of CKD advancement such as hyperphosphatemia, hyperparathyroidism and hypovitaminosis D, considering early as emerging cardiovascular risk factors in CKD patients [5, 26]. In addition, in interventional trials, intake of phosphate binders, cinacalcet or active vitamin D did not exert a consistently beneficial effect to reduce in cardiovascular

Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho...

http://dx.doi.org/10.5772/intechopen.69298

47

**2.1. The relation of FGF-23, Klotho and sclerostin with cardiovascular remodelling** 

ventricular hypertrophy (LVH) and an increase in cardiovascular mortality [7, 29–31].

Mineral bone disorders (MBD) in CKD are the main contributor in CVC risk and in general

If the increase in FGF-23 serum levels at early CKD stages is adaptive, then the rapid FGF-23 rising from 3B CKD stage acquires a pathological significance. It was shown that an increase in serum FGF-23 level in CKD 3B-5 stages is associated with an endothelium dysfunction, Left

It is also believed that a markedly increased FGF-23 level in CKD leads to a non-selective binding of it to FGF receptors in the heart, which are usually activated by local growth factors, such as FGF-2 [32]. Thus, an elevated FGF-23 level was directly associated with an increased risk of LVH development, which was detected with prolonged exposure with FGF-2 in experiment. In addition, it was found that an increase in left ventricular mass index (LVMI) accompanied with increased serum FGF-23 was independent from serum phosphorus level [7, 9].

FGF-23 is an earlier, than phosphorus, marker of CVC in patients with CKD, even when a phosphorus serum level is within the normal range [8, 9]. The pathogenetic relationship

**Figure 1.** The position of MBD among the main causes of mortality in CKD haemodialysis patients (according to Block

event rate [28].

**and calcification in CKD**

GA et al. J. Am. Soc. Nephrol. 2004).

prognosis of this patient cohort (**Figure 1**).

In recent years, there is increasing evidence that sKlotho decreasing, as CKD advancement, occurs early (2–3A stage of CKD) and may be also an important reason for the inducing of FGF-23 serum increase. Koh et al. [20], based on the analysis of the kidney biopsy that results in ten patients with a histological nephrosclerosis, found a significant decrease in the expression of Klotho mRNA as well as in sKlotho level and also the role of Klotho deficiency as nephrosclerosis advances, in the development of numerous complications of CKD, including uncontrolled FGF-23 serum increase.

The reduced expression of Klotho transmembrane form on the surface of parathyroid glands (PTGs) cell membranes (Klotho is also a co-receptor for FGF-23 in PTGs) at advanced stages of CKD is attributed to the resistance of PTG receptors to FGF-23, even in FGF-23 maximum concentrations [10, 12, 21].

In recent years, data on the important role of sclerostin glycoprotein in CKD are accumulating [22, 23]. Sclerostin, synthesized by osteocytes, blocks Wnt signalling pathway that leads to suppression of bone formation, as a result of decreased osteoblast differentiation and proliferation and osteocyte apoptosis [24]. The level of sclerostin increases as CKD advances [22, 25].

To date, sclerostin is an established regulator of bone mineralization, while its role in the pathophysiology of vessels in CKD is actively explored [22, 26]. It is important to determine the clinical significance of changes in sclerostin metabolism in CKD, because the relationship between adynamic bone disease (ABD) and calcification of the heart and blood vessels in patients with CKD is considered proven [27]. At the same time, available-to-date publications on the role of sclerostin in ectopic calcification still remain contradictory [22, 23, 25, 26].

It has been shown in experimental studies that in the case of hyperphosphatemia, the function of the skeleton as a phosphorus reservoir is blocked, although the need of bone in phosphorus, on the contrary, is increased, which stimulates a rising of its level in the blood, and soft tissues and vessels become a new reservoir for phosphate deposition [27].

Thus, in patients with end CKD stages, hyperphosphatemia, Klotho's and 1,25(OH)<sup>2</sup> D3 deficiency and increased PTH and sclerostin occur, despite a very high level of FGF-23. At the same time, the frequency of ABD associated with a relatively low PTH and high sclerostin serum levels increases [12, 24, 27]. These changes, together with a decreased calcium excretion, may be responsible for the development of such complications of CKD as renal osteodystrophy, cardiovascular calcification following CVC and adverse outcomes in CKD [6, 7, 26].

It is suggested that an increase in sclerostin serum levels leads to a slowdown in osteogenesis in CKD. At the same time, there are reasons to believe that this mechanism is blocked in CKD and an increase in sclerostin is directed mainly to the inhibition of the extraosteal calcification [22, 25]. In addition it is believed that an increase in sclerostin expression by osteocytes in CKD causes bone resistance to PTH [24].

According to the results of recent studies, a disorder of the FGF-23-Klotho-sclerostin ratio in CKD is an early biomarker of the degree of chronic renal damage, preceded to the changes in other established markers of CKD advancement such as hyperphosphatemia, hyperparathyroidism and hypovitaminosis D, considering early as emerging cardiovascular risk factors in CKD patients [5, 26]. In addition, in interventional trials, intake of phosphate binders, cinacalcet or active vitamin D did not exert a consistently beneficial effect to reduce in cardiovascular event rate [28].

## **2.1. The relation of FGF-23, Klotho and sclerostin with cardiovascular remodelling and calcification in CKD**

Unlike the membrane form, the secreted form of Klotho has systemic effects: it regulates endothelial production of NO [15], maintains the integrity and permeability of the endothelium [16] and calcium homeostasis in the kidneys [17] and suppresses intracellular signals of insulin and insulin-like growth factor-1 as mechanisms evolutionarily associated with life expectancy [18]. The low serum level of sKlotho is associated with an increase of CVC [6] and

In recent years, there is increasing evidence that sKlotho decreasing, as CKD advancement, occurs early (2–3A stage of CKD) and may be also an important reason for the inducing of FGF-23 serum increase. Koh et al. [20], based on the analysis of the kidney biopsy that results in ten patients with a histological nephrosclerosis, found a significant decrease in the expression of Klotho mRNA as well as in sKlotho level and also the role of Klotho deficiency as nephrosclerosis advances, in the development of numerous complications of CKD, including

The reduced expression of Klotho transmembrane form on the surface of parathyroid glands (PTGs) cell membranes (Klotho is also a co-receptor for FGF-23 in PTGs) at advanced stages of CKD is attributed to the resistance of PTG receptors to FGF-23, even in FGF-23 maximum

In recent years, data on the important role of sclerostin glycoprotein in CKD are accumulating [22, 23]. Sclerostin, synthesized by osteocytes, blocks Wnt signalling pathway that leads to suppression of bone formation, as a result of decreased osteoblast differentiation and proliferation and osteocyte apoptosis [24]. The level of sclerostin increases as CKD advances [22, 25]. To date, sclerostin is an established regulator of bone mineralization, while its role in the pathophysiology of vessels in CKD is actively explored [22, 26]. It is important to determine the clinical significance of changes in sclerostin metabolism in CKD, because the relationship between adynamic bone disease (ABD) and calcification of the heart and blood vessels in patients with CKD is considered proven [27]. At the same time, available-to-date publications on the role of sclerostin in ectopic calcification still remain contradictory [22, 23, 25, 26].

It has been shown in experimental studies that in the case of hyperphosphatemia, the function of the skeleton as a phosphorus reservoir is blocked, although the need of bone in phosphorus, on the contrary, is increased, which stimulates a rising of its level in the blood, and soft

ciency and increased PTH and sclerostin occur, despite a very high level of FGF-23. At the same time, the frequency of ABD associated with a relatively low PTH and high sclerostin serum levels increases [12, 24, 27]. These changes, together with a decreased calcium excretion, may be responsible for the development of such complications of CKD as renal osteodystrophy, cardiovascular calcification following CVC and adverse outcomes in CKD [6, 7, 26]. It is suggested that an increase in sclerostin serum levels leads to a slowdown in osteogenesis in CKD. At the same time, there are reasons to believe that this mechanism is blocked in CKD and an increase in sclerostin is directed mainly to the inhibition of the extraosteal calcification [22, 25]. In addition it is believed that an increase in sclerostin expression by osteocytes in

D3 defi-

tissues and vessels become a new reservoir for phosphate deposition [27].

Thus, in patients with end CKD stages, hyperphosphatemia, Klotho's and 1,25(OH)<sup>2</sup>

all causes mortality [19].

uncontrolled FGF-23 serum increase.

46 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

CKD causes bone resistance to PTH [24].

concentrations [10, 12, 21].

Mineral bone disorders (MBD) in CKD are the main contributor in CVC risk and in general prognosis of this patient cohort (**Figure 1**).

If the increase in FGF-23 serum levels at early CKD stages is adaptive, then the rapid FGF-23 rising from 3B CKD stage acquires a pathological significance. It was shown that an increase in serum FGF-23 level in CKD 3B-5 stages is associated with an endothelium dysfunction, Left ventricular hypertrophy (LVH) and an increase in cardiovascular mortality [7, 29–31].

It is also believed that a markedly increased FGF-23 level in CKD leads to a non-selective binding of it to FGF receptors in the heart, which are usually activated by local growth factors, such as FGF-2 [32]. Thus, an elevated FGF-23 level was directly associated with an increased risk of LVH development, which was detected with prolonged exposure with FGF-2 in experiment. In addition, it was found that an increase in left ventricular mass index (LVMI) accompanied with increased serum FGF-23 was independent from serum phosphorus level [7, 9].

FGF-23 is an earlier, than phosphorus, marker of CVC in patients with CKD, even when a phosphorus serum level is within the normal range [8, 9]. The pathogenetic relationship

**Figure 1.** The position of MBD among the main causes of mortality in CKD haemodialysis patients (according to Block GA et al. J. Am. Soc. Nephrol. 2004).

between FGF-23 serum level and LVH was fully confirmed in the fundamental clinical work of Faul and Ansel [7] which showed that an increase in serum FGF-23 levels can directly lead to LVH development in CKD patients. The study consists of several stages; at the first stage, more than 3000 patients with renal insufficiency were examined for serum FGF-23 and echocardiography (EchoCG) at baseline and 1 year later. Each increase in serum FGF-23 on 1 logarithmic unit was associated with an increase in LVMI on 1.5 g/m<sup>2</sup> . After 2.9 ± 0.5 years, the researchers re-examined 411 patients who had normal EchoCG parameters at the beginning of the study. In 84 (20%) patients with normal blood pressure (BP) levels, LVH was firstly detected. At the same time, each increase in FGF23 on 1 logarithmic unit led to an increase in the frequency of LVH de novo detection by 4.4 times; and significantly high levels of FGF-23 caused a sevenfold increase in the frequency of LVH detection, independently of the arterial hypertension (AH).

independent predictor of annual mortality and the patients with high levels of FGF-23 from a higher quartile had a sixfold increase in the risk of mortality compared to similar patients

Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho...

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49

In another prospective the mild to moderate kidney disease (MMKD) study [38] involving 227 patients with nondiabetic CKD 1–4 stages, the patients were followed up for 53 months to assess the progression of the nephropathy. Based on the results, an independent direct relationship between increased serum FGF-23 level and CKD progression rate was established. FGF-23 was recognized as an important independent predictor of adverse renal and cardiovascular prognosis, and in addition, in the regression Cox analysis, phosphorus levels lost

Accumulating recent data allow to consider FGF-23 as an earlier and important predictor of mortality than serum phosphorus and PTH levels in patients with CKD. Elevated serum FGF-23 level is currently considered as an independent trigger factor in the pathogenesis of uremic cardiomyopathy and vascular calcification that served as the basis for suggesting FGF-23 *as a* 

At the same time, part of the pathological effects of FGF-23 may be due to Klotho deficiency in CKD advancement. It has been shown that kidneys are the main producers of Klotho forms in organism [5, 10, 14], so CKD is a state of Klotho deficiency. Deficit of Klotho causes development of multiple systemic manifestations (i.e. premature ageing syndrome), an integral part of which is severe cardiovascular impairments [6, 13, 15]. According to recent update, it has been proved now that Klotho downregulation is not merely an early biomarker for kidney damage but also plays a pathogenic independent role in the advancing of CKD as well as in principal complications of CKD, important part of which is vascular calcification [6, 9]. As it was recently summarized, Klotho's anti-calcification effect is possibly via at least three mechanisms: a phosphaturic hormone, the preservation of GFR and a direct effect on soft tissues including the vascular smooth muscle [6, 21]. In experiment Klotho overexpression slowed down CKD advancement, improves phosphate metabolism and protects the vasculature from

The role of soluble Klotho form in phosphate homeostasis was recognized as soon as Klotho was discovered, because Klotho-deficient mouse demonstrates severe hyperphosphatemia [10, 13, 18]. This was further confirmed by the fact that there was low serum phosphate in Klotho-overexpressing mice [18]. A patient with homozygous missense mutation (H193R) in Klotho gene had severe calcinosis, dural and carotid artery calcifications, severe hyperphos-

conceivably destabilizes KL1 domain of Klotho, thereby attenuating production of membrane-bound and sKlotho protein [40]. Therefore, Klotho is now considerable as a novel can-

It was established that a decrease in Klotho level is also possible due to the inhibition of its extrarenal production. In this connection, the results of Takeshita et al. [41] study, indicating the presence of Klotho gene expression in sinoatrial node and a high rate of sudden cardiac death due to arrhythmias caused by dysfunction of sinoatrial node in mice with blocked

vitamin D and FGF-23. This mutation

from the lower quartile according to multidimensional corrected model.

prognostic value after adjustment to serum FGF-23 level.

phatemia, hypercalcemia and high-serum 1,25(OH)<sup>2</sup>

didate gene for genetic hyperphosphatemia and calcinosis.

*new uremic toxin*, earlier than PTH [39].

calcification [5, 6, 10].

Klotho gene, are interesting.

In order to confirm the hypothesis of the direct influence of FGF-23 on cardiomyocytes, Kardami [32] conducted the experimental study in which an effect of exogenous FGF-23 on the cardiomyocytes of newborn rats was evaluated using immunohistochemical and morphometric analysis. As a result, the hypertrophy of cardiomyocytes was revealed, as well as the increase in them, a level of alpha-actinin protein that indicates an increase of sequentially connected sacrometer units in the cardiomyocytes, and an increase in expression of heavy embryonic beta-myosin chains and depression of mature alpha-myosin chains. This switching of heavy chains from mature to embryonic isoforms indicates on the reactivation of embryonic gene programme, which is associated with hypertrophic transformation.

In the work of Di Marco et al. [33], prohypertrophic effect of FGF-23 and FGF-2 on cardiomyocytes was noted, which disappeared after the use of FGF-23 receptor inhibitor, PD173074, that authors consider as evidence of direct FGF-23 action, independently of Klotho protein. It is important to note that the use of PD173074 prevented the development of LVH in rats, despite the presence of hypertension in them.

According to our data [34], an increase in serum FGF-23 levels was associated with a moderately elevated level of troponin I. At the same time, in the patients with increased central BP (>120/80 mm Hg) as well as with normal central BP (90–120/60–79 mm Hg), mean levels of FGF-23 were about the same [629 ± 118 and 489 ± 85, respectively], indicating, an independent from the BP, FGF-23 action on the myocardium. The association of troponins with ischaemic heart disease and their role as predictors of an unfavourable cardiovascular outcome is known that also allows to suggest FGF-23 as an important prognostic cardiomarker in CKD.

In addition, it was established [35] that an increase in serum FGF-23 levels accelerated the development of vascular arteriosclerosis almost by sixfold, with the direct correlation with vascular calcification. However, in multivariate analysis, this relationship was statistically weak, which may indicate a possible indirect effect of FGF-23 on vascular calcification. Further obtained data indicate the effect of FGF-23 on fetuin A level, which is known to be synthesized by osteoblasts and is an inhibitor of vascular smooth muscle cell (VSMS) calcification [35, 36].

In the prospective cohort ArMORR study [37] involving 10,044 patients, it was shown that a high FGF-23 serum level of patients, starting treatment with programmed HD, is an independent predictor of annual mortality and the patients with high levels of FGF-23 from a higher quartile had a sixfold increase in the risk of mortality compared to similar patients from the lower quartile according to multidimensional corrected model.

between FGF-23 serum level and LVH was fully confirmed in the fundamental clinical work of Faul and Ansel [7] which showed that an increase in serum FGF-23 levels can directly lead to LVH development in CKD patients. The study consists of several stages; at the first stage, more than 3000 patients with renal insufficiency were examined for serum FGF-23 and echocardiography (EchoCG) at baseline and 1 year later. Each increase in serum FGF-23 on

the researchers re-examined 411 patients who had normal EchoCG parameters at the beginning of the study. In 84 (20%) patients with normal blood pressure (BP) levels, LVH was firstly detected. At the same time, each increase in FGF23 on 1 logarithmic unit led to an increase in the frequency of LVH de novo detection by 4.4 times; and significantly high levels of FGF-23 caused a sevenfold increase in the frequency of LVH detection, independently of the arterial

In order to confirm the hypothesis of the direct influence of FGF-23 on cardiomyocytes, Kardami [32] conducted the experimental study in which an effect of exogenous FGF-23 on the cardiomyocytes of newborn rats was evaluated using immunohistochemical and morphometric analysis. As a result, the hypertrophy of cardiomyocytes was revealed, as well as the increase in them, a level of alpha-actinin protein that indicates an increase of sequentially connected sacrometer units in the cardiomyocytes, and an increase in expression of heavy embryonic beta-myosin chains and depression of mature alpha-myosin chains. This switching of heavy chains from mature to embryonic isoforms indicates on the reactivation of embryonic

In the work of Di Marco et al. [33], prohypertrophic effect of FGF-23 and FGF-2 on cardiomyocytes was noted, which disappeared after the use of FGF-23 receptor inhibitor, PD173074, that authors consider as evidence of direct FGF-23 action, independently of Klotho protein. It is important to note that the use of PD173074 prevented the development of LVH in rats, despite

According to our data [34], an increase in serum FGF-23 levels was associated with a moderately elevated level of troponin I. At the same time, in the patients with increased central BP (>120/80 mm Hg) as well as with normal central BP (90–120/60–79 mm Hg), mean levels of FGF-23 were about the same [629 ± 118 and 489 ± 85, respectively], indicating, an independent from the BP, FGF-23 action on the myocardium. The association of troponins with ischaemic heart disease and their role as predictors of an unfavourable cardiovascular outcome is known that also allows to suggest FGF-23 as an important prognostic cardiomarker in CKD. In addition, it was established [35] that an increase in serum FGF-23 levels accelerated the development of vascular arteriosclerosis almost by sixfold, with the direct correlation with vascular calcification. However, in multivariate analysis, this relationship was statistically weak, which may indicate a possible indirect effect of FGF-23 on vascular calcification. Further obtained data indicate the effect of FGF-23 on fetuin A level, which is known to be synthesized by osteoblasts and is an inhibitor of vascular smooth muscle cell (VSMS)

In the prospective cohort ArMORR study [37] involving 10,044 patients, it was shown that a high FGF-23 serum level of patients, starting treatment with programmed HD, is an

. After 2.9 ± 0.5 years,

1 logarithmic unit was associated with an increase in LVMI on 1.5 g/m<sup>2</sup>

48 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

gene programme, which is associated with hypertrophic transformation.

hypertension (AH).

the presence of hypertension in them.

calcification [35, 36].

In another prospective the mild to moderate kidney disease (MMKD) study [38] involving 227 patients with nondiabetic CKD 1–4 stages, the patients were followed up for 53 months to assess the progression of the nephropathy. Based on the results, an independent direct relationship between increased serum FGF-23 level and CKD progression rate was established. FGF-23 was recognized as an important independent predictor of adverse renal and cardiovascular prognosis, and in addition, in the regression Cox analysis, phosphorus levels lost prognostic value after adjustment to serum FGF-23 level.

Accumulating recent data allow to consider FGF-23 as an earlier and important predictor of mortality than serum phosphorus and PTH levels in patients with CKD. Elevated serum FGF-23 level is currently considered as an independent trigger factor in the pathogenesis of uremic cardiomyopathy and vascular calcification that served as the basis for suggesting FGF-23 *as a new uremic toxin*, earlier than PTH [39].

At the same time, part of the pathological effects of FGF-23 may be due to Klotho deficiency in CKD advancement. It has been shown that kidneys are the main producers of Klotho forms in organism [5, 10, 14], so CKD is a state of Klotho deficiency. Deficit of Klotho causes development of multiple systemic manifestations (i.e. premature ageing syndrome), an integral part of which is severe cardiovascular impairments [6, 13, 15]. According to recent update, it has been proved now that Klotho downregulation is not merely an early biomarker for kidney damage but also plays a pathogenic independent role in the advancing of CKD as well as in principal complications of CKD, important part of which is vascular calcification [6, 9]. As it was recently summarized, Klotho's anti-calcification effect is possibly via at least three mechanisms: a phosphaturic hormone, the preservation of GFR and a direct effect on soft tissues including the vascular smooth muscle [6, 21]. In experiment Klotho overexpression slowed down CKD advancement, improves phosphate metabolism and protects the vasculature from calcification [5, 6, 10].

The role of soluble Klotho form in phosphate homeostasis was recognized as soon as Klotho was discovered, because Klotho-deficient mouse demonstrates severe hyperphosphatemia [10, 13, 18]. This was further confirmed by the fact that there was low serum phosphate in Klotho-overexpressing mice [18]. A patient with homozygous missense mutation (H193R) in Klotho gene had severe calcinosis, dural and carotid artery calcifications, severe hyperphosphatemia, hypercalcemia and high-serum 1,25(OH)<sup>2</sup> vitamin D and FGF-23. This mutation conceivably destabilizes KL1 domain of Klotho, thereby attenuating production of membrane-bound and sKlotho protein [40]. Therefore, Klotho is now considerable as a novel candidate gene for genetic hyperphosphatemia and calcinosis.

It was established that a decrease in Klotho level is also possible due to the inhibition of its extrarenal production. In this connection, the results of Takeshita et al. [41] study, indicating the presence of Klotho gene expression in sinoatrial node and a high rate of sudden cardiac death due to arrhythmias caused by dysfunction of sinoatrial node in mice with blocked Klotho gene, are interesting.

One of the most important effects of Klotho and sclerostin is its ability to inhibit Wnt signal pathway and through it to slow down vascular calcification [42]. Reduction of serum Klotho levels impairs this protective effect. Besides this, it has been demonstrated that Klotho mitigates the increased cell senescence and apoptosis triggered by oxidative stress in endothelial cells [43] and Klotho also suppresses TNF-β-induced expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, attenuates NF-kappaB activation and reverses the inhibition of eNOS phosphorylation by TNF-α. Thus Klotho protein also protects the vascular endothelium by inhibition of endothelial inflammation [44].

binds to co-receptors, Frizzled and low-density lipoprotein receptor-related protein (LRP), which induces β-catenin translocation to the nucleus to regulate the transcription of Wnt target genes. The Wnt pathway is involved in many aspects of biology including cell survival, stem cell development and cell differentiation, including bone and vascular lineages [24, 42]. Register et al. [25] found that high sclerostin was associated with less calcified carotid plaque in diabetic African American men and was not associated with aortic or coronary calcification. Authors' hypothesis to explain this situation is that increased overproduction of sclerostin

Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho...

http://dx.doi.org/10.5772/intechopen.69298

51

Sclerostin slows the canonical Wnt signalling pathway and inhibits osteoblast activity and bone formation by sequestering LRP5 and LRP6 [24, 42]. Retarding the Wnt signalling pathway by using a dominant-negative LRP has been depicted to significantly reduce VSMC proliferation. In addition to VSMC proliferation, animal models of intimal thickening have revealed increased β-catenin levels, which suggest the involvement of the Wnt-β-catenin pathway also in VSMC migration. Moreover, Wnt proteins are also known to promote the migration of various cell types, including monocytes and endothelial cells. Furthermore, the Wnt pathway has been described to play an important role in the regulation of endothelial inflammation, vascular calcification and mesenchymal stem cell differentiation. As a result, considering the fact that atherosclerosis and calcification are both an actively regulated and progressive process, we might speculate that high sclerostin levels might be indicative of a sort of defensive mechanism that may attenuate the upregulation of the canonical Wnt pathway and lead to the

restoration of quiescent Wnt signalling observed under healthy conditions [24, 49].

Sclerostin has been demonstrated to be upregulated in VSMC, which previously transformed into osteocytic phenotype under calcifying circumstances [22, 24]. Recently, it has been suggested that increased circulating sclerostin levels might protect dialysis patients from cardiovascular calcification and that low bone-specific alkaline phosphatase activity may be the causal pathway [23, 49]. Sclerostin is a potent inhibitor of alkaline phosphatase activity, which inactivates the potent calcification inhibitor, the inorganic pyrophosphate. Accumulating data suggest that Wnt signalling pathway inhibitor overexpression in calcifying vasculature (advanced carotid plaques and calcified aortas) might be vasculoprotective and anti-calcific

PTH increases FGF-23 expression via Wnt and protein kinase (PKA) signalling pathways by

According to several authors, the overexpression of sclerostin by osteocytes in patients on haemodialysis is associated with a decrease in overall cause's mortality, including CVC, in

In the same time, more research for confirmation of sclerostin role in FGF-23-Klotho-sclerostin system as a protector of pathogenic transformation of VSMC, triggered by phosphate and FGF-23, is seen as a priority. It is likely that sclerostin confronts effects of low Klotho levels and high levels of FGF-23, allowing for some time to maintain a certain compensatory balance in the system of FGF-23-Klotho-sclerostin. Increasing levels of sclerostin in CKD are likely directed at suppression of processes of calcification, but cannot fully inhibit them, because

may be a physiological adaptation to increased calcification.

blocking the inhibitory effect of sclerostin (**Figure 2**).

[25, 49].

dialysis patients [49].

The most definitive study to date of the direct effects of Klotho on the endothelium was conducted by Kusaba et al. [16]. Klotho-deficient mice have increased VEGF-mediated calcium influx, downregulation of vascular endothelial cadherin, increased apoptosis and excessive permeability of vessels. The KL2 domain of Klotho protein binds directly to VEGF receptor 2 and endothelial transient-receptor potential Ca2+ channel 1 on the extracellular side and promotes their co-internalization, thereby reducing the Ca2+-activated and caspase-mediated destruction of catenin and vascular endothelial cadherin on the cell surface. Thus, it may be one more effect of soluble Klotho's protein cardioprotection.

In vitro studies have shown that along with the increase in phosphaturia, stabilization of GFR and regulation of vascular endothelial permeability, Klotho suppresses Na-dependent capture of phosphorus by the endothelium and vascular smooth muscle cell (VSMC) and prevents differentiation of VSMC and mineralization induced by hyperphosphatemia [5, 14].

In our study, an association of increased serum FGF-23 and low Klotho levels with the presence of inflammation (as C-reactive protein level increasing) as well as with protein-energy deficiency, and proteinuria, was found [45]. These data are in agreement with the results of other authors [44, 46] who consider CKD as a state of chronic inflammation, based on the consideration of elevated C-reactive protein level as a nonspecific marker of inflammation and endothelial dysfunction in CKD patients. Frequent coexistence triad—malnutrition, inflammation and atherosclerosis (MIA) syndrome—contributes to the risk of CVC in CKD [2, 3, 47]. The obtained data clearly indicate that circulating form of Klotho protein functions as a humoral factor that protects the cardiovascular system from the development of inflammatory endothelial changes and prevents the progression of atherosclerosis and pathological calcification [5, 14–16].

Less understood is the role of sclerostin in CV calcification processes in CKD. Our data go in agreement with the results of authors, who demonstrated a protective effect of sclerostin in calcification in CKD [22, 48, 49]. Its inhibitory effect on osteogenesis and negative association of sclerostin with level of parathyroid hormone as uremic toxin can attest in favour of this date [48, 49].

Viaene et al. [50] showed that in patients on haemodialysis, the serum concentration of sclerostin is higher than in general population. In the future, these data will be repeatedly confirmed by the results of other studies devoted to identify the role of sclerostin in patients on regular haemodialysis [23, 49].

Emerging evidence indicates that Wnt plays a role in vascular biology including vascular calcification, angiogenesis and atherosclerosis [42]. Wnt signalling occurs when the Wnt ligand binds to co-receptors, Frizzled and low-density lipoprotein receptor-related protein (LRP), which induces β-catenin translocation to the nucleus to regulate the transcription of Wnt target genes. The Wnt pathway is involved in many aspects of biology including cell survival, stem cell development and cell differentiation, including bone and vascular lineages [24, 42].

One of the most important effects of Klotho and sclerostin is its ability to inhibit Wnt signal pathway and through it to slow down vascular calcification [42]. Reduction of serum Klotho levels impairs this protective effect. Besides this, it has been demonstrated that Klotho mitigates the increased cell senescence and apoptosis triggered by oxidative stress in endothelial cells [43] and Klotho also suppresses TNF-β-induced expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, attenuates NF-kappaB activation and reverses the inhibition of eNOS phosphorylation by TNF-α. Thus Klotho protein also protects

The most definitive study to date of the direct effects of Klotho on the endothelium was conducted by Kusaba et al. [16]. Klotho-deficient mice have increased VEGF-mediated calcium influx, downregulation of vascular endothelial cadherin, increased apoptosis and excessive permeability of vessels. The KL2 domain of Klotho protein binds directly to VEGF receptor 2 and endothelial transient-receptor potential Ca2+ channel 1 on the extracellular side and promotes their co-internalization, thereby reducing the Ca2+-activated and caspase-mediated destruction of catenin and vascular endothelial cadherin on the cell surface. Thus, it may be

In vitro studies have shown that along with the increase in phosphaturia, stabilization of GFR and regulation of vascular endothelial permeability, Klotho suppresses Na-dependent capture of phosphorus by the endothelium and vascular smooth muscle cell (VSMC) and prevents differentiation of VSMC and mineralization induced by hyperphosphatemia [5, 14]. In our study, an association of increased serum FGF-23 and low Klotho levels with the presence of inflammation (as C-reactive protein level increasing) as well as with protein-energy deficiency, and proteinuria, was found [45]. These data are in agreement with the results of other authors [44, 46] who consider CKD as a state of chronic inflammation, based on the consideration of elevated C-reactive protein level as a nonspecific marker of inflammation and endothelial dysfunction in CKD patients. Frequent coexistence triad—malnutrition, inflammation and atherosclerosis (MIA) syndrome—contributes to the risk of CVC in CKD [2, 3, 47]. The obtained data clearly indicate that circulating form of Klotho protein functions as a humoral factor that protects the cardiovascular system from the development of inflammatory endothelial changes and prevents the progression of atherosclerosis and pathological calcification [5, 14–16].

Less understood is the role of sclerostin in CV calcification processes in CKD. Our data go in agreement with the results of authors, who demonstrated a protective effect of sclerostin in calcification in CKD [22, 48, 49]. Its inhibitory effect on osteogenesis and negative association of sclerostin with level of parathyroid hormone as uremic toxin can attest in favour of this

Viaene et al. [50] showed that in patients on haemodialysis, the serum concentration of sclerostin is higher than in general population. In the future, these data will be repeatedly confirmed by the results of other studies devoted to identify the role of sclerostin in patients

Emerging evidence indicates that Wnt plays a role in vascular biology including vascular calcification, angiogenesis and atherosclerosis [42]. Wnt signalling occurs when the Wnt ligand

the vascular endothelium by inhibition of endothelial inflammation [44].

one more effect of soluble Klotho's protein cardioprotection.

50 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

date [48, 49].

on regular haemodialysis [23, 49].

Register et al. [25] found that high sclerostin was associated with less calcified carotid plaque in diabetic African American men and was not associated with aortic or coronary calcification. Authors' hypothesis to explain this situation is that increased overproduction of sclerostin may be a physiological adaptation to increased calcification.

Sclerostin slows the canonical Wnt signalling pathway and inhibits osteoblast activity and bone formation by sequestering LRP5 and LRP6 [24, 42]. Retarding the Wnt signalling pathway by using a dominant-negative LRP has been depicted to significantly reduce VSMC proliferation. In addition to VSMC proliferation, animal models of intimal thickening have revealed increased β-catenin levels, which suggest the involvement of the Wnt-β-catenin pathway also in VSMC migration. Moreover, Wnt proteins are also known to promote the migration of various cell types, including monocytes and endothelial cells. Furthermore, the Wnt pathway has been described to play an important role in the regulation of endothelial inflammation, vascular calcification and mesenchymal stem cell differentiation. As a result, considering the fact that atherosclerosis and calcification are both an actively regulated and progressive process, we might speculate that high sclerostin levels might be indicative of a sort of defensive mechanism that may attenuate the upregulation of the canonical Wnt pathway and lead to the restoration of quiescent Wnt signalling observed under healthy conditions [24, 49].

Sclerostin has been demonstrated to be upregulated in VSMC, which previously transformed into osteocytic phenotype under calcifying circumstances [22, 24]. Recently, it has been suggested that increased circulating sclerostin levels might protect dialysis patients from cardiovascular calcification and that low bone-specific alkaline phosphatase activity may be the causal pathway [23, 49]. Sclerostin is a potent inhibitor of alkaline phosphatase activity, which inactivates the potent calcification inhibitor, the inorganic pyrophosphate. Accumulating data suggest that Wnt signalling pathway inhibitor overexpression in calcifying vasculature (advanced carotid plaques and calcified aortas) might be vasculoprotective and anti-calcific [25, 49].

PTH increases FGF-23 expression via Wnt and protein kinase (PKA) signalling pathways by blocking the inhibitory effect of sclerostin (**Figure 2**).

According to several authors, the overexpression of sclerostin by osteocytes in patients on haemodialysis is associated with a decrease in overall cause's mortality, including CVC, in dialysis patients [49].

In the same time, more research for confirmation of sclerostin role in FGF-23-Klotho-sclerostin system as a protector of pathogenic transformation of VSMC, triggered by phosphate and FGF-23, is seen as a priority. It is likely that sclerostin confronts effects of low Klotho levels and high levels of FGF-23, allowing for some time to maintain a certain compensatory balance in the system of FGF-23-Klotho-sclerostin. Increasing levels of sclerostin in CKD are likely directed at suppression of processes of calcification, but cannot fully inhibit them, because

hyperphosphatasemia and nutritional status disorders on the maintenance of Klotho protein

Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho...

http://dx.doi.org/10.5772/intechopen.69298

53

Since the serum FGF-23 level (as more earlier marker of MBD than PTH in CKD) rises before serum phosphorus increases as CKD advances, a preventive decrease in phosphorus diet content in CKD patients with elevated serum FGF-23 levels and the use of phosphate-binding drugs (for the control of serum phosphorus levels below 6.5 mg/dL) in CKD advancing are becoming an important therapeutic task in CKD patients. It can contribute not only in the

In our study [51], in the group of CKD 5D, patients who managed to reach and maintain the target level of serum phosphorus (0.9–1.45 mmol/L), compared to the matched group of patients with uncorrected hyperphosphatemia (>1.45 mmol/L), lower FGF-23 and PTH (*p* < 0.01 and *p* < 0.05 respectively) in serum were noted, mainly among those patients who used phosphate-binding drugs that did not contain calcium (sevelamer hydrochloride) for correc-

Among 17 patients who received low-protein diet (LPD) in combination with phosphate binders for at least 12 months before starting HD and who achieved the target level of serum phosphorus during the first year of treatment with regular HD, the formation of SGPT was

tion of elevated serum phosphorus simultaneously starting with haemodialysis treatment. In these patients, CVC such as worsening of the functional class of angina pectoris, acute coro-

In experimental studies, increased Klotho expression was accompanied by a decrease in proteinuria and a significant decrease in angiotensin II in the hypertensive chronic glomerulone-

Data on the role of the asymmetric dimethylarginine complex 17/transforming growth factor-α/endothelial growth factor (ADAM17/TGF-α/EGFR) induced both due to reninangiotensin system (RAS) activation and calcitriol deficiency, in the restructuring of the PTGs and in the decrease of Klotho expression in kidneys, allows to suggest the importance of the effective blockade of RAS by renin angiotensin blockers as well as D-hormone deficiency correction for the prevention and treatment of SGPT [55]. Our preliminary results [53, 56] confirm the experimental studies on the ability of AT II blockers to maintain the renal produc-

It has been reported that angiotensin II and aldosterone, through the initiation of oxidative stress, have the ability to low Klotho expression in rat kidneys, even in minimal concentrations, while exogenous sKlotho infusion contributed to the inversion of renal damage caused

In our study in patients with CKD stages 1–5D [56] when comparing the patients with hypertension who were receiving antihypertensive monotherapy, the highest serum levels of Klotho protein were observed in those of them whose target BP level was achieved primarily through angiotensin II receptor blockers, compared to those who were administered with another drug group or have not reached the target blood pressure level (*p* = 0.008 and *p* = 0.067 respectively).

nary syndrome and acute myocardial infarction [51] were also reliably less noted.

= 8, 2; *p* < 0.05) than among those patients who has begun correc-

synthesis and FGF-23 overproduction suppression [51–53].

prevention of SGPT but of CVC in CKD.

tion of hyperphosphatasemia.

noted significantly less (*χ*<sup>2</sup>

phritis mice [54, 55].

tion of sKlotho protein.

by angiotensin II [55].

**Figure 2.** The relationship between PTH, FGF-23 and sclerostin (materials of ISN Nexus Symposium «Bone and the Kidney» September 2012, Copenhagen, Denmark).

reduction of Klotho may be much more potent stimulus for progression of calcification, and increased PTH suppresses sclerostin. Because levels of sclerostin increase as CKD progresses and as levels of Klotho at the same time reduce, some authors may mistakenly interpret the role of sclerostin as a factor, which potentiates calcification. In reality (the results of the multivariate analysis), it is likely that dramatic fall of Klotho levels in the course of CKD outbalances and levels down protective effects of sclerostin.

To sum up, we can consider all three factors (FGF-23, Klotho, sclerostin) as a discrete system of factors influencing cardiovascular risk. Apparently, such high CV risk is determined by joint effect of all of these three factors that appear along with early CKD stages and connect not only between themselves but also with traditional factors, which snowballed quickly following added, potentiate one another as CKD advanced and thereby strongly increase the risk of CV mortality. Influence of each group of these factors may have different impacts depending on the stage of CKD. Importantly, date indeed suggests that the FGF-23-Klotho-sclerostin axis may be a potential novel target in cardio-renal medicine.

## **3. Possibilities for correction of FGF-23, soluble Klotho and sclerostin serum disorders in CKD by traditional renoprotective therapy**

The appearance preliminary results of few clinical trials indicate the possibility of influencing traditional renoprotective therapy such as early correction of arterial hypertension, anaemia, hyperphosphatasemia and nutritional status disorders on the maintenance of Klotho protein synthesis and FGF-23 overproduction suppression [51–53].

Since the serum FGF-23 level (as more earlier marker of MBD than PTH in CKD) rises before serum phosphorus increases as CKD advances, a preventive decrease in phosphorus diet content in CKD patients with elevated serum FGF-23 levels and the use of phosphate-binding drugs (for the control of serum phosphorus levels below 6.5 mg/dL) in CKD advancing are becoming an important therapeutic task in CKD patients. It can contribute not only in the prevention of SGPT but of CVC in CKD.

In our study [51], in the group of CKD 5D, patients who managed to reach and maintain the target level of serum phosphorus (0.9–1.45 mmol/L), compared to the matched group of patients with uncorrected hyperphosphatemia (>1.45 mmol/L), lower FGF-23 and PTH (*p* < 0.01 and *p* < 0.05 respectively) in serum were noted, mainly among those patients who used phosphate-binding drugs that did not contain calcium (sevelamer hydrochloride) for correction of hyperphosphatasemia.

Among 17 patients who received low-protein diet (LPD) in combination with phosphate binders for at least 12 months before starting HD and who achieved the target level of serum phosphorus during the first year of treatment with regular HD, the formation of SGPT was noted significantly less (*χ*<sup>2</sup> = 8, 2; *p* < 0.05) than among those patients who has begun correction of elevated serum phosphorus simultaneously starting with haemodialysis treatment. In these patients, CVC such as worsening of the functional class of angina pectoris, acute coronary syndrome and acute myocardial infarction [51] were also reliably less noted.

In experimental studies, increased Klotho expression was accompanied by a decrease in proteinuria and a significant decrease in angiotensin II in the hypertensive chronic glomerulonephritis mice [54, 55].

reduction of Klotho may be much more potent stimulus for progression of calcification, and increased PTH suppresses sclerostin. Because levels of sclerostin increase as CKD progresses and as levels of Klotho at the same time reduce, some authors may mistakenly interpret the role of sclerostin as a factor, which potentiates calcification. In reality (the results of the multivariate analysis), it is likely that dramatic fall of Klotho levels in the course of CKD outbal-

**Figure 2.** The relationship between PTH, FGF-23 and sclerostin (materials of ISN Nexus Symposium «Bone and the

To sum up, we can consider all three factors (FGF-23, Klotho, sclerostin) as a discrete system of factors influencing cardiovascular risk. Apparently, such high CV risk is determined by joint effect of all of these three factors that appear along with early CKD stages and connect not only between themselves but also with traditional factors, which snowballed quickly following added, potentiate one another as CKD advanced and thereby strongly increase the risk of CV mortality. Influence of each group of these factors may have different impacts depending on the stage of CKD. Importantly, date indeed suggests that the FGF-23-Klotho-sclerostin axis may be a potential novel target in cardio-renal

**3. Possibilities for correction of FGF-23, soluble Klotho and sclerostin** 

The appearance preliminary results of few clinical trials indicate the possibility of influencing traditional renoprotective therapy such as early correction of arterial hypertension, anaemia,

**serum disorders in CKD by traditional renoprotective therapy**

ances and levels down protective effects of sclerostin.

52 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Kidney» September 2012, Copenhagen, Denmark).

medicine.

Data on the role of the asymmetric dimethylarginine complex 17/transforming growth factor-α/endothelial growth factor (ADAM17/TGF-α/EGFR) induced both due to reninangiotensin system (RAS) activation and calcitriol deficiency, in the restructuring of the PTGs and in the decrease of Klotho expression in kidneys, allows to suggest the importance of the effective blockade of RAS by renin angiotensin blockers as well as D-hormone deficiency correction for the prevention and treatment of SGPT [55]. Our preliminary results [53, 56] confirm the experimental studies on the ability of AT II blockers to maintain the renal production of sKlotho protein.

It has been reported that angiotensin II and aldosterone, through the initiation of oxidative stress, have the ability to low Klotho expression in rat kidneys, even in minimal concentrations, while exogenous sKlotho infusion contributed to the inversion of renal damage caused by angiotensin II [55].

In our study in patients with CKD stages 1–5D [56] when comparing the patients with hypertension who were receiving antihypertensive monotherapy, the highest serum levels of Klotho protein were observed in those of them whose target BP level was achieved primarily through angiotensin II receptor blockers, compared to those who were administered with another drug group or have not reached the target blood pressure level (*p* = 0.008 and *p* = 0.067 respectively).

On experimental model of mice with CKD and arterial hypertension (AH), it was established that one of the mechanisms of sKlotho cardioprotection is also its ability to block the calcium channels in cardiomyocytes (TRPC6) that contributes to more adequate correction of AH and slower remodelling of the left ventricular myocardium [57].

[2]. And this very high mortality risk cannot be explained solely by influence of traditional CVD risk factors, which are highly prevalent in patients with CKD as well as by traditional CKD factors such as phosphorus and PTH, correction of which did not result to enough ben-

Disorders in the System of Mineral and Bone Metabolism Regulators—FGF-23, Klotho...

http://dx.doi.org/10.5772/intechopen.69298

55

Initial disturbances of mineral bone metabolism begin early, already with 3A stage of CKD, with an increase in serum FGF-23 and sclerostin and decrease of Klotho levels. The manifestation of these early changes may be as an increase in phosphorus excretion. From this moment, cardiovascular risk begins to be pawned, although the levels of phosphorus and

The accumulated data allow to consider the disturbances in FGF-23-Klotho-sclerostin ratio as one of the early markers of CKD advancement, disorders of mineral metabolism developing and cardiovascular prognosis. Alteration of the FGF-23/sKlotho/sclerostin ratio in serum as CKD advancement is accompanied by the development of vascular calcification, formation of cardiac remodelling and increasing risk of death from cardiovascular events, independently of the serum phosphorus and PTH levels. Changing the ratio of FGF-23, sKlotho and sclerostin can be regarded as independent early marker of cardiovascular and overall prognosis of

In the reduction of Klotho expression in the kidneys, the role of ischemia, oxidative stress, intracellular elevation of angiotensin II and inflammation was established. These changes require careful correction to maintain Klotho's production as a potent strong cardio-renopro-

The preliminary results obtained on the positive effects of hypertension and anaemia correction on sKlotho protein maintenance, as well as the possibility of the FGF-23 overproduction suppression by correcting hyperphosphatemia, demonstrate the need for a personalized approach to the choice of cardio-renoprotective therapy from the early stages of CKD based on the degree of morphogenetic proteins and sclerostin system dysfunction as well as open

prospects for studying of cardio-nephroprotective strategy in the new aspect.

This work was supported by Russian Science Foundation (grant №.14-15-00947 2014).

Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

\*Address all correspondence to: ludm.milovanova@gmail.com

Ludmila Y. Milovanova\*, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Nikolay A. Mukhin,

eficial effects on cardiovascular survival.

PTH in serum are usually normal yet.

patients with CKD.

**Acknowledgements**

**Author details**

Aigul Zh. Usubalieva

tective factor.

A number of studies have shown that hypoxia due to anaemia is an independent factor of sKlotho protein production reduction as CKD advances [5, 6, 14]. According to our data, in patients with CKD with anaemia who managed to reach the target haemoglobin with the help of epoetin and iron and maintain it in this range and, as a result, eliminating the hypoxia of vital organs, including the kidneys, the preservation of decreasing of sKlotho protein was noted [58].

According to the results of our study [52], the use of Low Protein Diet (LPD) in combination with keto/amino acids, during not less than 12 months, in patients with 3B–4 stages of CKD, can prevent the development of nutritional status disorders, as well as stimulate sKlotho expression and suppress FGF-23 production. In addition, in these group patients, impairment of vascular damping function (according to the assessment of pulse wave velocity and augmentation indices by «SphygmoCor» device) as well as cardiac (by EchoCG, semiquantitative scale) and aorta calcification (by Kauppila method), and the formation of LVH, was less common.

In addition, according to our data, in patients with CKD 3B–4 stages using of LPD (0.6 g protein per kg body weight/day) supplemented with calcium salts of keto acids, it was possible to achieve and maintain the target level of serum phosphorus and calcium by using lower doses of phosphate-binding drugs, compared with the patients who used LPD, but did not take keto/amino acids [51, 52].

Maintenance of the phosphorus and calcium target serum levels can be a factor that inhibits FGF-23 overproduction and reduces the risk of ectopic mineralization and FGF-23-dependent LVH in CKD 3B–4 stages [51].

It is known that sKlotho paracrine functions include the activation of calcium channel receptors (TRPVs), especially TRPV5 and TRPV6 [14, 59]. TRPV5 are located mainly in the distal renal tubules and participate in the reabsorption of calcium in the kidneys [14]. TRPV6 is expressed in intestinal epithelial cells, where it is involved in the intestinal calcium absorption [14, 59]. In mice with a defect in Klotho gene expression, an increase in the serum level of phosphorus and calcium was revealed [5, 14]. Taking into account the participation of sKlotho in providing the constancy of serum calcium concentration by changing its reabsorption in the kidneys and intestines, it can be assumed that as a result of the intake of calcium salts of keto acids, it is possible to stimulate sKlotho production with its effect on the prevention of transient hypercalcaemia episodes in CKD advancement.

## **4. Conclusion**

Understanding of the role of Klotho, FGF-23 and sclerostin in CKD is important, because it is known that mortality from cardiovascular complications in 20-year-old patients with terminal kidney disease is comparable with such of 80-year-old subjects in total population [2]. And this very high mortality risk cannot be explained solely by influence of traditional CVD risk factors, which are highly prevalent in patients with CKD as well as by traditional CKD factors such as phosphorus and PTH, correction of which did not result to enough beneficial effects on cardiovascular survival.

Initial disturbances of mineral bone metabolism begin early, already with 3A stage of CKD, with an increase in serum FGF-23 and sclerostin and decrease of Klotho levels. The manifestation of these early changes may be as an increase in phosphorus excretion. From this moment, cardiovascular risk begins to be pawned, although the levels of phosphorus and PTH in serum are usually normal yet.

The accumulated data allow to consider the disturbances in FGF-23-Klotho-sclerostin ratio as one of the early markers of CKD advancement, disorders of mineral metabolism developing and cardiovascular prognosis. Alteration of the FGF-23/sKlotho/sclerostin ratio in serum as CKD advancement is accompanied by the development of vascular calcification, formation of cardiac remodelling and increasing risk of death from cardiovascular events, independently of the serum phosphorus and PTH levels. Changing the ratio of FGF-23, sKlotho and sclerostin can be regarded as independent early marker of cardiovascular and overall prognosis of patients with CKD.

In the reduction of Klotho expression in the kidneys, the role of ischemia, oxidative stress, intracellular elevation of angiotensin II and inflammation was established. These changes require careful correction to maintain Klotho's production as a potent strong cardio-renoprotective factor.

The preliminary results obtained on the positive effects of hypertension and anaemia correction on sKlotho protein maintenance, as well as the possibility of the FGF-23 overproduction suppression by correcting hyperphosphatemia, demonstrate the need for a personalized approach to the choice of cardio-renoprotective therapy from the early stages of CKD based on the degree of morphogenetic proteins and sclerostin system dysfunction as well as open prospects for studying of cardio-nephroprotective strategy in the new aspect.

## **Acknowledgements**

This work was supported by Russian Science Foundation (grant №.14-15-00947 2014).

## **Author details**

On experimental model of mice with CKD and arterial hypertension (AH), it was established that one of the mechanisms of sKlotho cardioprotection is also its ability to block the calcium channels in cardiomyocytes (TRPC6) that contributes to more adequate correction of AH and

A number of studies have shown that hypoxia due to anaemia is an independent factor of sKlotho protein production reduction as CKD advances [5, 6, 14]. According to our data, in patients with CKD with anaemia who managed to reach the target haemoglobin with the help of epoetin and iron and maintain it in this range and, as a result, eliminating the hypoxia of vital organs, including the kidneys, the preservation of decreasing of sKlotho protein was noted [58]. According to the results of our study [52], the use of Low Protein Diet (LPD) in combination with keto/amino acids, during not less than 12 months, in patients with 3B–4 stages of CKD, can prevent the development of nutritional status disorders, as well as stimulate sKlotho expression and suppress FGF-23 production. In addition, in these group patients, impairment of vascular damping function (according to the assessment of pulse wave velocity and augmentation indices by «SphygmoCor» device) as well as cardiac (by EchoCG, semiquantitative scale) and aorta calcification (by Kauppila method), and the formation of LVH, was

In addition, according to our data, in patients with CKD 3B–4 stages using of LPD (0.6 g protein per kg body weight/day) supplemented with calcium salts of keto acids, it was possible to achieve and maintain the target level of serum phosphorus and calcium by using lower doses of phosphate-binding drugs, compared with the patients who used LPD, but did not

Maintenance of the phosphorus and calcium target serum levels can be a factor that inhibits FGF-23 overproduction and reduces the risk of ectopic mineralization and FGF-23-dependent

It is known that sKlotho paracrine functions include the activation of calcium channel receptors (TRPVs), especially TRPV5 and TRPV6 [14, 59]. TRPV5 are located mainly in the distal renal tubules and participate in the reabsorption of calcium in the kidneys [14]. TRPV6 is expressed in intestinal epithelial cells, where it is involved in the intestinal calcium absorption [14, 59]. In mice with a defect in Klotho gene expression, an increase in the serum level of phosphorus and calcium was revealed [5, 14]. Taking into account the participation of sKlotho in providing the constancy of serum calcium concentration by changing its reabsorption in the kidneys and intestines, it can be assumed that as a result of the intake of calcium salts of keto acids, it is possible to stimulate sKlotho production with its effect on the prevention of

Understanding of the role of Klotho, FGF-23 and sclerostin in CKD is important, because it is known that mortality from cardiovascular complications in 20-year-old patients with terminal kidney disease is comparable with such of 80-year-old subjects in total population

slower remodelling of the left ventricular myocardium [57].

54 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

less common.

take keto/amino acids [51, 52].

LVH in CKD 3B–4 stages [51].

**4. Conclusion**

transient hypercalcaemia episodes in CKD advancement.

Ludmila Y. Milovanova\*, Victor V. Fomin, Lidia V. Lysenko (Kozlovskaya), Nikolay A. Mukhin, Svetlana Y. Milovanova, Marina V. Taranova, Yuriy S. Milovanov, Vasiliy V. Kozlov and Aigul Zh. Usubalieva

\*Address all correspondence to: ludm.milovanova@gmail.com

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

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[47] KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3 (Suppl.1 ) KDIGO-CKD-MBD 2009Work Group. KDIGO clinical practice guideline for the diagnosis, evolution, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney

[48] Milovanova LYu, Milovanov YuS, Kudryavtseva DV, et al. Role of the morphogenetic proteins FGF-23 and Klotho and the glycoprotein sclerostin in the assessment of the risk of cardiovascular diseases and the prognosis of chronic kidney disease. Terapevticheskii

Arkhiv. 2015;**87**(6):10-16. DOI: https://www.ncbi.nlm.nih.gov/pubmed/26281189 [49] Drechsler C, Evenepoel P, Vervloet MG. High levels of circulating sclerostin are associated with better cardiovascular survival in incident dialysis patients: Results from the NECOSAD study. Nephrology, Dialysis, Transplantation. 2015;**30**(2):288-293. DOI:

[50] Viaene L, Behets G, Claes K, et al. Sclerostin: Another bone-related protein related to all-cause mortality in hemodialysis? Nephrology, Dialysis, Transplantation.

[51] Mukhin NA, Milovanov YS, Kozlovskaya LV, et al. The serum level of the morphogenetic protein fibroblast growth factor 23 (FGF-23) as a marker for the efficiency of hyperphosphatemia therapy with phosphate-binding agents in chronic kidney disease. Terapevticheskii Arkhiv. 2016;**88**(4):41-45. DOI: https://www.ncbi.nlm.nih.gov/

[52] Milovanova LY, Dobrosmislov IA, Milovanov YS. Influence of essential amino acids ketoanalogs and protein restriction to phosphoric-calcium metabolism regulators production—morphogenetic proteins (FGF-23 and Klotho) in CKD patients 3B-4 stages.

Nephrology. 2016;**20**(2):15-20. DOI: http://nefr.elpub.ru/jour/article/view/170/171

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[41] Takeshita K, Fujimori T, Kurotaki Y, et al. Sinoatrial node dysfunction and early unexpected death of mice with a defect of klotho gene expression. Circulation. 2004;**109**(14):1776-1782. DOI: 10.1161/01.CIR.0000124224.48962

[27] Brandenburg VM, Floege J. Adynamic bone disease—bone and beyond. NDT Plus.

[28] Seiler S. Associations of FGF-23 and Klotho with cardiovascular outcomes among patients with CKD stage 2-4. Clinical Journal of the American Society of Nephrology.

[29] Gutiérrez OM, Januzzi JL, Isakova T, et al. Fibroblast growth factor-23 and left ventricular hypertrophy in chronic kidney disease Circulation 2009;**119**(19):2545-2552. DOI:

[30] Yilmaz MI, Sonmez A, Saglam M, et al. FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney International. 2010;**78**:679-685. DOI:

[31] Gutierrez O, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among hemodialysis patients. New England Journal of Medicine. 2008;**359**:584-592.

[32] Kardami E. Fibroblast growth factor 2 isoforms and cardiac hypertrophy. Cardiovascular Research. 2004;**63**(3):458-466. DOI: https://doi.org/10.1016/j.cardiores.2004.04.024 [33] Di Marco GS, Reuter S, Kentrup D, et al. Treatment of established left ventricular hypertrophy with fibroblast growth factor receptor blockade in an animal model of CKD.

[34] Milovanova LY, Kozlovskaya LV, Milovanova SY, et al. Associations of fibroblast growth factor 23, soluble Klotho, troponin I in CKD patients. International Research Journal.

[35] Majd A, Mirza I, Hansen T, et al. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol. Dial. Transplant. 2009;**24**(10):3125-3131.

[36] Coen G, Ballanti P, Silvestrini G, et al. Immunohistochemical localization and mRNA expression of matrix Gla-protein and fetuin-A in bone biopsies of hemodialysis patients.

[37] Gutiérrez OM, Mannstadt M, Isakova T, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. New England Journal of Medicine.

[38] Fliser D, Kollerits B, Neyer U, et al. Fibroblast growth factor 23 (FGF-23) predicts progression of chronic kidney disease. The Mild to Moderate Kidney Disease (MMKD) study. Journal of the American Society of Nephrology. 2007;**18**(9):2601-2608. DOI:

[39] Kuczera P, Adamczak M, Wiecek A. Fibroblast growth factor-23—A potential uremic

[40] Ichikawa S, Imel EA, Kreiter ML, et al. A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. Journal of Clinical Investigation 2007;

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[53] Milovanova LY, Kozlovscaya LV, Milovanova SY, et al. Influence of traditional cardionephroprotective therapy on cardiovascular risk markers (FGF-23, Klotho) in patients with chronic kidney disease. International Research Journal. 2016;**7**(38 part 5):39-41. DOI: 10.18454/IRJ.2227-6017

**Chapter 3**

**Provisional chapter**

**Mechanisms and Clinical Implications of Vascular**

**Mechanisms and Clinical Implications of Vascular** 

DOI: 10.5772/intechopen.72717

Chronic kidney disease (CKD), a major public health problem that affects up to 10–13% of the general population worldwide, imposes considerable socio-economic burden due to both the need for renal replacement therapy and, even more important, the negative influence on the overall patients' health status. Cardiovascular (CV) diseases are the main cause of death in CKD patients and are triggered not only by the traditional CV risk factors but also by specific, uremia-related, factors. Among these, calcium-phosphate and bone metabolism disorders play a central role. Abnormalities of mineral metabolism occur early, evolve silently as the kidney function deteriorates, and are associated with CV morbidity and mortality, mainly by the development of valvular and vascular calcifications. This chapter aims to summarize the recent knowledge on the types and mechanisms of arterial calcifications, as well as their clinical implications, in the setting of CKD. The issue is significant for both nephrologists and cardiologists and could be an example of the requirement for interdisciplinary collaboration in the medical practice.

**Keywords:** atherosclerosis and arteriosclerosis, arterial stiffness, calcifications,

cardiovascular morbidity, chronic kidney disease

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

The prevalence of chronic kidney disease (CKD) is constantly growing [1] largely due to the shift in age distribution of the population toward individuals older than 60 years, in which CKD is more common, accounted for by the combined effect of physiologic decline in glomerular filtration rate (GFR) and systemic atherosclerosis, and also due to increasing prevalence of arterial hypertension, diabetes mellitus, and obesity, all risk factors for CKD. Notably, the mortality of CKD patients is higher than their non-CKD counterparts, predominantly with respect to cardiovascular mortality. Abnormalities of arterial and left ventricular functions,

**Calcifications in Chronic Kidney Disease**

**Calcifications in Chronic Kidney Disease**

Cristina Capusa and Daria Popescu

Cristina Capusa and Daria Popescu

http://dx.doi.org/10.5772/intechopen.72717

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter


**Provisional chapter**

## **Mechanisms and Clinical Implications of Vascular Calcifications in Chronic Kidney Disease Calcifications in Chronic Kidney Disease**

**Mechanisms and Clinical Implications of Vascular** 

DOI: 10.5772/intechopen.72717

Cristina Capusa and Daria Popescu Cristina Capusa and Daria Popescu

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72717

#### **Abstract**

[53] Milovanova LY, Kozlovscaya LV, Milovanova SY, et al. Influence of traditional cardionephroprotective therapy on cardiovascular risk markers (FGF-23, Klotho) in patients with chronic kidney disease. International Research Journal. 2016;**7**(38 part 5):39-41.

[54] Maltese G, Karalliedde J. The putative role of the antiageing protein klotho in cardiovascular and renal disease. International Journal of Hypertension. 2012;**12**:5. DOI:

[55] Yoon HE, Ghee JY, Piao S, et al. Angiotensin II blockage upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrology, Dialysis, Transplantation. 2011;**26**:800-813. DOI: https://doi.

[56] Milovanova LY, Mukhin NA, Kozlovskaya LV, et al. Decreased serum levels of Klotho protein in CKD patients: Clinical importance. Annals of the Russian Academy of Medical

[57] Xie J, Cha S-K, An S-W, et al. Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nature Communications. 2012;**3**:1238-1242. DOI:

[58] Milovanov YS, Mukhin NA, Kozlovskaya LV, et al. Impact of anemia correction on the production of the circulating morphogenetic protein α-Klotho in patients with Stages 3B—4 chronic kidney disease: A new direction of cardionephroprotection.

[59] Cha SK, Ortega B, Kurosu H, et al. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1. Proceedings of the National Academy of Science of the United States of America. 2008;**105**:9805-9810. DOI:

Terapevticheskii Arkhiv. 2016;**88**(6):21-25. DOI: 10.17116/terarkh201688621-25

Science. 2016;**71**(4):288-296. DOI: 10.15690/vramn581

DOI: 10.18454/IRJ.2227-6017

60 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

10.1155/2012/757469

org/10.1093/ndt/gfq537

10.1038/ncomms2240

10.1073/pnas.0803223105

Chronic kidney disease (CKD), a major public health problem that affects up to 10–13% of the general population worldwide, imposes considerable socio-economic burden due to both the need for renal replacement therapy and, even more important, the negative influence on the overall patients' health status. Cardiovascular (CV) diseases are the main cause of death in CKD patients and are triggered not only by the traditional CV risk factors but also by specific, uremia-related, factors. Among these, calcium-phosphate and bone metabolism disorders play a central role. Abnormalities of mineral metabolism occur early, evolve silently as the kidney function deteriorates, and are associated with CV morbidity and mortality, mainly by the development of valvular and vascular calcifications. This chapter aims to summarize the recent knowledge on the types and mechanisms of arterial calcifications, as well as their clinical implications, in the setting of CKD. The issue is significant for both nephrologists and cardiologists and could be an example of the requirement for interdisciplinary collaboration in the medical practice.

**Keywords:** atherosclerosis and arteriosclerosis, arterial stiffness, calcifications, cardiovascular morbidity, chronic kidney disease

## **1. Introduction**

The prevalence of chronic kidney disease (CKD) is constantly growing [1] largely due to the shift in age distribution of the population toward individuals older than 60 years, in which CKD is more common, accounted for by the combined effect of physiologic decline in glomerular filtration rate (GFR) and systemic atherosclerosis, and also due to increasing prevalence of arterial hypertension, diabetes mellitus, and obesity, all risk factors for CKD. Notably, the mortality of CKD patients is higher than their non-CKD counterparts, predominantly with respect to cardiovascular mortality. Abnormalities of arterial and left ventricular functions,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

such as arterial stiffness, atherosclerosis and arteriosclerosis, left ventricular hypertrophy, and systolic and end-diastolic stiffness, which are common in CKD patients, were incriminated [2]. The pathophysiology of cardiovascular disease (CVD) in CKD is complex, with both traditional and uremia-related risk factors being involved. Among the latter, calcium-phosphate metabolism anomalies are more and more debated, and the concept of chronic kidney diseasemineral and bone disorder (CKD-MBD) has been adopted. It is a broad term that refers to a systemic disorder of mineral metabolism due to the kidneys' failure to maintain homeostasis of calcium (Ca), phosphate (PO4 ), and active vitamin D, which leads to maladaptive alterations in related hormones, namely fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH), and results in defective bone architecture and extraskeletal calcifications [3, 4]. CKD-MBD occurs early in the course of CKD, progresses as kidney function declines, and it is manifested by three separate, but interrelated, components that are not necessarily present concurrently in all patients, any combination of these component being possible [4]:

Mönckeberg's sclerosis, and it has radiographically been described as "railroad tracks" on the peripheral arteries of upper and lower limbs [6, 8]. This type of calcification is related to non-traditional risk factors such as hyperphosphatemia, excess PTH, and cytokines of chronic inflammation (**Table 1**), and it is more prevalent in patients with CKD and diabetes [6]. The vessel lumen is reduced concentrically due to amorphous mineral that forms circumferentially along or within one or more elastic lamellae of the media [7]. It induces arterial stiffness, which contributes to increased pulse pressure and, consequently, to left

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63

ventricular hypertrophy and altered coronary perfusion [9, 10].

**Figure 1.** Main types of arterial calcifications and their consequences. VSMCs, vascular smooth muscle cells.

Arterial hypertension Hyperphosphatemia, high calcium-phosphate product

Anemia

**Table 1.** Risk factors for vascular calcification in chronic kidney disease patients (modified from Román-García et al. [5]).

Metabolic abnormalities: hypoalbuminemia, hyperhomocysteinemia

Decrease of calcification inhibitors (Fetuin-A)

**Traditional risk factors Non-traditional (CKD-related) risk factors**

Dyslipidemia Hyper- or hypoparathyroidism

Smoking Chronic inflammation

Old age Oxidative stress

Family history of premature coronary heart

CKD: chronic kidney disease.

disease

Diabetes mellitus High dosage of vitamin D metabolites


The vascular calcifications at least partially account for increased cardiovascular (CV) risk in CKD patients, so it is worth to draw attention on the mechanisms involved in their development.

## **2. Types and characteristics of vascular calcification in chronic kidney disease**

Even at early ages, CKD patients develop vascular calcifications at all the levels (large vessel arteries such as the aorta, medium arteries like the coronary arteries, as well as small-caliber arteries of the skin), in a much greater proportion than the general population, and the prevalence and severity of arterial and valvular calcifications increase as kidney function decreases [5].

The main types of arterial calcifications, both commonly seen in CKD, are distinguished by their location in the structure of the arterial wall (**Figure 1**) and their association with atherosclerotic plaque formation:


Mönckeberg's sclerosis, and it has radiographically been described as "railroad tracks" on the peripheral arteries of upper and lower limbs [6, 8]. This type of calcification is related to non-traditional risk factors such as hyperphosphatemia, excess PTH, and cytokines of chronic inflammation (**Table 1**), and it is more prevalent in patients with CKD and diabetes [6]. The vessel lumen is reduced concentrically due to amorphous mineral that forms circumferentially along or within one or more elastic lamellae of the media [7]. It induces arterial stiffness, which contributes to increased pulse pressure and, consequently, to left ventricular hypertrophy and altered coronary perfusion [9, 10].

such as arterial stiffness, atherosclerosis and arteriosclerosis, left ventricular hypertrophy, and systolic and end-diastolic stiffness, which are common in CKD patients, were incriminated [2]. The pathophysiology of cardiovascular disease (CVD) in CKD is complex, with both traditional and uremia-related risk factors being involved. Among the latter, calcium-phosphate metabolism anomalies are more and more debated, and the concept of chronic kidney diseasemineral and bone disorder (CKD-MBD) has been adopted. It is a broad term that refers to a systemic disorder of mineral metabolism due to the kidneys' failure to maintain homeostasis

tions in related hormones, namely fibroblast growth factor-23 (FGF23) and parathyroid hormone (PTH), and results in defective bone architecture and extraskeletal calcifications [3, 4]. CKD-MBD occurs early in the course of CKD, progresses as kidney function declines, and it is manifested by three separate, but interrelated, components that are not necessarily present

**2.** Bone abnormalities regarding turnover, mineralization, volume, linear growth, or strength;

The vascular calcifications at least partially account for increased cardiovascular (CV) risk in CKD patients, so it is worth to draw attention on the mechanisms involved in their development.

Even at early ages, CKD patients develop vascular calcifications at all the levels (large vessel arteries such as the aorta, medium arteries like the coronary arteries, as well as small-caliber arteries of the skin), in a much greater proportion than the general population, and the prevalence and severity of arterial and valvular calcifications increase as kidney function decreases [5]. The main types of arterial calcifications, both commonly seen in CKD, are distinguished by their location in the structure of the arterial wall (**Figure 1**) and their association with athero-

**1.** *Atherosclerosis* consists in the calcification of the intimal layer in association with cellular necrosis, inflammation, atherosclerotic plaques, and lipid deposition [6]. This type of calcification is related to traditional risk factors such as arterial hypertension and dyslipidemia (**Table 1**). The vessel lumen is eccentrically reduced and deformed due to patchy calcification of the atherosclerotic plaques [7]. It produces arterial stenosis which accounts for tissular ischemia and infarction and may predispose to plaque rupture generating life-threatening thrombi. **2.** *Arteriosclerosis*, which represents the calcification of the medial layer, occurs in the elastic lamina of large-caliber and medium- to small-size arteries. It seems to be independent of atherosclerosis, although both can coexist [6, 7]. Medial calcification was known initially as

concurrently in all patients, any combination of these component being possible [4]:

phatase—ALP), which reflect mineral and hormonal abnormalities;

**2. Types and characteristics of vascular calcification in chronic** 

**3.** Soft tissue (vascular, valvular, and periarticular) calcifications.

), and active vitamin D, which leads to maladaptive altera-

, vitamin D, PTH, FGF23, and alkaline phos-

of calcium (Ca), phosphate (PO4

and

**kidney disease**

sclerotic plaque formation:

**1.** Changes in biochemistry profile (Ca, PO<sup>4</sup>

62 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**Figure 1.** Main types of arterial calcifications and their consequences. VSMCs, vascular smooth muscle cells.


**Table 1.** Risk factors for vascular calcification in chronic kidney disease patients (modified from Román-García et al. [5]).

These two types of calcifications encountered in CKD also vary based on their localization on the arterial tree. Intimal calcifications are found more proximally, while medial ones have a predilection for distal sites [10].

The balance among promoters and inhibitors of calcification plays the key role during miner-

Mechanisms and Clinical Implications of Vascular Calcifications in Chronic Kidney Disease

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65

The main known inhibitor molecules involved in both bone and extra-osseous sites calcifica-

**Figure 2.** Regulating molecules of the mineralization/calcification processes. RANKL, receptor activator of nuclear

**1.** *Matrix GLA protein* (MGP, matrix γ-carboxyglutamate protein), an extracellular protein has roles in normal bone formation as well as inhibition of vascular calcification [15, 16]. The inactive MGP (desphospho-uncarboxylated MGP, dp-ucMGP) needs two subsequent modifications (serine phosphorylation and glutamate carboxylation) in order to exert its function [17]. Circulating levels of dp-uc MGP are considered a biomarker associated with cardiovascular risk and mortality, severity of the vascular damage, and all-cause mortality [17]. MGP is able to bind calcium and hydroxyapatite, thanks to its vitamin K-dependent γ-carboxylation, inhibiting their precipitation and mineralization [16]. MGP synthesis has been detected in cartilage, lung, heart, kidney, arteries, and calcified atherosclerotic plaques attesting to MGP's role in inhibition of soft tissue calcifications [18]. In addition, recent works suggested a link between MGP and renal microvasculature, and argued in favor of a possible renoprotective action of activated MGP and, consequently, emphasized

**2.** *Osteoprotegerin* (OPG) is a soluble cytokine and tumor necrosis factor (TNF) receptor-like molecule that acts as an inhibitor of osteoclast differentiation by binding the receptor activator of nuclear factor κB-ligand (RANKL), thus blocking RANKL-mediated activation of osteoclasts [11, 19]. OPG is present in many human tissues: bone (osteoblasts), vessels (endothelial and vascular smooth muscle cells), lung, heart, liver, kidney, hypothalamus, lymphoid organs and B-cells, bone marrow, articular chondrocytes, and breasts [19, 20]. Its expression in bone is regulated by osteoblasts through the same pathway that regulates bone formation, indicating RANKL/OPG ratio is a major determinant of bone mass and OPG has an osteoprotective role [21]. However, its functions in the vascular system are still a matter of debate. While experimental studies sustain an anti-calcification role (due to

the importance of having adequate vitamin K stores [17].

alization (**Figure 2**).

tion, are:

factor-kB ligand; (+), stimulation; (−), inhibition.

Etiologically, vascular calcifications may be categorized as metastatic calcifications, those which arise from systemically high calcium and phosphate product, or dystrophic calcifications, which take place under pathologic conditions of cell death or apoptosis [9]. *Metastatic calcifications* occur when the calcium-phosphate product exceeds its solubility in serum resulting in its deposition in healthy, extraskeletal tissue such as the arterial wall, the viscera, the conjunctiva, articulations, or tumors [8]. In contrast, *dystrophic calcifications* result from the de novo deposition of calcium and phosphate in diseased or damaged tissue. This occurs when cells die as a result of direct injury or apoptosis and release their intracellular calcium contents which can serve as a foundation for further calcium deposition [8].

## **3. Pathogenesis of vascular calcifications in chronic kidney disease**

## **3.1. Overview on the molecular basis of mineralization and vascular calcifications**

Although not yet entirely elucidated, the process of vascular calcification was extensively studied and the bulk of its steps were unveiled. The common feature to almost all physiologic mineralization mechanisms, either inside the bone or in extra-osseous tissues, involves matrix vesicles, which form the nidus for hydroxyapatite crystals nucleation [11]. These matrix vesicles are membrane-bound particles of 20–200 nm where mineral crystals are arranged by interaction with specific regulators, like membrane transporters and enzymes, with crucial roles in the influx of calcium and phosphate ions into the vesicles [9]. For example, tissue nonspecific alkaline phosphatase hydrolyzes pyrophosphate and generates inorganic phosphate, which is further transported through the vesicle membrane by the sodium-phosphate cotransporter type III [12]. On the other hand, annexins function as ion channels and provide a way for calcium to enter inside the matrix vesicle, where the accumulation of both divalent ions induces crystalline nucleation [9, 12].

In the bone, matrix vesicles bud off from the plasma membrane of chondrocytes or osteoblasts, at the epiphyseal plate of growing bone and are released into the premineralized organic matrix where they serve as a vehicle for the interaction of calcium and phosphate ions to form hydroxyapatite and initiate mineralization of the organic substance [11]. Hydroxyapatite crystals that are released from vesicles serve as templates for subsequent crystal formation, creating the lattice of the bone [9, 13]. Therefore, matrix vesicles have an osteogenic role.

Growing body of evidence supports significant resemblance between bone and vascular calcifications, leading to the belief that ectopic calcifications and normal osteogenesis are driven alike. Indeed, many cellular and molecular signaling processes are identical in vascular calcification and osteogenesis. Among these, matrix vesicle release and expression of mineralizationregulating proteins by vascular smooth muscle cells (VSMCs) are seen in the vessel wall [14]. Consequently, vascular calcification is also considered a regulated biomineralization process.

The balance among promoters and inhibitors of calcification plays the key role during mineralization (**Figure 2**).

These two types of calcifications encountered in CKD also vary based on their localization on the arterial tree. Intimal calcifications are found more proximally, while medial ones have a

Etiologically, vascular calcifications may be categorized as metastatic calcifications, those which arise from systemically high calcium and phosphate product, or dystrophic calcifications, which take place under pathologic conditions of cell death or apoptosis [9]. *Metastatic calcifications* occur when the calcium-phosphate product exceeds its solubility in serum resulting in its deposition in healthy, extraskeletal tissue such as the arterial wall, the viscera, the conjunctiva, articulations, or tumors [8]. In contrast, *dystrophic calcifications* result from the de novo deposition of calcium and phosphate in diseased or damaged tissue. This occurs when cells die as a result of direct injury or apoptosis and release their intracellular calcium contents

which can serve as a foundation for further calcium deposition [8].

**3. Pathogenesis of vascular calcifications in chronic kidney disease**

**3.1. Overview on the molecular basis of mineralization and vascular calcifications**

Although not yet entirely elucidated, the process of vascular calcification was extensively studied and the bulk of its steps were unveiled. The common feature to almost all physiologic mineralization mechanisms, either inside the bone or in extra-osseous tissues, involves matrix vesicles, which form the nidus for hydroxyapatite crystals nucleation [11]. These matrix vesicles are membrane-bound particles of 20–200 nm where mineral crystals are arranged by interaction with specific regulators, like membrane transporters and enzymes, with crucial roles in the influx of calcium and phosphate ions into the vesicles [9]. For example, tissue nonspecific alkaline phosphatase hydrolyzes pyrophosphate and generates inorganic phosphate, which is further transported through the vesicle membrane by the sodium-phosphate cotransporter type III [12]. On the other hand, annexins function as ion channels and provide a way for calcium to enter inside the matrix vesicle, where the accumulation of both divalent

In the bone, matrix vesicles bud off from the plasma membrane of chondrocytes or osteoblasts, at the epiphyseal plate of growing bone and are released into the premineralized organic matrix where they serve as a vehicle for the interaction of calcium and phosphate ions to form hydroxyapatite and initiate mineralization of the organic substance [11]. Hydroxyapatite crystals that are released from vesicles serve as templates for subsequent crystal formation, creating the lattice of the bone [9, 13]. Therefore, matrix vesicles have an

Growing body of evidence supports significant resemblance between bone and vascular calcifications, leading to the belief that ectopic calcifications and normal osteogenesis are driven alike. Indeed, many cellular and molecular signaling processes are identical in vascular calcification and osteogenesis. Among these, matrix vesicle release and expression of mineralizationregulating proteins by vascular smooth muscle cells (VSMCs) are seen in the vessel wall [14]. Consequently, vascular calcification is also considered a regulated biomineralization process.

predilection for distal sites [10].

64 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

ions induces crystalline nucleation [9, 12].

osteogenic role.

**Figure 2.** Regulating molecules of the mineralization/calcification processes. RANKL, receptor activator of nuclear factor-kB ligand; (+), stimulation; (−), inhibition.

The main known inhibitor molecules involved in both bone and extra-osseous sites calcification, are:


inhibition of apoptotic passive calcification and the alkaline phosphatase-mediated osteogenic differentiation of vascular cells), elevated serum levels of OPG were found in various cardiovascular diseases and were hypothesized as a promoter of atherosclerosis progression [19]. Osteoprotegerin expression was significantly lower and RANKL was identified in calcified valves of human aortic stenosis, indicating that in the absence of inhibition by OPG, RANKL may promote matrix calcification and induce the expression of osteoblastassociated genes (bone alkaline phosphatase and osteocalcin) [22].

as a scaffold for the interaction of nucleic acids and regulatory factors that are involved in the expression of a number of downstream proteins essential for osteoblastic differentiation,

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**3.** *Type I collagen* makes up over 90% of the organic component of bone where it forms the framework necessary for mineralization [13, 31]. It was shown that ex vivo cells grown on type I collagen were found to mineralize three times faster and incorporate two times more calcium than cells grown in plastic media. Moreover, rapidly mineralizing cells generate a matrix that contains three times the amount of collagen type I and fibronectin but 70% less collagen type IV than their non-mineralizing counterparts. These findings indicate a regulatory role of the matrix composition on arterial calcification development [31].

**4.** *Osteocalcin* is a protein secreted by active osteoblasts into the extracellular matrix where it binds hydroxyapatite via 3 γ-carboxylated glutamic acid residues during bone mineraliza-

**5.** *Osteopontin*, also known as secreted phosphoprotein 1 or bone sialoprotein 1, is an extracellular structural component of bone (of the non-collagenous organic bone matrix) and an important modulator of bone mineralization, which can either promote or inhibit hydroxyapatite formation, depending on its post-translational modifications [11, 15]. Non-phosphorylated osteopontin shows a stimulatory effect on calcification, while phosphorylation of osteopontin converts it into a potent inhibitor of ectopic calcifications, proportional to the number of phosphorylated sites [33]. Overexpression of osteopontin was found in human atherosclerotic plaques, in calcified smooth muscle cells, in medial layers of arteries of diabetic patient, and calcified heart valves, suggesting it intervenes in the

In conclusion, mineralization and calcification processes are tightly regulated through the complex interactions of various tissular and circulating molecules, many of which suffer profound

Vascular calcifications in CKD patients are thought to arise due to disruptions in the balance between promoters and inhibitors of calcification, leading to osteoblastic transformation of vascular smooth muscle cells (VSMCs) [5, 35]. Because VSMCs and osteoblasts derive from a similar mesenchymal cell precursor, VSMCs can be induced to differentiate along osteoblastic lines. The process involves an increase in calcification promoters, decrease in calcification inhibitors, and formation of calcification vesicles culminating with the induction of a cellular

Concerning *promoters of calcification*, it is recognized that the osteoblastic differentiation, which is the initial step in vascular calcification, is revealed by the expression of pro-calcification factors such as Cbfa1 and BMP on vascular cells [13, 15]. In vitro experiments showed that changes in serum composition like those that occurred in the course of CKD may upregulate expression of Cbfa1, while in vivo studies found higher expression of Cbfa1 in both the

tion. For this reason, it is often used as a marker for bone formation [32].

such as type I collagen, osteocalcin, and osteopontin [13].

development of ectopic calcifications [34].

**3.2. How does chronic kidney disease favor vascular calcifications?**

*3.2.1. Imbalance between pro- and counter-calcification factors*

phenotypic change from VSMCs to osteoblast-like cells [5].

changes in chronic kidney disease.


Other main factors with essential contribution to the processes of mineralization and calcification are those involved in the signaling pathways, like:


as a scaffold for the interaction of nucleic acids and regulatory factors that are involved in the expression of a number of downstream proteins essential for osteoblastic differentiation, such as type I collagen, osteocalcin, and osteopontin [13].


In conclusion, mineralization and calcification processes are tightly regulated through the complex interactions of various tissular and circulating molecules, many of which suffer profound changes in chronic kidney disease.

## **3.2. How does chronic kidney disease favor vascular calcifications?**

## *3.2.1. Imbalance between pro- and counter-calcification factors*

inhibition of apoptotic passive calcification and the alkaline phosphatase-mediated osteogenic differentiation of vascular cells), elevated serum levels of OPG were found in various cardiovascular diseases and were hypothesized as a promoter of atherosclerosis progression [19]. Osteoprotegerin expression was significantly lower and RANKL was identified in calcified valves of human aortic stenosis, indicating that in the absence of inhibition by OPG, RANKL may promote matrix calcification and induce the expression of osteoblast-

**3.** *Extracellular pyrophosphate* (PPi) is a small molecule made of two phosphate ions linked by an ester bond, which regulates cell differentiation and serves as an essential physiologic inhibitor of calcification by negatively interfering with hydroxyapatite formation and crystal growth [11]. PPi is produced from the hydrolyses of extracellular adenosine-5′-triphosphate by the enzyme ectonucleotide pyrophosphatase/phosphodiesterase [23]. On the other hand, alkaline phosphatase (ALP) catalyzes the hydrolysis of phospho-monoesters (including

alization inhibitor, thus ensuring normal bone mineralization [11, 24]. However, through this action, ALP also acts as a powerful inducer of vascular calcification partially as a result

**4.** *Fetuin-A*, a circulating glycoprotein from the cystatin superfamily of proteins, produced by the liver, functions as a potent inhibitor of de novo hydroxyapatite formation from supersaturated mineral solutions, and it also acts as a negative acute phase reactant, thus being downregulated in acute and chronic systemic inflammation [25–27]. In experimental and clinical studies, it was shown that serum containing fetuin-A inhibited precipitation of calcium salts in a dose-dependent manner, and its serum concentrations were inversely correlated to C-reactive protein, calcifications, and cardiovascular and all-cause mortality, even when the serum calcium-phosphate product was close to the normal range [26, 28]. Hence, it was assumed that a major link between low fetuin-A levels and mortality consists

Other main factors with essential contribution to the processes of mineralization and calcifica-

**1.** *Bone morphogenetic proteins* (BMPs) are cytokines with multiple functions, which modulate gene expression through phosphorylation of regulatory Smad transcription factors [16, 27]. Smad6 and Smad7 proteins act as negative regulators and thus are crucial to limit the osteogenic vascular response induced by BMPs [27]. For example, BMP 2—a protein that belongs to the transforming growth factor-β (TGF-β) superfamily of cell regulatory proteins—is involved in both osteogenic and chondrogenic differentiation of multipotent mesenchymal progenitors and drives the formation of cartilage and bone [29]. It also participates in vascular calcification probably through inducing osteoblastic differentiation of VSMCs. Conversely, BMP 7, primarily expressed in the kidney where it is required for the normal development of the organ, was found to restore the bone anabolic balance, reduce

**2.** *Core-binding factor alpha 1* (Cbfa1), also known as runt-related transcription factor 2 (Runx2), is a nuclear protein essential for osteoblastic development and skeletal morphogenesis, and it is believed to be the switch that turns a mesenchymal cell into an osteoblast [11, 13, 30]. It acts

) in order to avoid accumulation of this miner-

associated genes (bone alkaline phosphatase and osteocalcin) [22].

PPi) with release of inorganic phosphate (Pi

66 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

of promoting accelerated cardiovascular calcification [26].

serum phosphate levels, and reduce vascular calcification [27].

tion are those involved in the signaling pathways, like:

of increased PPi degradation [23].

Vascular calcifications in CKD patients are thought to arise due to disruptions in the balance between promoters and inhibitors of calcification, leading to osteoblastic transformation of vascular smooth muscle cells (VSMCs) [5, 35]. Because VSMCs and osteoblasts derive from a similar mesenchymal cell precursor, VSMCs can be induced to differentiate along osteoblastic lines. The process involves an increase in calcification promoters, decrease in calcification inhibitors, and formation of calcification vesicles culminating with the induction of a cellular phenotypic change from VSMCs to osteoblast-like cells [5].

Concerning *promoters of calcification*, it is recognized that the osteoblastic differentiation, which is the initial step in vascular calcification, is revealed by the expression of pro-calcification factors such as Cbfa1 and BMP on vascular cells [13, 15]. In vitro experiments showed that changes in serum composition like those that occurred in the course of CKD may upregulate expression of Cbfa1, while in vivo studies found higher expression of Cbfa1 in both the media and intima of calcified arteries compared to non-calcified arteries of the same patients, thus emphasizing the important role of Cbfa1 in vascular calcifications [5, 36]. In addition, since positive immunostaining for bone matrix proteins (like osteonectin, osteopontin, bone sialoprotein, alkaline phosphatase, and type I collagen) were more common than overt calcifications but were proportional with their extent, it appears that the deposition of these proteins precedes calcification [36]. Another modulator of calcification—osteocalcin—has been detected in VSMCs where it may potentially regulate their glucose utilization, promoting a phenotypic change in these cells [32]. Furthermore, an inverse correlation between osteopontin plasma levels and glomerular filtration rate (GFR) was reported, suggesting that reduced renal excretion due to impaired kidney function may lead to increased circulating levels [37]. Increased osteopontin and other promoters of calcification in CKD can be accounted for by different mechanisms also. For example, in experimental settings, high concentrations of phosphorus, uremic serum, oxidized lipids, cytokines, and high glucose (abnormalities commonly seen in CKD patients as well) were able to stimulate the VSMCs and vascular pericytes to produce bone-forming transcription factors and proteins [36]. Taken together, these findings suggest that biochemical changes that occur during the progression of CKD (hyperphosphatemia, hypercalcemia, accumulating uremic toxins, cytokines, oxidized lipoproteins, and advanced glycation end products) tip the balance in favor of promoters of vascular calcification.

but treatment with calcium salts and vitamin D derivatives can induce a positive calcium balance or even overt hypercalcemia [30]. In this context, it is possible that in patients with advanced kidney disease, calcium that is absorbed from the gastrointestinal tract cannot be excreted by the failing kidneys nor can it be deposited in bones with altered turnover (either high or low turnover is detrimental) and is therefore deposited at extra-osseous sites, such as the vascular bed [5, 6]. Calcium changes in the external milieu have a direct effect on the nearby cells. Normally, VSMCs recognize these changes via the membrane such as calcium sensing receptor (CaR) and a G-protein-coupled receptor, which was shown to be downregulated in calcified arteries from CKD patients, suggesting that calcium sensing is disrupted in these patients [6, 40]. In response to elevated extracellular calcium, VSMCs release calciumladen vesicles, as an attempt to prevent intracellular calcium overload. When the vesicles do not contain enough calcification inhibitors (as in CKD), this adaptive response in fact promotes extracellular matrix calcification by serving as a site of origin for propagated calcification [35]. Besides calcium, *hyperphosphatemia* that is so common in advanced CKD, has emerged as a major culprit of vascular calcifications [41]. Increased serum levels of phosphate induce osteoblastic transformation of VSMCs, while the decrease of phosphatemia reduces the expression of proteins responsible for active bone mineral deposition in vascular cells [15, 35]. As suggested by in vitro studies, phenotypic transformation of VSMCs in response to hyperphosphatemia is mediated by Pit-1 (a type III sodium-phosphate cotransporter), which allow the influx of phosphate into VSMCs and predisposes the cells to undergo mineralization. It was observed that the first step of vascular calcification requires an increased uptake of calcium

Mechanisms and Clinical Implications of Vascular Calcifications in Chronic Kidney Disease

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69

In addition to sodium-phosphate cotransport, alkaline phosphatase is necessary for the uptake of phosphorus into the cell and the subsequent induction of osteopontin. Moreover, VSMCs treated with pooled uremic sera from CKD patients also increased expression of osteopontin and mineral deposition, suggesting that uremic serum plays a role in vascular calcifications [43]. Clinical data also support the link between elevated phosphate and vascular calcifications. For example, in a population-based cohort without CKD, serum phosphate levels at the upper end of normal range were associated with aortic valve sclerosis and mitral annular calcification, independent of PTH or calcium values [44]. Moreover, each 1 mg/dL increase in serum phosphate appears to predict higher risk for de novo coronary artery calcification (CAC) over time, with an impact similar to traditional cardiovascular risk factors, in relatively healthy subjects [45]. As in general population, phosphate serum concentration correlated with a greater risk of ectopic calcification in patients with moderate CKD (stage 3), as each 1 mg/dL increase in phosphatemia, even within normal laboratory ranges, was associated with a 21, 33, 25, and 62% higher prevalence of coronary and thoracic arteries, aortic and mitral valves calcifications, respectively [46]. Furthermore, in the presence of increased phosphate, even modest increases in calcium can substantially exacerbate calcification, by inducing nucleation of basic calcium-phosphate and, consequently, the growth of nascent vesicles that are released from both viable and apoptotic VSMCs [47]. The dominant role of phosphate is further supported by experimental studies which showed that dietary phosphate restriction in FGF23-null mice (an animal model characterized by hyperphosphatemia, markedly elevated circulating calcitriol levels, extensive vascular calcifications, and early mortality) yielded complete resolution of ectopic calcifications, a

result which was not obtained with the vitamin D-deficient diet [48].

and phosphate by the VSMCs [42].

On the other hand, abnormalities of *calcification inhibitors* can also contribute to the pathogenesis of vascular calcifications in CKD. For example, lower levels of matrix Gla protein were associated with decreased kidney function, probably because metabolic abnormalities due to CKD, such as vitamin D deficiency, may suppress MGP production. Alternatively, MGP may be lost from circulation as it binds to hydroxyapatite crystals in vascular calcifications. Regardless of the mechanism, reduced plasma MGP has been suggested as a marker for the presence and severity of vascular calcifications in patients with CKD [38]. Also, lower levels of circulating fetuin-A were described in CKD and were associated with coronary artery calcification, valvular calcifications, and increased mortality in dialysis patients [36].

These changes in the levels of both promoters and inhibitors of vascular calcification, that occur in CKD patients, ultimately culminate in the *transdifferentiation of VSMCs to an osteoblast phenotype* through an active, cell-mediated, osteogenic process, with the release of calcium matrix vesicles that can nucleate hydroxyapatite and form the first nidus for calcification [11, 30]. The process is driven by upregulation of bone-forming transcription factors and proteins on VSMCs, such as Cbfa1 and bone morphogenetic protein 2, which control the expression of osteogenic proteins (osteocalcin, osteonectin, alkaline phosphatase, collagen type I, and bone sialoprotein). Exposure to high levels of calcium, phosphate, cytokines, and so on, along with the deficit of calcification inhibitors (such as fetuin-A, matrix Gla protein, pyrophosphate) are required for the cells' phenotypic switch [39]. The transformed cells deposit collagen and non-collagenous proteins in the arterial wall and incorporate calcium and phosphorus into matrix vesicles to initiate mineralization and crystal growth. The overall positive calcium and phosphorus balance from CKD patients supports both the cellular transformation and the generation of matrix vesicles [36].

#### *3.2.2. Mineral metabolism abnormalities and vascular calcifications*

*Elevated calcium levels* have long been implicated in the vascular calcifications observed in CKD patients. Early on, these patients are usually hypocalcemic as a result of calcitriol deficiency, but treatment with calcium salts and vitamin D derivatives can induce a positive calcium balance or even overt hypercalcemia [30]. In this context, it is possible that in patients with advanced kidney disease, calcium that is absorbed from the gastrointestinal tract cannot be excreted by the failing kidneys nor can it be deposited in bones with altered turnover (either high or low turnover is detrimental) and is therefore deposited at extra-osseous sites, such as the vascular bed [5, 6]. Calcium changes in the external milieu have a direct effect on the nearby cells. Normally, VSMCs recognize these changes via the membrane such as calcium sensing receptor (CaR) and a G-protein-coupled receptor, which was shown to be downregulated in calcified arteries from CKD patients, suggesting that calcium sensing is disrupted in these patients [6, 40]. In response to elevated extracellular calcium, VSMCs release calciumladen vesicles, as an attempt to prevent intracellular calcium overload. When the vesicles do not contain enough calcification inhibitors (as in CKD), this adaptive response in fact promotes extracellular matrix calcification by serving as a site of origin for propagated calcification [35].

media and intima of calcified arteries compared to non-calcified arteries of the same patients, thus emphasizing the important role of Cbfa1 in vascular calcifications [5, 36]. In addition, since positive immunostaining for bone matrix proteins (like osteonectin, osteopontin, bone sialoprotein, alkaline phosphatase, and type I collagen) were more common than overt calcifications but were proportional with their extent, it appears that the deposition of these proteins precedes calcification [36]. Another modulator of calcification—osteocalcin—has been detected in VSMCs where it may potentially regulate their glucose utilization, promoting a phenotypic change in these cells [32]. Furthermore, an inverse correlation between osteopontin plasma levels and glomerular filtration rate (GFR) was reported, suggesting that reduced renal excretion due to impaired kidney function may lead to increased circulating levels [37]. Increased osteopontin and other promoters of calcification in CKD can be accounted for by different mechanisms also. For example, in experimental settings, high concentrations of phosphorus, uremic serum, oxidized lipids, cytokines, and high glucose (abnormalities commonly seen in CKD patients as well) were able to stimulate the VSMCs and vascular pericytes to produce bone-forming transcription factors and proteins [36]. Taken together, these findings suggest that biochemical changes that occur during the progression of CKD (hyperphosphatemia, hypercalcemia, accumulating uremic toxins, cytokines, oxidized lipoproteins, and advanced

68 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

glycation end products) tip the balance in favor of promoters of vascular calcification.

cification, valvular calcifications, and increased mortality in dialysis patients [36].

*3.2.2. Mineral metabolism abnormalities and vascular calcifications*

On the other hand, abnormalities of *calcification inhibitors* can also contribute to the pathogenesis of vascular calcifications in CKD. For example, lower levels of matrix Gla protein were associated with decreased kidney function, probably because metabolic abnormalities due to CKD, such as vitamin D deficiency, may suppress MGP production. Alternatively, MGP may be lost from circulation as it binds to hydroxyapatite crystals in vascular calcifications. Regardless of the mechanism, reduced plasma MGP has been suggested as a marker for the presence and severity of vascular calcifications in patients with CKD [38]. Also, lower levels of circulating fetuin-A were described in CKD and were associated with coronary artery cal-

These changes in the levels of both promoters and inhibitors of vascular calcification, that occur in CKD patients, ultimately culminate in the *transdifferentiation of VSMCs to an osteoblast phenotype* through an active, cell-mediated, osteogenic process, with the release of calcium matrix vesicles that can nucleate hydroxyapatite and form the first nidus for calcification [11, 30]. The process is driven by upregulation of bone-forming transcription factors and proteins on VSMCs, such as Cbfa1 and bone morphogenetic protein 2, which control the expression of osteogenic proteins (osteocalcin, osteonectin, alkaline phosphatase, collagen type I, and bone sialoprotein). Exposure to high levels of calcium, phosphate, cytokines, and so on, along with the deficit of calcification inhibitors (such as fetuin-A, matrix Gla protein, pyrophosphate) are required for the cells' phenotypic switch [39]. The transformed cells deposit collagen and non-collagenous proteins in the arterial wall and incorporate calcium and phosphorus into matrix vesicles to initiate mineralization and crystal growth. The overall positive calcium and phosphorus balance from CKD patients supports both the cellular transformation and the generation of matrix vesicles [36].

*Elevated calcium levels* have long been implicated in the vascular calcifications observed in CKD patients. Early on, these patients are usually hypocalcemic as a result of calcitriol deficiency, Besides calcium, *hyperphosphatemia* that is so common in advanced CKD, has emerged as a major culprit of vascular calcifications [41]. Increased serum levels of phosphate induce osteoblastic transformation of VSMCs, while the decrease of phosphatemia reduces the expression of proteins responsible for active bone mineral deposition in vascular cells [15, 35]. As suggested by in vitro studies, phenotypic transformation of VSMCs in response to hyperphosphatemia is mediated by Pit-1 (a type III sodium-phosphate cotransporter), which allow the influx of phosphate into VSMCs and predisposes the cells to undergo mineralization. It was observed that the first step of vascular calcification requires an increased uptake of calcium and phosphate by the VSMCs [42].

In addition to sodium-phosphate cotransport, alkaline phosphatase is necessary for the uptake of phosphorus into the cell and the subsequent induction of osteopontin. Moreover, VSMCs treated with pooled uremic sera from CKD patients also increased expression of osteopontin and mineral deposition, suggesting that uremic serum plays a role in vascular calcifications [43].

Clinical data also support the link between elevated phosphate and vascular calcifications. For example, in a population-based cohort without CKD, serum phosphate levels at the upper end of normal range were associated with aortic valve sclerosis and mitral annular calcification, independent of PTH or calcium values [44]. Moreover, each 1 mg/dL increase in serum phosphate appears to predict higher risk for de novo coronary artery calcification (CAC) over time, with an impact similar to traditional cardiovascular risk factors, in relatively healthy subjects [45]. As in general population, phosphate serum concentration correlated with a greater risk of ectopic calcification in patients with moderate CKD (stage 3), as each 1 mg/dL increase in phosphatemia, even within normal laboratory ranges, was associated with a 21, 33, 25, and 62% higher prevalence of coronary and thoracic arteries, aortic and mitral valves calcifications, respectively [46].

Furthermore, in the presence of increased phosphate, even modest increases in calcium can substantially exacerbate calcification, by inducing nucleation of basic calcium-phosphate and, consequently, the growth of nascent vesicles that are released from both viable and apoptotic VSMCs [47]. The dominant role of phosphate is further supported by experimental studies which showed that dietary phosphate restriction in FGF23-null mice (an animal model characterized by hyperphosphatemia, markedly elevated circulating calcitriol levels, extensive vascular calcifications, and early mortality) yielded complete resolution of ectopic calcifications, a result which was not obtained with the vitamin D-deficient diet [48].

The relationship between *vitamin D* and vascular calcification appears to follow a biphasic doseresponse curve, with adverse effects associated with very high and very low calcidiol levels [49]. At certain levels, vitamin D promotes bone formation by increasing the expression of critical matrix proteins in osteoblasts, leading to the incorporation of calcium into bone, thus taking it away from the vasculature. In addition, vitamin D may also prevent vascular calcifications through modulation of inflammatory responses [50]. Indeed, in dialysis patients, serum levels of calcidiol were inversely correlated with the extent of coronary calcifications [51], and clinical observations revealed that vitamin D receptor agonists were associated with decreased deposition of calcium, improved therapeutic outcomes, and survival benefits, independent of baseline levels of calcium, phosphate, parathyroid hormone, measured comorbidities, and kidney function [6, 15, 52].

The relationships of *Fibroblast growth factor 23* (FGF23) and its receptor—*Klotho*—with calcifications were also investigated, but conflicting results were reported. Some authors found an association of increased FGF23 with carotid artery calcification in stages 3 and 4 CKD patients [61], and with abdominal aortic calcifications in hemodialysis patients [62], while others observed contrary findings [63]. To date, it is not clear whether FGF23 can directly act on vascular cells to promote or inhibit matrix calcification. It is possible that the involvement of FGF23 in vascular calcification would be only indirect, through the related calcium-phosphate metabolism disturbances [64]. Alternatively, since FGF23 needs Klotho as mandatory co-receptor and Klotho (which controls the dedifferentiation of VSMCs by blocking the expression sodium-phosphate cotransporters) decreases from the early stages of CKD, the ability of FGF23 to interact with vascular cells is consequently altered [64, 65]. Despite the fact that experimental data are congruent to suggest that the effect of Klotho is protective against vascular calcifications, it still remains unknown whether or not Klotho is expressed in the vessel wall [64]. Thus, no definitive conclusions regarding the direct effects of FGF23 or Klotho on VSMCs functions can be drawn based on the current state

Mechanisms and Clinical Implications of Vascular Calcifications in Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.72717

71

**4. Clinical consequences of vascular calcifications in chronic kidney** 

Observational studies point to cardiovascular disease (CVD) as the leading cause of morbidity and mortality in CKD patients. The annual 2014 report of the United States Renal Data System estimates that, in patients with CKD, the prevalence of CVD is 69.8% compared to 34.8% in patients without renal disease, and these numbers increase with decline in kidney function [66]. In fact, the risk of any cardiovascular (CV) event seems to increase as estimated glomerular filtration rate (eGFR) decreases, ranging from a 43% increase in risk with an estimated GFR

The burden of CVD in patients with CKD is, at least in part, accounted for by the presence of non-traditional risk factors, which are much more prevalent in this group. Among these, mineral metabolism abnormalities and vascular calcifications are commonly seen. For example, Russo et al. reported that 40% of patients with stage 3 CKD had coronary artery calcification compared with only 13% of the control subjects with no renal impairment [68]. Similar data were found in our own experience: a cross-sectional, unicentric study that enrolled 110 stable CKD patients not on renal replacement therapy, and 34 age- and gender-matched patients without CKD showed higher prevalence of coronary artery disease (defined as past myocardial infarction, angor pectoris associated with electrocardiographic or ultrasound indices, coronary angioplasty or bypass) in CKD (49% vs. 19%, *p* = 0.001). In addition, more CKD patients than Controls had valvular (38% vs. 17%, *p* = 0.02), and vascular calcification (carotid plaques 60% vs. 29%, *p* = 0.02 and abdominal aorta calcifications 54% vs. 26%, *p* = 0.003), irrespective of the

to a 600% increase in cardiovascular (CV) risk at an estimated GFR of

of knowledge.

of 45–59 mL/min/1.73 m<sup>2</sup>

CKD stage [69].

less than 15 mL/min/1.73 m<sup>2</sup>

[67].

**disease**

However, vitamin D excess was associated with medial calcification and arterial stiffness [49]. Indeed, high doses of vitamin D may actually increase the risk of vascular calcification in CKD owing to its effects on increasing intestinal calcium and phosphate absorption, as well as the mobilization of these minerals from bone, leading to hypercalcemia and hyperphosphatemia, especially in patients already taking calcium-based phosphate binders [13, 50, 52]. Besides its indirect effects due to interactions with the other major factors involved in osteoblastic transformation of VSMCs, vitamin D appears to directly induce the phenotypic switch through the vitamin D receptors on VSMCs resulting in upregulation of proteins involved in calcium transport and mineralization such as osteopontin and osteocalcin [35, 53].

Taken together, these data suggest that excess calcitriol can promote vascular calcifications through several interrelated mechanisms, while moderate physiological or pharmacological doses are beneficial (by suppressing the expression of osteoblastic genes in VSMCs). Debate also exists concerning the potential differential effects and benefits of native vitamin D as compared to active vitamin D receptor agonists, with an assumption that early administration of nutritional supplementation in CKD patients may prevent vascular calcification [54]. However, this remains to be proven by future research.

*Secondary hyperparathyroidism* may also be involved, indirectly, in the osteoblastic transformation of VSMCs since its excessive action on bone resorption results in hypercalcemia and hyperphosphatemia [55]. Also, arterial hypertension which may result from persistently increased parathyroid hormone (PTH), through the stimulation of renin-angiotensinaldosterone and sympathetic nervous systems, is another indirect pathway to endothelial dysfunction and arterial calcification [56]. Despite these pathogenetic links, the exact contribution of PTH on vascular calcification is not known yet. In various clinical trials, therapies directed to decrease PTH (parathyroidectomy and calcimimetics) provided discordant results on prevention or regression of vascular calcifications [57–59]. Moreover, both hyperparathyroidism (which induce high bone turnover and activation of osteoclasts with calcium and phosphorus release into the circulation) and suppressed PTH (which induce adynamic bone disease with low bone turnover and reduce uptake of calcium and phosphate into the bone) were associated with extensive arterial calcifications [60]. Consequently, it was hypothesized that parathyroid hormone does not exert a direct intervention in the pathogenesis of vascular calcification in CKD, so its exact role on this matter remains to be elucidated.

The relationships of *Fibroblast growth factor 23* (FGF23) and its receptor—*Klotho*—with calcifications were also investigated, but conflicting results were reported. Some authors found an association of increased FGF23 with carotid artery calcification in stages 3 and 4 CKD patients [61], and with abdominal aortic calcifications in hemodialysis patients [62], while others observed contrary findings [63]. To date, it is not clear whether FGF23 can directly act on vascular cells to promote or inhibit matrix calcification. It is possible that the involvement of FGF23 in vascular calcification would be only indirect, through the related calcium-phosphate metabolism disturbances [64]. Alternatively, since FGF23 needs Klotho as mandatory co-receptor and Klotho (which controls the dedifferentiation of VSMCs by blocking the expression sodium-phosphate cotransporters) decreases from the early stages of CKD, the ability of FGF23 to interact with vascular cells is consequently altered [64, 65]. Despite the fact that experimental data are congruent to suggest that the effect of Klotho is protective against vascular calcifications, it still remains unknown whether or not Klotho is expressed in the vessel wall [64]. Thus, no definitive conclusions regarding the direct effects of FGF23 or Klotho on VSMCs functions can be drawn based on the current state of knowledge.

The relationship between *vitamin D* and vascular calcification appears to follow a biphasic doseresponse curve, with adverse effects associated with very high and very low calcidiol levels [49]. At certain levels, vitamin D promotes bone formation by increasing the expression of critical matrix proteins in osteoblasts, leading to the incorporation of calcium into bone, thus taking it away from the vasculature. In addition, vitamin D may also prevent vascular calcifications through modulation of inflammatory responses [50]. Indeed, in dialysis patients, serum levels of calcidiol were inversely correlated with the extent of coronary calcifications [51], and clinical observations revealed that vitamin D receptor agonists were associated with decreased deposition of calcium, improved therapeutic outcomes, and survival benefits, independent of baseline levels of calcium, phosphate, parathyroid hormone, measured comorbidities, and kidney function [6, 15, 52].

70 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

However, vitamin D excess was associated with medial calcification and arterial stiffness [49]. Indeed, high doses of vitamin D may actually increase the risk of vascular calcification in CKD owing to its effects on increasing intestinal calcium and phosphate absorption, as well as the mobilization of these minerals from bone, leading to hypercalcemia and hyperphosphatemia, especially in patients already taking calcium-based phosphate binders [13, 50, 52]. Besides its indirect effects due to interactions with the other major factors involved in osteoblastic transformation of VSMCs, vitamin D appears to directly induce the phenotypic switch through the vitamin D receptors on VSMCs resulting in upregulation of proteins involved in

Taken together, these data suggest that excess calcitriol can promote vascular calcifications through several interrelated mechanisms, while moderate physiological or pharmacological doses are beneficial (by suppressing the expression of osteoblastic genes in VSMCs). Debate also exists concerning the potential differential effects and benefits of native vitamin D as compared to active vitamin D receptor agonists, with an assumption that early administration of nutritional supplementation in CKD patients may prevent vascular calcification [54]. However, this

*Secondary hyperparathyroidism* may also be involved, indirectly, in the osteoblastic transformation of VSMCs since its excessive action on bone resorption results in hypercalcemia and hyperphosphatemia [55]. Also, arterial hypertension which may result from persistently increased parathyroid hormone (PTH), through the stimulation of renin-angiotensinaldosterone and sympathetic nervous systems, is another indirect pathway to endothelial dysfunction and arterial calcification [56]. Despite these pathogenetic links, the exact contribution of PTH on vascular calcification is not known yet. In various clinical trials, therapies directed to decrease PTH (parathyroidectomy and calcimimetics) provided discordant results on prevention or regression of vascular calcifications [57–59]. Moreover, both hyperparathyroidism (which induce high bone turnover and activation of osteoclasts with calcium and phosphorus release into the circulation) and suppressed PTH (which induce adynamic bone disease with low bone turnover and reduce uptake of calcium and phosphate into the bone) were associated with extensive arterial calcifications [60]. Consequently, it was hypothesized that parathyroid hormone does not exert a direct intervention in the pathogenesis of vascular calcification in CKD, so its exact role on this matter remains to be elucidated.

calcium transport and mineralization such as osteopontin and osteocalcin [35, 53].

remains to be proven by future research.

## **4. Clinical consequences of vascular calcifications in chronic kidney disease**

Observational studies point to cardiovascular disease (CVD) as the leading cause of morbidity and mortality in CKD patients. The annual 2014 report of the United States Renal Data System estimates that, in patients with CKD, the prevalence of CVD is 69.8% compared to 34.8% in patients without renal disease, and these numbers increase with decline in kidney function [66]. In fact, the risk of any cardiovascular (CV) event seems to increase as estimated glomerular filtration rate (eGFR) decreases, ranging from a 43% increase in risk with an estimated GFR of 45–59 mL/min/1.73 m<sup>2</sup> to a 600% increase in cardiovascular (CV) risk at an estimated GFR of less than 15 mL/min/1.73 m<sup>2</sup> [67].

The burden of CVD in patients with CKD is, at least in part, accounted for by the presence of non-traditional risk factors, which are much more prevalent in this group. Among these, mineral metabolism abnormalities and vascular calcifications are commonly seen. For example, Russo et al. reported that 40% of patients with stage 3 CKD had coronary artery calcification compared with only 13% of the control subjects with no renal impairment [68]. Similar data were found in our own experience: a cross-sectional, unicentric study that enrolled 110 stable CKD patients not on renal replacement therapy, and 34 age- and gender-matched patients without CKD showed higher prevalence of coronary artery disease (defined as past myocardial infarction, angor pectoris associated with electrocardiographic or ultrasound indices, coronary angioplasty or bypass) in CKD (49% vs. 19%, *p* = 0.001). In addition, more CKD patients than Controls had valvular (38% vs. 17%, *p* = 0.02), and vascular calcification (carotid plaques 60% vs. 29%, *p* = 0.02 and abdominal aorta calcifications 54% vs. 26%, *p* = 0.003), irrespective of the CKD stage [69].

#### **4.1. Arterial stiffness**

Clinical consequences of vascular calcifications in CKD include loss of arterial elasticity with resultant rise in arterial stiffness due to reduced compliance of large arteries, lower delivery of oxygen to the tissues, and endothelial dysfunction. Arterial stiffness represents the functional disturbance of vascular calcification and predominantly results from greater medial calcification. The main consequence of arterial stiffness is increased pulse pressure, which contributes to left ventricular hypertrophy and impaired coronary perfusion by increasing ventricular afterload and reducing coronary blood flow during diastole [70]. In response to higher pressure or flow, the arterial wall undergoes a remodeling process, which consists of either reorganization of cellular and noncellular elements (eutrophic remodeling) or increased muscle mass (hypertrophic remodeling), both with significant impact on altered arterial function, that is, the reduced ability to buffer pressure, and pulsatile flow oscillations [71].

to central hemodynamic parameters. Thus, it was found that calcium channel blockers but not beta-blockers, lower the central pulse pressure [77], so the presence of arterial stiffness could

Mechanisms and Clinical Implications of Vascular Calcifications in Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.72717

73

Atherosclerotic lesions, which refer to intimal deposition of material with consecutive occlusive consequences, are highly prevalent in CKD patients mainly due to traditional CV risk factors. Specific features of atherosclerosis in chronic kidney disease comprise a higher proportion of calcified plaques among atherosclerotic plaques and a greater intervention of inflammatory stimuli than in general population [71]. Atherosclerosis represents one link between serum calcium and CVD with the content of coronary artery calcium emerging as a predictor of coronary heart disease [78]. Indeed, Budoff et al. showed a graded relationship between decreased kidney function in CKD patients and higher coronary artery calcification scores [79], connecting calcium and kidney function with the development of cardiovascular disease, in

Even in the general population, lower level of kidney function was associated with increased 5-year probability of atherosclerotic cardiovascular disease [80]. Many studies found an inverse association between the glomerular filtration rate and the risk of occurrence or progression of atherosclerosis. For example, a cross-sectional retrospective study on almost 450 subjects with moderate to severe CKD (eGFR below 60 mL/min) and acute coronary syndrome suggested that estimated kidney function is an independent risk factor for atherosclerotic multivessel cardiovascular disease, as the decreased eGFR independently predicted a three-vessel coronary stenosis, with a magnitude dependent on the severity of renal impairment. The risk was seven times higher in patients with CKD stages 4–5 than in those with stage 1 CKD [81]. However, it should be mentioned that a significant proportion of cardiovascular death among CKD patients is not strictly related to atherosclerosis (i.e., it is not due to myocardial infarction, stroke, and heart failure), as the main event is sudden cardiac death which has a multifactorial

Atherosclerotic lesions are usually accompanied by impairment of the endothelium. Endothelial function is often abnormal in CKD patients, who have diminished endothelium-dependent dilatation compared with controls and increased von Willebrand factor, regardless of the stage of renal disease and coexisting risk factors, suggesting that atherosclerosis may develop early in the progression of chronic kidney disease [83]. Besides common factors like age, hypertension, diabetes, smoking, dyslipidemia, and atherosclerosis, endothelial dysfunction is also accounted for by retention of uremic toxins, fluid overload, anemia, phosphate load, increased FGF23, increased homocysteine, enhanced oxidative stress, impaired nitric oxide metabolism (accumulation of asymmetrical dimethyl l-arginine), accumulation of advanced glycation end

Vascular calcifications of the large arteries, like abdominal aorta (assessed by the lumbar aortic calcification score—ACS) is not only a predictor of the cardiovascular morbidity and mortality, but it could also provide an indirect estimation of the intrarenal vascular status, as we

products, proinflammatory cytokines, and impaired angiogenesis [84].

impact the choice of blood-pressure-lowering medication in CKD patients.

**4.2. Atherosclerotic cardiovascular disease**

particular ischemic heart disease.

causation [82].

Aortic pulse wave velocity, an accurate and reproducible parameter of arterial stiffness and a marker of cardiovascular dysfunction, is linked to several other CV risk factors such as microalbuminuria and proteinuria, vascular calcifications, and left ventricular hypertrophy [72]. Wang and coworkers, in a study on 102 non-dialysis CKD patients, found an inverse relation between pulse wave velocity and estimated glomerular filtration rate, with a significant stepwise increase in pulse wave corresponding to the advance in CKD from stage 1 to 5 [73], suggesting that arterial stiffness increases with decreased kidney function. Contrary to this result, but in line with others which did not detect independent associations between eGFR and aortic stiffness [74, 75], in a cross-sectional, single-center study on 135 stable patients (79% with CKD), we found increased cardio-ankle vascular index (CAVI, a stiffness marker less influenced by blood pressure than pulse wave velocity) in 73% subjects, irrespective of chronic kidney disease presence and severity [76].

It is largely accepted that arterial stiffness is a powerful independent predictor of mortality and CVD in advanced CKD, as well as in general population [70].

More debatable is the influence of arterial stiffness on kidney function. In theory, besides the effects on myocardium, the decreased compliance of the large arteries would be followed by the transmission of cyclic blood flow from the aorta to peripheral microcirculations in various organs (including the kidneys) because its transformation in the physiological continuous capillary flow fails. Consequently, the protective autoregulatory mechanisms of the glomerular microcirculation are overpassed, and renal tissue becomes more vulnerable to the high blood pressure–related damage, favoring the decline in glomerular filtration [71]. Despite these pathogenetic explanations, clinical studies yielded conflicting results, as mentioned earlier. The majority of large population-based studies (adult or elderly cohorts) seem to support an independent association of aortic stiffness (measured by carotid-femoral pulse wave velocity) with the risk of incident CKD, but not with the risk of CKD progression (even if, the latter is not a unanimously reported result) [71].

The presence of arterial stiffness in CKD patients is important also from the therapeutic point of view, since numerous trials investigating the efficacy of anti-hypertensive drugs in cardiologic cohorts showed significant differences among various therapeutic regimens with regard to central hemodynamic parameters. Thus, it was found that calcium channel blockers but not beta-blockers, lower the central pulse pressure [77], so the presence of arterial stiffness could impact the choice of blood-pressure-lowering medication in CKD patients.

## **4.2. Atherosclerotic cardiovascular disease**

**4.1. Arterial stiffness**

72 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

kidney disease presence and severity [76].

is not a unanimously reported result) [71].

and CVD in advanced CKD, as well as in general population [70].

Clinical consequences of vascular calcifications in CKD include loss of arterial elasticity with resultant rise in arterial stiffness due to reduced compliance of large arteries, lower delivery of oxygen to the tissues, and endothelial dysfunction. Arterial stiffness represents the functional disturbance of vascular calcification and predominantly results from greater medial calcification. The main consequence of arterial stiffness is increased pulse pressure, which contributes to left ventricular hypertrophy and impaired coronary perfusion by increasing ventricular afterload and reducing coronary blood flow during diastole [70]. In response to higher pressure or flow, the arterial wall undergoes a remodeling process, which consists of either reorganization of cellular and noncellular elements (eutrophic remodeling) or increased muscle mass (hypertrophic remodeling), both with significant impact on altered arterial function,

Aortic pulse wave velocity, an accurate and reproducible parameter of arterial stiffness and a marker of cardiovascular dysfunction, is linked to several other CV risk factors such as microalbuminuria and proteinuria, vascular calcifications, and left ventricular hypertrophy [72]. Wang and coworkers, in a study on 102 non-dialysis CKD patients, found an inverse relation between pulse wave velocity and estimated glomerular filtration rate, with a significant stepwise increase in pulse wave corresponding to the advance in CKD from stage 1 to 5 [73], suggesting that arterial stiffness increases with decreased kidney function. Contrary to this result, but in line with others which did not detect independent associations between eGFR and aortic stiffness [74, 75], in a cross-sectional, single-center study on 135 stable patients (79% with CKD), we found increased cardio-ankle vascular index (CAVI, a stiffness marker less influenced by blood pressure than pulse wave velocity) in 73% subjects, irrespective of chronic

It is largely accepted that arterial stiffness is a powerful independent predictor of mortality

More debatable is the influence of arterial stiffness on kidney function. In theory, besides the effects on myocardium, the decreased compliance of the large arteries would be followed by the transmission of cyclic blood flow from the aorta to peripheral microcirculations in various organs (including the kidneys) because its transformation in the physiological continuous capillary flow fails. Consequently, the protective autoregulatory mechanisms of the glomerular microcirculation are overpassed, and renal tissue becomes more vulnerable to the high blood pressure–related damage, favoring the decline in glomerular filtration [71]. Despite these pathogenetic explanations, clinical studies yielded conflicting results, as mentioned earlier. The majority of large population-based studies (adult or elderly cohorts) seem to support an independent association of aortic stiffness (measured by carotid-femoral pulse wave velocity) with the risk of incident CKD, but not with the risk of CKD progression (even if, the latter

The presence of arterial stiffness in CKD patients is important also from the therapeutic point of view, since numerous trials investigating the efficacy of anti-hypertensive drugs in cardiologic cohorts showed significant differences among various therapeutic regimens with regard

that is, the reduced ability to buffer pressure, and pulsatile flow oscillations [71].

Atherosclerotic lesions, which refer to intimal deposition of material with consecutive occlusive consequences, are highly prevalent in CKD patients mainly due to traditional CV risk factors. Specific features of atherosclerosis in chronic kidney disease comprise a higher proportion of calcified plaques among atherosclerotic plaques and a greater intervention of inflammatory stimuli than in general population [71]. Atherosclerosis represents one link between serum calcium and CVD with the content of coronary artery calcium emerging as a predictor of coronary heart disease [78]. Indeed, Budoff et al. showed a graded relationship between decreased kidney function in CKD patients and higher coronary artery calcification scores [79], connecting calcium and kidney function with the development of cardiovascular disease, in particular ischemic heart disease.

Even in the general population, lower level of kidney function was associated with increased 5-year probability of atherosclerotic cardiovascular disease [80]. Many studies found an inverse association between the glomerular filtration rate and the risk of occurrence or progression of atherosclerosis. For example, a cross-sectional retrospective study on almost 450 subjects with moderate to severe CKD (eGFR below 60 mL/min) and acute coronary syndrome suggested that estimated kidney function is an independent risk factor for atherosclerotic multivessel cardiovascular disease, as the decreased eGFR independently predicted a three-vessel coronary stenosis, with a magnitude dependent on the severity of renal impairment. The risk was seven times higher in patients with CKD stages 4–5 than in those with stage 1 CKD [81].

However, it should be mentioned that a significant proportion of cardiovascular death among CKD patients is not strictly related to atherosclerosis (i.e., it is not due to myocardial infarction, stroke, and heart failure), as the main event is sudden cardiac death which has a multifactorial causation [82].

Atherosclerotic lesions are usually accompanied by impairment of the endothelium. Endothelial function is often abnormal in CKD patients, who have diminished endothelium-dependent dilatation compared with controls and increased von Willebrand factor, regardless of the stage of renal disease and coexisting risk factors, suggesting that atherosclerosis may develop early in the progression of chronic kidney disease [83]. Besides common factors like age, hypertension, diabetes, smoking, dyslipidemia, and atherosclerosis, endothelial dysfunction is also accounted for by retention of uremic toxins, fluid overload, anemia, phosphate load, increased FGF23, increased homocysteine, enhanced oxidative stress, impaired nitric oxide metabolism (accumulation of asymmetrical dimethyl l-arginine), accumulation of advanced glycation end products, proinflammatory cytokines, and impaired angiogenesis [84].

Vascular calcifications of the large arteries, like abdominal aorta (assessed by the lumbar aortic calcification score—ACS) is not only a predictor of the cardiovascular morbidity and mortality, but it could also provide an indirect estimation of the intrarenal vascular status, as we found in a cross-sectional study that enrolled 77 stages 2–5 non-dialysis CKD patients, older than 50 years, and with known atherosclerotic disease. This study described increased aortic calcification as eGFR declines and found that higher lumbar aortic calcification score was independently associated with lower ankle-brachial index and higher intima-media thickness, suggesting a relationship of abdominal calcifications with the extension of atherosclerosis in other territories [85]. In addition, the novel finding of the study was the ability of an aortic calcification score >5 to predict with 65% sensitivity and 68% specificity a pathologic (<0.7) renal resistive index (marker of intrarenal atherosclerotic lesions on Doppler ultrasound) [85].

mineral and bone disorder on the patients' outcome is not yet known and controversies exist especially regarding the influence of intestinal phosphate binders and vitamin D receptor acti-

Mechanisms and Clinical Implications of Vascular Calcifications in Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.72717

75

[1] Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, Hobbs FDR. Global prevalence of chronic kidney disease: A systematic review and meta-analysis. PLoS One.

[2] Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT. For the Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet. 2010;**375**:

[3] Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.

[4] Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney International.

[5] Román-García P, Rodríguez-García M, Cabezas-Rodríguez I, López-Ongil S, Díaz-López B, Cannata-Andía JB. Vascular calcification in patients with chronic kidney disease: Types, clinical impact and pathogenesis. Medical Principles and Practice. 2011;**20**:203-211. DOI:

[6] Mizobuchi M, Towler D, Slatopolsky E. Vascular calcification: The killer of patients with chronic kidney disease. Journal of the American Society of Nephrology. 2009;**20**(7):1453-

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Kidney International. 2013;(Suppl. 3):S1-S150. DOI: 10.1038/kisup.2012.73

vators on arterial calcifications.

Cristina Capusa1,2\* and Daria Popescu<sup>1</sup>

\*Address all correspondence to: ccalexandr@yahoo.com

1 "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania 2 "Dr. Carol Davila" Teaching Hospital of Nephrology, Bucharest, Romania

2016;**11**(7):e0158765. DOI: 10.1371/journal.pone.0158765

2073-2081. DOI: 10.1016/S0140-6736(10)60674-5

2009;(Suppl. 113):S1-S130. DOI: 10.1038/ki.2009.188

10.1159/000323434

1464. DOI: 10.1681/ASN.2008070692

**Author details**

**References**

#### **4.3. Calcific uremic arteriolopathy**

Previously referred to as *calciphylaxis*, this is another form of vascular calcification almost exclusive to chronic kidney disease patients with kidney failure, although some cases were scarcely reported in non-CKD patients. Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are among the risk factors of calcific uremic arteriolopathy [86]. It is typically found in end-stage kidney disease, obese, diabetic females, often associated with secondary hyperparathyroidism, hypercalcemia, hyperphosphatemia, malnutrition, chronic warfarin therapy, or hypercoagulability [87].

Calcific uremic arteriolopathy involves diffuse medial calcification of small- to medium-sized subcutaneous arteries and arterioles of up to 50-μm diameter, with intimal fibroproliferative occlusions that lead to necrosis. Histological abnormalities include intimal hyperplasia, inflammation, obliterative endovascular fibrosis, arteriolar medial calcification, and thrombotic cutaneous ischemia. The result is dermal, subdermal, and adipose tissue necrosis with subsequent skin ulceration. Calciphylaxis occurs independent of osteogenic activity, when the physiological calcium phosphate solubility threshold exceeds 60 mg<sup>2</sup> /dL<sup>2</sup> [13, 86].

Overt clinical signs include livedo reticularis advancing to patches of ischemic necrosis and painful skin ulcers, especially on the legs, thighs, abdomen, or breasts. Often, the initial presenting complaint is a dull deep dermal pain with periods of neuritic-type dysesthesia associated with palpable subcutaneous nodules or dermal plaques, which evolve to livedo reticularis and then nonhealing ulcerations [7, 88]. These lesions predispose the patients to life-threatening skin necrosis or acral gangrene susceptible to supra-infectious complications. Dermal fat, lung, and mesentery are most commonly affected [7, 86].

Sepsis, which is also the main cause of death due to calcific uremic arteriolopathy, and amputation are among the severe morbidities associated with this obliterative disease.

## **5. Conclusions**

In chronic kidney disease, even in non-dialysis stages, the prevalence of atherosclerotic lesions, vascular calcifications, and arterial stiffness are significantly higher as compared to patients of same-age without kidney damage. Because the interplay of multiple factors is responsible for the arterial disorders in CKD, the exact mechanism involved is still a matter of debate. Therefore, the best therapeutic approach to minimize the adverse impact of CKD-related mineral and bone disorder on the patients' outcome is not yet known and controversies exist especially regarding the influence of intestinal phosphate binders and vitamin D receptor activators on arterial calcifications.

## **Author details**

found in a cross-sectional study that enrolled 77 stages 2–5 non-dialysis CKD patients, older than 50 years, and with known atherosclerotic disease. This study described increased aortic calcification as eGFR declines and found that higher lumbar aortic calcification score was independently associated with lower ankle-brachial index and higher intima-media thickness, suggesting a relationship of abdominal calcifications with the extension of atherosclerosis in other territories [85]. In addition, the novel finding of the study was the ability of an aortic calcification score >5 to predict with 65% sensitivity and 68% specificity a pathologic (<0.7) renal resistive index (marker of intrarenal atherosclerotic lesions on Doppler ultrasound) [85].

Previously referred to as *calciphylaxis*, this is another form of vascular calcification almost exclusive to chronic kidney disease patients with kidney failure, although some cases were scarcely reported in non-CKD patients. Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are among the risk factors of calcific uremic arteriolopathy [86]. It is typically found in end-stage kidney disease, obese, diabetic females, often associated with secondary hyperparathyroidism, hypercalcemia, hyperphosphatemia, malnutrition, chronic

Calcific uremic arteriolopathy involves diffuse medial calcification of small- to medium-sized subcutaneous arteries and arterioles of up to 50-μm diameter, with intimal fibroproliferative occlusions that lead to necrosis. Histological abnormalities include intimal hyperplasia, inflammation, obliterative endovascular fibrosis, arteriolar medial calcification, and thrombotic cutaneous ischemia. The result is dermal, subdermal, and adipose tissue necrosis with subsequent skin ulceration. Calciphylaxis occurs independent of osteogenic activity, when

Overt clinical signs include livedo reticularis advancing to patches of ischemic necrosis and painful skin ulcers, especially on the legs, thighs, abdomen, or breasts. Often, the initial presenting complaint is a dull deep dermal pain with periods of neuritic-type dysesthesia associated with palpable subcutaneous nodules or dermal plaques, which evolve to livedo reticularis and then nonhealing ulcerations [7, 88]. These lesions predispose the patients to life-threatening skin necrosis or acral gangrene susceptible to supra-infectious complications. Dermal fat,

Sepsis, which is also the main cause of death due to calcific uremic arteriolopathy, and ampu-

In chronic kidney disease, even in non-dialysis stages, the prevalence of atherosclerotic lesions, vascular calcifications, and arterial stiffness are significantly higher as compared to patients of same-age without kidney damage. Because the interplay of multiple factors is responsible for the arterial disorders in CKD, the exact mechanism involved is still a matter of debate. Therefore, the best therapeutic approach to minimize the adverse impact of CKD-related

tation are among the severe morbidities associated with this obliterative disease.

/dL<sup>2</sup>

[13, 86].

the physiological calcium phosphate solubility threshold exceeds 60 mg<sup>2</sup>

lung, and mesentery are most commonly affected [7, 86].

**5. Conclusions**

**4.3. Calcific uremic arteriolopathy**

74 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

warfarin therapy, or hypercoagulability [87].

Cristina Capusa1,2\* and Daria Popescu<sup>1</sup>

\*Address all correspondence to: ccalexandr@yahoo.com


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**Chapter 4**

**Provisional chapter**

**Cardiovascular Risk Factors: The Old Ones and a Closer**

Patients with chronic kidney disease (CKD) are particularly susceptible to cardiovascular complications, and cardiovascular disease (CVD) accounts for more than 50% of all deaths in this population. Cardiac diseases are independently associated with a deterioration of renal function and worsening of existing kidney disease. On the other hand, chronic kidney disease is an independent risk factor for increased cardiovascular morbidity and mortality. It has a complex pathogenesis, and traditional risk factors are not able to fully explain its high incidence and prevalence. Several substances have been identified, and they seem to play important roles in different physiological functions. This chapter will review traditional risk factors such as hypertension, diabetes, dyslipidemia, and left ventricular hypertrophy. The most relevant bibliography will be referred, and also interventional studies will be discussed. Other new emerging factors associated with the osteomineral metabolism have been described, mainly in advanced stages of CKD, and frequently are associated with higher cardiovascular risk, which in turn will

**Keywords:** cardiovascular risk factors, chronic kidney disease, mineral metabolism

**Cardiovascular Risk Factors: The Old Ones and a Closer** 

DOI: 10.5772/intechopen.69323

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

The burden of chronic kidney disease (CKD) throughout the world is steadily increasing. Patients with CKD face a particularly high risk of cardiovascular disease (CVD). Cardiovascular events, regardless of the stage of kidney disease, are the leading cause of premature death in patients with CKD, with the rate of CVD progression being twice as common compared with the general population [1–3]. Over the last 30 years, it has become clear that

**Look to the Mineral Metabolism**

**Look to the Mineral Metabolism**

Ana Paula Silva, Anabela Malho Guedes and

Ana Paula Silva, Anabela Malho Guedes and

Additional information is available at the end of the chapter

contribute to the unfavorable prognosis of this population.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69323

Pedro Leão Neves

**Abstract**

**1. Introduction**

Pedro Leão Neves


**Provisional chapter**

## **Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism Look to the Mineral Metabolism**

**Cardiovascular Risk Factors: The Old Ones and a Closer** 

DOI: 10.5772/intechopen.69323

Ana Paula Silva, Anabela Malho Guedes and Pedro Leão Neves Pedro Leão Neves

Ana Paula Silva, Anabela Malho Guedes and

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69323

#### **Abstract**

[79] Budoff MJ, Rader DJ, Reilly MP, Mohler ER 3rd, Lash J, Yang W, Rosen L, Glenn M, Teal V, Feldman HI, for CRIC Study Investigators. Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) study. American Journal of Kidney Diseases. 2011;**58**(4):519-526. DOI: 10.1053/j.ajkd.2011.04.024

[80] Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. Journal of the American College of Cardiology.

[81] Olechnowicz-Tietz S, Gluba A, Paradowska A, Banach M, Rysz J. The risk of atherosclerosis in patients with chronic kidney disease. International Urology and Nephrology.

[82] Whitman IR, Feldman HI, Deo R. CKD and sudden cardiac death: Epidemiology, mechanisms, and therapeutic approaches. Journal of the American Society of Nephrology.

[83] Thambyrajaha J, Landraya MJ, McGlynnb FJ, Jonesa HJ, Wheelerb DC, Townenda JN. Abnormalities of endothelial function in patients with predialysis renal failure. Heart.

[84] Goligorsky MS. Pathogenesis of endothelial cell dysfunction in chronic kidney disease: A retrospective and what the future may hold. Kidney Research and Clinical Practice. 2015;

[85] Stefan G, Capusa C, Stancu S, Petrescu L, Nedelcu ED, Andreiana I, Mircescu G.Abdominal aortic calcification and renal resistive index in patients with chronic kidney disease: Is there a connection? Journal of Nephrology. 2014;**27**(2):173-179. DOI: 10.1007/s40620-013-0021-4

[86] Disthabanchong S. Vascular calcification in chronic kidney disease: Pathogenesis and clinical implication. World Journal of Nephrology. 2012;**1**(2):43-53. DOI: 10.5527/wjn.v1.i2.43

[87] Schiffrin EL, Lipman M, Mann JFE. Chronic kidney disease: Effects on the cardiovascular system. Circulation. 2007;**116**(1):85-97. DOI: 10.1161/CIRCULATIONAHA.106.678342

[88] Sowers KM, Hayden MR. Calcific uremic arteriolopathy: Pathophysiology, reactive oxygen species and therapeutic approaches. Oxidative Medicine and Cellular Longevity.

2003;**41**(1):47-55. DOI: 10.1016/S0735-1097(02)02663-3

82 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2013;**45**(6):1605-1612. DOI: 10.1007/s11255-013-0407-1

2012;**23**(12):1929-1939. DOI: 10.1681/ASN.2012010037

2000;**83**:205-209. DOI: 10.1136/heart.83.2.205

**34**(2):76-82. DOI: 10.1016/j.krcp.2015.05.003

2010;**3**(2):109-121. DOI: 10.4161/oxim.3.2.5

Patients with chronic kidney disease (CKD) are particularly susceptible to cardiovascular complications, and cardiovascular disease (CVD) accounts for more than 50% of all deaths in this population. Cardiac diseases are independently associated with a deterioration of renal function and worsening of existing kidney disease. On the other hand, chronic kidney disease is an independent risk factor for increased cardiovascular morbidity and mortality. It has a complex pathogenesis, and traditional risk factors are not able to fully explain its high incidence and prevalence. Several substances have been identified, and they seem to play important roles in different physiological functions. This chapter will review traditional risk factors such as hypertension, diabetes, dyslipidemia, and left ventricular hypertrophy. The most relevant bibliography will be referred, and also interventional studies will be discussed. Other new emerging factors associated with the osteomineral metabolism have been described, mainly in advanced stages of CKD, and frequently are associated with higher cardiovascular risk, which in turn will contribute to the unfavorable prognosis of this population.

**Keywords:** cardiovascular risk factors, chronic kidney disease, mineral metabolism

## **1. Introduction**

The burden of chronic kidney disease (CKD) throughout the world is steadily increasing. Patients with CKD face a particularly high risk of cardiovascular disease (CVD). Cardiovascular events, regardless of the stage of kidney disease, are the leading cause of premature death in patients with CKD, with the rate of CVD progression being twice as common compared with the general population [1–3]. Over the last 30 years, it has become clear that

the risk of CVD increases early in the course of progressive kidney disease and that the epidemiology, pathophysiology, prevention, and treatment of CVD and CKD are closely related and interdependent [4].

Traditional risk factors for development of CVD include hypertension, diabetes, dyslipidemia, smoking, increased body mass index, older age, male gender, physical inactivity, stress, and positive family history [11]. The same traditional risk factors can incite renal dysfunction. As renal function deteriorates, nontraditional risk factors play an increasing role both in glomerular filtration rate (GFR) loss and in cardiovascular damage [5]. The higher mortality from CVD persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. It seems that CVD and CKD can initiate, enhance, and perpetuate each other, eventually leading to vicious circle and premature death [11]. This has led to the current understanding that the pathophysiology of CVD in CKD involves a complex interplay of both the traditional and nontraditional, uremia-related risk factors [2], sequentially considering traditional risk factors as dominant for triggering initial renal damage and cardiovascular events in the general population, but with nontraditional risk factors becoming increas-

Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism

http://dx.doi.org/10.5772/intechopen.69323

85

Mineral metabolism disorders are a part of those uremia-related risk factors mentioned, but for their complexity and multiplicity of interplay mechanisms, as for their hidden precocious

Hypertension is simultaneously a cause and a consequence of chronic kidney disease (CKD), and this strong relationship has been recognized since the nineteenth century. As the renal function declines, the prevalence of hypertension increases, and for that reason, more than 80% of the patients beginning renal replacement therapy have high blood pressure [14]. The physiopathology of hypertension associated with CKD is complex and multifactorial, mainly in the late stages of CKD. In addition to the well-known factors such as increased intravascular volume and excessive activity of the RAS, there are new recognized players such as increased activity of the sympathetic nervous system, endothelial dysfunction, and alterations of several neural and humoral factors that increase the blood pressure [15]. Although hypertension is clearly a risk factor of cardiovascular disease in the general population, when we look to the renal population, this association is less evident due to the reverse epidemiology phenomenon [15, 16]. In CKD patients, hypertension is associated with ischemic heart disease, heart failure, and left ventricular hypertrophy [17–20]. Secondary analysis from randomized controlled trials such as the HOPE, IDNT, and ADVANCE studies demonstrated that hypertension treatment in CKD patients can reduce the risk of cardiovascular events [21–23]. Recently, the SPRINT study [24] showed that treatment of systolic blood pressure to a lower target (120 vs. 140 mmHg) reduced 25% of the composite CV outcome. However, in this study, less than 30% of the patients had CKD, and diabetic patients were excluded. There is a bulk of evidence that treating patients to lower blood pressure levels increases morbidity and mortality, mainly in elderly patients [17, 18, 24, 25]. The real challenge is how far we should go when we treat renal patients. The KDIGO guidelines recommend that the blood pressure

action on cardiovascular balance makes it obligatory to explore more deeply.

ingly important as renal function worsens [5].

**2. Traditional risk factors**

**2.1. Hypertension**

In this chapter, we initially describe the epidemiology of CKD and cardiovascular risk in CKD. We then discuss the common risk factors for CVD (traditional and nontraditional) and key aspects of its pathophysiology.

## **1.1. CKD epidemiology**

Patients with CKD represent an important segment of the population (7–10%) [5], which is projected to grow worldwide at a rate of 8% annually, with the fastest growth expected in developing nations [4, 6]. The National Health and Nutrition Examination Surveys (NHANES III and IV) stated that a moderate degree of renal impairment (glomerular filtration rate (GFR) 15–59ml/min/1.73m2 , as estimated by the Modification of Diet in Renal Disease (MDRD) formula) had 4.2 and 3.7% prevalence, respectively [5, 7]. In the AusDiab study, the prevalence of moderate renal failure (GFR<60, >30 ml/min/m<sup>2</sup> ) as assessed by the Cockcroft-Gault method was even more alarming, reaching 11% [5, 8]. The PREVEND study showed an incidence rate of moderate renal insufficiency of 4.2% in 4 years [9].

In a retrospective cohort study by the Kaiser Permanente Center, only a minority of patients (about 1%) with mild-to-moderate renal insufficiency developed ESRD over a 5-year followup [10]. However, as many as 19 and 24% of patients with mild and moderate renal insufficiency, respectively, died, mostly because of atherosclerotic complications, during the same 5 years. Thus, the true risk of renal insufficiency is cardiovascular rather renal [5, 10].

### **1.2. Cardiovascular risk in CKD**

The prevalence of CVD, including stroke, peripheral vascular disease, sudden death, coronary artery disease (CAD), and congestive heart failure, is about twice of that observed in general population and is increased over the entire span of CKD [4]. Coronary artery disease (CAD) is a leading cause of death among people with advanced CKD [4]. In addition, the onset of CVD frequently is premature when compared to general population [11]. In the last decade, the high frequency of renal impairment as an epiphenomenon of cardiovascular damage and/or cardiac dysfunction has been fully recognized [5]. The Cardiovascular Health Study analysis demonstrated that in every 10 mL/min per 1.73 m2 decrease in glomerular filtration rate (GFR), the risk of CVD and all-cause mortality increased by 5 and 6%, respectively [11]. It can be estimated that the (fully adjusted) risk associated with moderate renal insufficiency is about 40% higher than normal [10]. The risk increases linearly as renal function deteriorates until the GFR <15ml/min. Cardiovascular risk in patients who reach the end-stage phase of renal disease is staggering, being 5 times higher than normal in 85- to 95-year-old ESRD patients and 65 and 500 times higher than normal in those 45–54 years old and 25–35 years old, respectively [12].

On the other hand, in US Medicare patients admitted to the hospital with myocardial infarction and heart failure, the prevalence of moderate renal failure (creatinine clearance <60 ml/ min/1.73 m2 ) was very high, 60 and 52%, respectively, and these patients had a high risk of renal disease progression [13].

Traditional risk factors for development of CVD include hypertension, diabetes, dyslipidemia, smoking, increased body mass index, older age, male gender, physical inactivity, stress, and positive family history [11]. The same traditional risk factors can incite renal dysfunction. As renal function deteriorates, nontraditional risk factors play an increasing role both in glomerular filtration rate (GFR) loss and in cardiovascular damage [5]. The higher mortality from CVD persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. It seems that CVD and CKD can initiate, enhance, and perpetuate each other, eventually leading to vicious circle and premature death [11]. This has led to the current understanding that the pathophysiology of CVD in CKD involves a complex interplay of both the traditional and nontraditional, uremia-related risk factors [2], sequentially considering traditional risk factors as dominant for triggering initial renal damage and cardiovascular events in the general population, but with nontraditional risk factors becoming increasingly important as renal function worsens [5].

Mineral metabolism disorders are a part of those uremia-related risk factors mentioned, but for their complexity and multiplicity of interplay mechanisms, as for their hidden precocious action on cardiovascular balance makes it obligatory to explore more deeply.

## **2. Traditional risk factors**

## **2.1. Hypertension**

the risk of CVD increases early in the course of progressive kidney disease and that the epidemiology, pathophysiology, prevention, and treatment of CVD and CKD are closely related

In this chapter, we initially describe the epidemiology of CKD and cardiovascular risk in CKD. We then discuss the common risk factors for CVD (traditional and nontraditional) and

Patients with CKD represent an important segment of the population (7–10%) [5], which is projected to grow worldwide at a rate of 8% annually, with the fastest growth expected in developing nations [4, 6]. The National Health and Nutrition Examination Surveys (NHANES III and IV) stated that a moderate degree of renal impairment (glomerular filtration rate (GFR)

mula) had 4.2 and 3.7% prevalence, respectively [5, 7]. In the AusDiab study, the prevalence of

was even more alarming, reaching 11% [5, 8]. The PREVEND study showed an incidence rate

In a retrospective cohort study by the Kaiser Permanente Center, only a minority of patients (about 1%) with mild-to-moderate renal insufficiency developed ESRD over a 5-year followup [10]. However, as many as 19 and 24% of patients with mild and moderate renal insufficiency, respectively, died, mostly because of atherosclerotic complications, during the same 5 years. Thus, the true risk of renal insufficiency is cardiovascular rather renal [5, 10].

The prevalence of CVD, including stroke, peripheral vascular disease, sudden death, coronary artery disease (CAD), and congestive heart failure, is about twice of that observed in general population and is increased over the entire span of CKD [4]. Coronary artery disease (CAD) is a leading cause of death among people with advanced CKD [4]. In addition, the onset of CVD frequently is premature when compared to general population [11]. In the last decade, the high frequency of renal impairment as an epiphenomenon of cardiovascular damage and/or cardiac dysfunction has been fully recognized [5]. The Cardiovascular Health Study analysis

the risk of CVD and all-cause mortality increased by 5 and 6%, respectively [11]. It can be estimated that the (fully adjusted) risk associated with moderate renal insufficiency is about 40% higher than normal [10]. The risk increases linearly as renal function deteriorates until the GFR <15ml/min. Cardiovascular risk in patients who reach the end-stage phase of renal disease is staggering, being 5 times higher than normal in 85- to 95-year-old ESRD patients and 65 and 500 times higher than normal in those 45–54 years old and 25–35 years old, respectively [12]. On the other hand, in US Medicare patients admitted to the hospital with myocardial infarction and heart failure, the prevalence of moderate renal failure (creatinine clearance <60 ml/

) was very high, 60 and 52%, respectively, and these patients had a high risk of

, as estimated by the Modification of Diet in Renal Disease (MDRD) for-

) as assessed by the Cockcroft-Gault method

decrease in glomerular filtration rate (GFR),

and interdependent [4].

**1.1. CKD epidemiology**

15–59ml/min/1.73m2

key aspects of its pathophysiology.

**1.2. Cardiovascular risk in CKD**

min/1.73 m2

renal disease progression [13].

moderate renal failure (GFR<60, >30 ml/min/m<sup>2</sup>

of moderate renal insufficiency of 4.2% in 4 years [9].

84 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

demonstrated that in every 10 mL/min per 1.73 m2

Hypertension is simultaneously a cause and a consequence of chronic kidney disease (CKD), and this strong relationship has been recognized since the nineteenth century. As the renal function declines, the prevalence of hypertension increases, and for that reason, more than 80% of the patients beginning renal replacement therapy have high blood pressure [14]. The physiopathology of hypertension associated with CKD is complex and multifactorial, mainly in the late stages of CKD. In addition to the well-known factors such as increased intravascular volume and excessive activity of the RAS, there are new recognized players such as increased activity of the sympathetic nervous system, endothelial dysfunction, and alterations of several neural and humoral factors that increase the blood pressure [15]. Although hypertension is clearly a risk factor of cardiovascular disease in the general population, when we look to the renal population, this association is less evident due to the reverse epidemiology phenomenon [15, 16]. In CKD patients, hypertension is associated with ischemic heart disease, heart failure, and left ventricular hypertrophy [17–20]. Secondary analysis from randomized controlled trials such as the HOPE, IDNT, and ADVANCE studies demonstrated that hypertension treatment in CKD patients can reduce the risk of cardiovascular events [21–23]. Recently, the SPRINT study [24] showed that treatment of systolic blood pressure to a lower target (120 vs. 140 mmHg) reduced 25% of the composite CV outcome. However, in this study, less than 30% of the patients had CKD, and diabetic patients were excluded. There is a bulk of evidence that treating patients to lower blood pressure levels increases morbidity and mortality, mainly in elderly patients [17, 18, 24, 25]. The real challenge is how far we should go when we treat renal patients. The KDIGO guidelines recommend that the blood pressure should be less than 140/90 mmHg in CKD nondiabetic patients and less than 130/80 mmHg in CKD diabetic patients and nondiabetic proteinuric patients [26]. Kovesdy et al. proved that the optimal blood pressure in patients with CKD seems to be 130 to 159/70 to 89 mm Hg [18], and Agarwal [17] pointed out that higher levels of systolic and lower levels of diastolic blood pressure are associated with poorer cardiovascular outcomes. We should treat carefully our renal patients, lowering their systolic values but paying attention to the diastolic values. This concern is especially important in the elderly patients [27]. Regarding dialysis patients, there is a suggestion that treating hypertension decreases cardiovascular morbidity and mortality [28, 29], but there are no randomized controlled studies addressing the target of the blood pressure.

increased concentrations of small-dense LDL and apolipoprotein B [41]. Although dyslipidemia is clearly a risk factor of cardiovascular disease in the general population in kidney patients, this relationship is not straightforward. Chronic kidney disease is characterized by increased oxidative stress and inflammation, and these are the two major players responsible for the increased atherosclerosis in this group of patients [42–44]. This fact can explain, in part, why there is a solid association between inflammation and cardiovascular disease, and patients with low cholesterol may have poorer outcomes [45–47]. This phenomenon is called reverse epidemiology [45]. However, Koch et al. also found a positive association between

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Regarding therapy, statins improve the lipid profile and exert several pleiotropic effects. Nevertheless, concerning the cardiovascular outcomes, the timing of the initiation of the therapy is critical. The Prospective Pravastatin Pooling Project that included three studies has shown that pravastatin reduced significantly the CV composite outcome only in patients with moderate renal insufficiency [49]. We also found in an observational study that statins plus vitamin D reduced cardiovascular mortality in predialysis patients [50]. The SHARP trial also demonstrated the benefit of simvastatin plus ezetimibe in predialysis but not in patients already on dialysis [51]. This data according with the AURORA and 4D studies had not shown greater survival in patients on dialysis treated with statins when compared with placebo [52, 53]. The lack of benefit of using statins in dialysis patients can have several reasons: high mortality of dialysis patients due to sudden death and cardiomyopathy, existence of other pathways contributing to cardiovascular disease, or just because it is too late to interfere with the natural history of atherosclerosis [54]. Regarding prevention of cardiovascular disease in renal patients, there is a strong evidence of benefit in using statins only in predialysis patients, but their use is not recommended in dialysis patients [55]. The utilization of fibrates is not recommended in patients with advanced renal failure, and other approaches such as niacin, ezetimibe, or Ω-3 polyunsaturated fatty acids need randomized controlled

Left ventricular hypertrophy (LVH) is an established risk factor of cardiovascular morbidity and mortality in the general and also in the renal population. Its prevalence increases as the renal function deteriorates. It is estimated to be around 25% in the early stages of CKD and rises to 75 to 90% at the initiation of renal replacement therapy [56]. There are several factors associated to LVH in CKD. As it happens in the general population [57], age, hypertension, and existence of previous heart disease increase the risk of LVH in renal patients [58]. In these patients, other specific factors related to their condition also influence the left ventricular mass, such as anemia, disturbances of the mineral metabolism, inflammation, and oxidative stress [59, 60]. Concerning the mineral metabolism, recent studies revealed associations between vitamin D, FGF23, and Klotho with LVH [56, 59, 61]. In dialysis patients, the volume status, the presence of arteriovenous fistula, and the time on renal replacement therapy are also relevant aspects [56, 58, 62]. LVH contributes to a greater prevalence of ventricular arrhythmias and ischemic heart disease [63], as was demonstrated in the 4D study [52].

cholesterol values and the risk for cardiovascular events in CKD individuals [48].

studies to validate their effectiveness.

**2.4. Left ventricular hypertrophy**

### **2.2. Diabetes**

Diabetes mellitus is a major cause of CKD, and in most Western countries, the proportion of incident dialysis patients are between 22 and 44% [30].

Diabetes mellitus is a well-known risk factor of cardiovascular disease since the Framingham and other population-based studies. Once the renal population is under an increased risk of cardiovascular disease, not unexpectedly in patients with diabetic nephropathy, this risk increases exponentially. In fact, the NHANES III showed that the standardized mortality of patients with diabetes and CKD was 31.1% compared with a standardized mortality of 11.5% in patients with diabetes and of 7.7% in patients without diabetes or CKD [31]. The mechanisms of how diabetes increases atherogenesis are multiple, associated to hyperglycemia itself (*via* the polyol pathway, protein kinase C, AGEs, hexosamine pathway) and associated to other circumstances such as dyslipidemia, obesity, insulin resistance, and prothrombotic and proinflammatory states [32]. In the early stages of diabetic nephropathy, the presence of microalbuminuria is a harbinger of an increased cardiovascular risk [33], and this risk increases as the nephropathy progresses [34]. Diabetes continues to raise the risk of morbidity and mortality throughout the spectrum of kidney disease. Diabetic patients on dialysis maintain a poorer prognosis when compared with nondiabetic patients [35–37].

The treatment strategy includes the reduction of the progression of diabetic nephropathy with antagonists of the renin-angiotensin system [38, 39], the control of glycemia, and all the complex conditions associated.

## **2.3. Dyslipidemia**

The presence of alterations of the lipid profile is frequent in the early stages of renal disease. Renal patients have, in general, lower levels of HDL, LDL, and total cholesterol and higher levels of triglycerides. There is a clustering of low HDL and elevated Lp(a) and TG-rich apolipoprotein B (ApoB) containing VLDL and LDL [40]. The increased concentration of triglyceride-rich lipoproteins in renal patients is due to delayed catabolism and to the increased hepatic production [41]. The severity of hypercholesterolemia is also associated with the level of proteinuria in CKD predialysis patients. In HD patients, the serum lipid profile is similar of predialysis patients, but PD patients have higher total and LDL cholesterol values and increased concentrations of small-dense LDL and apolipoprotein B [41]. Although dyslipidemia is clearly a risk factor of cardiovascular disease in the general population in kidney patients, this relationship is not straightforward. Chronic kidney disease is characterized by increased oxidative stress and inflammation, and these are the two major players responsible for the increased atherosclerosis in this group of patients [42–44]. This fact can explain, in part, why there is a solid association between inflammation and cardiovascular disease, and patients with low cholesterol may have poorer outcomes [45–47]. This phenomenon is called reverse epidemiology [45]. However, Koch et al. also found a positive association between cholesterol values and the risk for cardiovascular events in CKD individuals [48].

Regarding therapy, statins improve the lipid profile and exert several pleiotropic effects. Nevertheless, concerning the cardiovascular outcomes, the timing of the initiation of the therapy is critical. The Prospective Pravastatin Pooling Project that included three studies has shown that pravastatin reduced significantly the CV composite outcome only in patients with moderate renal insufficiency [49]. We also found in an observational study that statins plus vitamin D reduced cardiovascular mortality in predialysis patients [50]. The SHARP trial also demonstrated the benefit of simvastatin plus ezetimibe in predialysis but not in patients already on dialysis [51]. This data according with the AURORA and 4D studies had not shown greater survival in patients on dialysis treated with statins when compared with placebo [52, 53]. The lack of benefit of using statins in dialysis patients can have several reasons: high mortality of dialysis patients due to sudden death and cardiomyopathy, existence of other pathways contributing to cardiovascular disease, or just because it is too late to interfere with the natural history of atherosclerosis [54]. Regarding prevention of cardiovascular disease in renal patients, there is a strong evidence of benefit in using statins only in predialysis patients, but their use is not recommended in dialysis patients [55]. The utilization of fibrates is not recommended in patients with advanced renal failure, and other approaches such as niacin, ezetimibe, or Ω-3 polyunsaturated fatty acids need randomized controlled studies to validate their effectiveness.

#### **2.4. Left ventricular hypertrophy**

should be less than 140/90 mmHg in CKD nondiabetic patients and less than 130/80 mmHg in CKD diabetic patients and nondiabetic proteinuric patients [26]. Kovesdy et al. proved that the optimal blood pressure in patients with CKD seems to be 130 to 159/70 to 89 mm Hg [18], and Agarwal [17] pointed out that higher levels of systolic and lower levels of diastolic blood pressure are associated with poorer cardiovascular outcomes. We should treat carefully our renal patients, lowering their systolic values but paying attention to the diastolic values. This concern is especially important in the elderly patients [27]. Regarding dialysis patients, there is a suggestion that treating hypertension decreases cardiovascular morbidity and mortality [28, 29], but there are no randomized controlled studies addressing the target of the blood

Diabetes mellitus is a major cause of CKD, and in most Western countries, the proportion of

Diabetes mellitus is a well-known risk factor of cardiovascular disease since the Framingham and other population-based studies. Once the renal population is under an increased risk of cardiovascular disease, not unexpectedly in patients with diabetic nephropathy, this risk increases exponentially. In fact, the NHANES III showed that the standardized mortality of patients with diabetes and CKD was 31.1% compared with a standardized mortality of 11.5% in patients with diabetes and of 7.7% in patients without diabetes or CKD [31]. The mechanisms of how diabetes increases atherogenesis are multiple, associated to hyperglycemia itself (*via* the polyol pathway, protein kinase C, AGEs, hexosamine pathway) and associated to other circumstances such as dyslipidemia, obesity, insulin resistance, and prothrombotic and proinflammatory states [32]. In the early stages of diabetic nephropathy, the presence of microalbuminuria is a harbinger of an increased cardiovascular risk [33], and this risk increases as the nephropathy progresses [34]. Diabetes continues to raise the risk of morbidity and mortality throughout the spectrum of kidney disease. Diabetic patients on dialysis main-

The treatment strategy includes the reduction of the progression of diabetic nephropathy with antagonists of the renin-angiotensin system [38, 39], the control of glycemia, and all the

The presence of alterations of the lipid profile is frequent in the early stages of renal disease. Renal patients have, in general, lower levels of HDL, LDL, and total cholesterol and higher levels of triglycerides. There is a clustering of low HDL and elevated Lp(a) and TG-rich apolipoprotein B (ApoB) containing VLDL and LDL [40]. The increased concentration of triglyceride-rich lipoproteins in renal patients is due to delayed catabolism and to the increased hepatic production [41]. The severity of hypercholesterolemia is also associated with the level of proteinuria in CKD predialysis patients. In HD patients, the serum lipid profile is similar of predialysis patients, but PD patients have higher total and LDL cholesterol values and

tain a poorer prognosis when compared with nondiabetic patients [35–37].

incident dialysis patients are between 22 and 44% [30].

86 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

pressure.

**2.2. Diabetes**

complex conditions associated.

**2.3. Dyslipidemia**

Left ventricular hypertrophy (LVH) is an established risk factor of cardiovascular morbidity and mortality in the general and also in the renal population. Its prevalence increases as the renal function deteriorates. It is estimated to be around 25% in the early stages of CKD and rises to 75 to 90% at the initiation of renal replacement therapy [56]. There are several factors associated to LVH in CKD. As it happens in the general population [57], age, hypertension, and existence of previous heart disease increase the risk of LVH in renal patients [58]. In these patients, other specific factors related to their condition also influence the left ventricular mass, such as anemia, disturbances of the mineral metabolism, inflammation, and oxidative stress [59, 60]. Concerning the mineral metabolism, recent studies revealed associations between vitamin D, FGF23, and Klotho with LVH [56, 59, 61]. In dialysis patients, the volume status, the presence of arteriovenous fistula, and the time on renal replacement therapy are also relevant aspects [56, 58, 62]. LVH contributes to a greater prevalence of ventricular arrhythmias and ischemic heart disease [63], as was demonstrated in the 4D study [52].

Therefore, it is vital to reduce the left ventricular mass, to control as far as possible the modifiable risk factors, such as the anemia, the mineral metabolism, the blood pressure, and the hypervolemia as was shown in quite a few studies [64, 65]. This reduction of the LVH is associated with diminution of the cardiac events and death [66].

the relationship between vascular calcification and serum P*i* in the presence of hyperphosphatemia, as seen in the CKD population. Vascular calcification is one of the mechanisms proposed for P*i*-related cardiovascular risk. In vitro studies show that P*i* participates actively in the vascular calcification process. Smooth muscle cells grown in a P*i*-rich medium transdifferentiate into osteoblast-like cells. P*i* is able to enter the smooth muscle cell via the type III sodium-phosphate cotransporter (PiT-1), activate a nuclear transcription factor called Cbfa-1/ RUNX-2, and stimulate cell transdifferentiation [85, 86]. The smooth muscle cells acquire phenotypical characteristics similar to osteoblasts and begin to express osteopontin, osteocalcin, alkaline phosphatase, and type I collagen, promoting an authentic "ossification" of the vascular tissue [87]. P*i* overload is also associated with increased production of reactive oxygen species [88], changes in angiogenesis, epithelial migration, and survival of endothelial cells [89]. One of the biggest difficulties in interpreting the harmful effects of P*i* in vivo is to determine if they are the result of their direct action or indirect mechanisms, e.g., via an increase in FGF23 and PTH. However, there is quite a few data demonstrating that the reduction of P*i* levels was associated with improvement in endothelial dysfunction, aortic stiffness, and left ventricular hypertrophy [90] and slowing of the progression of vascular calcification [91]. Furthermore, it was also shown that controlling P*i* through dietary restriction or with the use of sevelamer was effective in reducing mortality in uremic mice with established vascular calcification [92]. Although experimental studies suggest that a better control of P*i* levels is associated with a beneficial effect on the cardiovascular system, including mortality, interpretation of these findings is still controversial. Nevertheless, such findings are considered a strong evidence implicating P*i* as a cardiovascular disease-promoting agent and, as such, an important thera-

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89

The role played by vitamin D and PTH in cardiovascular function appears to be much more important than was originally thought. The discovery of a protein that binds to calcium, which is calcitriol-dependent and which is present in the myocardium, the vascular smooth

In an experimental context of vitamin D deficiency, it was observed that calcitriol normalizes the contractility of disorganized myocardial areas, promoting regulation of myocyte proliferation and hypertrophy [94]. It also stimulates the production of prostacyclin in the vascular smooth muscle tissue, which prevents thrombus formation, cell adhesion, and proliferation of smooth muscle tissue [97]. Calcitriol is also known to suppress the synthesis and secretion of atrial natriuretic peptide and increase production of the matrix protein carboxyglutamic acid,

The recent discovery of the 25(OH)D-1 hydroxylase enzyme—whose activity is regulated by the action of PTH and by estrogenic compounds—in the vascular smooth muscle cell has also contributed to the growing importance of vitamin D in vascular function [93, 96]. Cardiac tissue cells have receptors for both PTH and PTH-related peptides, which affect the physiology of the cardiovascular cell in a different way from the action they exert on classic bone tissue

muscle, and the endothelium, offered a clearer view on this subject [93–98].

which has a protective effect against arterial calcification [98, 99].

peutic target.

**3.2. Vitamin D and PTH**

## **3. Chronic kidney disease: mineral metabolism and cardiovascular risk**

#### **3.1. Phosphorus**

In recent years, numerous epidemiological studies have shown a link between high phosphorus (P*i*) levels and cardiovascular outcomes, in both the chronic renal failure population and the population as a whole.

The link between P*i* and morbidity and mortality was demonstrated some years ago, initially in the CKD population on dialysis in the classic study conducted by Block et al. [67], and was later confirmed by several other cohort studies both in individuals with CKD and in individuals with normal renal function [68–71]. Analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed that serum P*i* levels higher than 6.1 mg/dl at the start of the study were associated with an increased risk of death from any cause and from cardiovascular disease compared to P*i* levels within the normal reference range [68]. Very low P*i* levels were also associated with increased mortality, perhaps reflecting the poor nutritional status of these patients [68]. It is also known that high concentrations of P*i* are associated with the presence of vascular, valvular, and soft tissue calcifications in this population [72] even at earlier stages of CKD [73]. These observations were later extended to the general population, and, surprisingly, even P*i* levels at the upper limits of normal were found to be associated with greater cardiovascular disease (CARE post hoc analysis) [69]. This analysis showed that, after 5 years of follow-up, there was a positive, gradual association between baseline serum P*i* levels and mortality due to any cause, conferring a 27% increase in the risk of death for each 1 mg/dL increase in serum P*i*. The Framingham Heart Study cohort [74] and the Atherosclerosis Risk in Communities Study (ARIC) also showed an increased cardiovascular mortality in patients with higher levels of P*i* [71]. These last two studies draw attention to the fact that the serum P*i* levels were still within the normal range. At least two studies showed a correlation between P*i* and the severity of coronary lesions on angiography [75, 76]. This information emphasizes the possibly important role of P*i* in the processes of calcification and atherogenesis [76]. It is interesting to observe that the authors also demonstrated that P*i* was a predictor for atherosclerosis in other sites, such as the carotid arteries, [77, 78] as well as the left ventricular hypertrophy (LVH) in the general population [79]. The mechanisms by which P*i* increases mortality and the incidence of cardiovascular events have not yet been established, but it seems likely that it contributes directly, as a result of its participation in the pathogenesis of vascular calcification and in the atherosclerosis process, [80] and indirectly, by raising FGF23 levels [81]. Hyperphosphatemia, by raising parathyroid hormone (PTH) levels, can also have, indirectly, a harmful effect on cardiomyocytes [82, 83] and interfere with the mechanisms that regulate vascular calcification [84]. This mechanism would also explain the relationship between vascular calcification and serum P*i* in the presence of hyperphosphatemia, as seen in the CKD population. Vascular calcification is one of the mechanisms proposed for P*i*-related cardiovascular risk. In vitro studies show that P*i* participates actively in the vascular calcification process. Smooth muscle cells grown in a P*i*-rich medium transdifferentiate into osteoblast-like cells. P*i* is able to enter the smooth muscle cell via the type III sodium-phosphate cotransporter (PiT-1), activate a nuclear transcription factor called Cbfa-1/ RUNX-2, and stimulate cell transdifferentiation [85, 86]. The smooth muscle cells acquire phenotypical characteristics similar to osteoblasts and begin to express osteopontin, osteocalcin, alkaline phosphatase, and type I collagen, promoting an authentic "ossification" of the vascular tissue [87]. P*i* overload is also associated with increased production of reactive oxygen species [88], changes in angiogenesis, epithelial migration, and survival of endothelial cells [89].

One of the biggest difficulties in interpreting the harmful effects of P*i* in vivo is to determine if they are the result of their direct action or indirect mechanisms, e.g., via an increase in FGF23 and PTH. However, there is quite a few data demonstrating that the reduction of P*i* levels was associated with improvement in endothelial dysfunction, aortic stiffness, and left ventricular hypertrophy [90] and slowing of the progression of vascular calcification [91]. Furthermore, it was also shown that controlling P*i* through dietary restriction or with the use of sevelamer was effective in reducing mortality in uremic mice with established vascular calcification [92].

Although experimental studies suggest that a better control of P*i* levels is associated with a beneficial effect on the cardiovascular system, including mortality, interpretation of these findings is still controversial. Nevertheless, such findings are considered a strong evidence implicating P*i* as a cardiovascular disease-promoting agent and, as such, an important therapeutic target.

## **3.2. Vitamin D and PTH**

Therefore, it is vital to reduce the left ventricular mass, to control as far as possible the modifiable risk factors, such as the anemia, the mineral metabolism, the blood pressure, and the hypervolemia as was shown in quite a few studies [64, 65]. This reduction of the LVH is asso-

**3. Chronic kidney disease: mineral metabolism and cardiovascular risk**

In recent years, numerous epidemiological studies have shown a link between high phosphorus (P*i*) levels and cardiovascular outcomes, in both the chronic renal failure population and

The link between P*i* and morbidity and mortality was demonstrated some years ago, initially in the CKD population on dialysis in the classic study conducted by Block et al. [67], and was later confirmed by several other cohort studies both in individuals with CKD and in individuals with normal renal function [68–71]. Analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS) showed that serum P*i* levels higher than 6.1 mg/dl at the start of the study were associated with an increased risk of death from any cause and from cardiovascular disease compared to P*i* levels within the normal reference range [68]. Very low P*i* levels were also associated with increased mortality, perhaps reflecting the poor nutritional status of these patients [68]. It is also known that high concentrations of P*i* are associated with the presence of vascular, valvular, and soft tissue calcifications in this population [72] even at earlier stages of CKD [73]. These observations were later extended to the general population, and, surprisingly, even P*i* levels at the upper limits of normal were found to be associated with greater cardiovascular disease (CARE post hoc analysis) [69]. This analysis showed that, after 5 years of follow-up, there was a positive, gradual association between baseline serum P*i* levels and mortality due to any cause, conferring a 27% increase in the risk of death for each 1 mg/dL increase in serum P*i*. The Framingham Heart Study cohort [74] and the Atherosclerosis Risk in Communities Study (ARIC) also showed an increased cardiovascular mortality in patients with higher levels of P*i* [71]. These last two studies draw attention to the fact that the serum P*i* levels were still within the normal range. At least two studies showed a correlation between P*i* and the severity of coronary lesions on angiography [75, 76]. This information emphasizes the possibly important role of P*i* in the processes of calcification and atherogenesis [76]. It is interesting to observe that the authors also demonstrated that P*i* was a predictor for atherosclerosis in other sites, such as the carotid arteries, [77, 78] as well as the left ventricular hypertrophy (LVH) in the general population [79]. The mechanisms by which P*i* increases mortality and the incidence of cardiovascular events have not yet been established, but it seems likely that it contributes directly, as a result of its participation in the pathogenesis of vascular calcification and in the atherosclerosis process, [80] and indirectly, by raising FGF23 levels [81]. Hyperphosphatemia, by raising parathyroid hormone (PTH) levels, can also have, indirectly, a harmful effect on cardiomyocytes [82, 83] and interfere with the mechanisms that regulate vascular calcification [84]. This mechanism would also explain

ciated with diminution of the cardiac events and death [66].

88 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**3.1. Phosphorus**

the population as a whole.

The role played by vitamin D and PTH in cardiovascular function appears to be much more important than was originally thought. The discovery of a protein that binds to calcium, which is calcitriol-dependent and which is present in the myocardium, the vascular smooth muscle, and the endothelium, offered a clearer view on this subject [93–98].

In an experimental context of vitamin D deficiency, it was observed that calcitriol normalizes the contractility of disorganized myocardial areas, promoting regulation of myocyte proliferation and hypertrophy [94]. It also stimulates the production of prostacyclin in the vascular smooth muscle tissue, which prevents thrombus formation, cell adhesion, and proliferation of smooth muscle tissue [97]. Calcitriol is also known to suppress the synthesis and secretion of atrial natriuretic peptide and increase production of the matrix protein carboxyglutamic acid, which has a protective effect against arterial calcification [98, 99].

The recent discovery of the 25(OH)D-1 hydroxylase enzyme—whose activity is regulated by the action of PTH and by estrogenic compounds—in the vascular smooth muscle cell has also contributed to the growing importance of vitamin D in vascular function [93, 96]. Cardiac tissue cells have receptors for both PTH and PTH-related peptides, which affect the physiology of the cardiovascular cell in a different way from the action they exert on classic bone tissue [100]. PTH-related peptide is produced by the vascular smooth muscle cells, which regulate the arterial smooth muscle tissue proliferation rate, producing positive chronotropic and inotropic effects, not attributable to PTH, in isolated cardiomyocytes [96]. PTH is responsible for the expression of fetal proteins in the cardiomyocytes and, if present in excess, may be related to hypertrophic growth of the myocytes [100]. In animal studies, a relation between PTH levels and a permissive role in fibroblast activation and cardiac fibrosis has been observed, possibly via transformation of growth factor 1, a promoter of cardiac fibrosis [82, 101, 102].

Recent experimental and clinical studies have confirmed the role of FGF23 in the physiology of MBD and CV disease [120]. FGF23 is produced by osteocytes and osteoblasts, and it acts on the kidneys in the proximal tubular cells, increasing renal excretion of phosphorus and decreasing

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Elevated FGF23 is observed after dietary ingestion due to a resulting increase in intestinal absorption of phosphorus after administration of PTH in experimental work with CKD [123, 124]. The rise in FGF23 associated with the resulting decrease in intestinal absorption of phosphorus, mediated by the decrease in calcitriol, contributes to maintaining adequate blood phosphate levels in the initial stages of kidney disease [125]. In CKD, there are concomitant increases in the levels of phosphorus, PTH, and FGF23, which reflects an increased production and decreased degradation, leading to their accumulation to levels much higher than those in the general popu-

The action of FGF23 is obtained only when it is bound to the FGFR1c receptor associated with the Klotho cofactor. The Klotho protein is specifically expressed in the distal tubule of the normal kidney, but it is produced in many other tissues and organs [118, 127, 128]. The main targets of FGF23 are defined by the expression of the FGFR1c-Klotho complex. However, important actions of FGF23 on cardiomyocytes occur even in the absence of Klotho, via intracellular mechanisms that are not yet fully understood [129]. Elevated FGF23 levels imply an increase in the mortality rate adjusted for classic CV-KD factors and other traditional CKD

This link between elevated serum levels of FGF23 and the occurrence of relevant clinical events was initially established in patients with kidney disease who were on hemodialysis [130, 131]. Faul et al. in a cohort study of 3000 patients demonstrated that, in the early stages of kidney disease, FGF23 is an independent risk factor for LVH [132]. The cardiac hypertrophic effects of FGF23 are mediated by FGFR-dependent activation of the calcineurin nuclear factor of the activated T-cell (NFAT) signaling cascade, but do not require Klotho as a co-receptor [133].

The available studies that evaluated FGF23 and cardiovascular changes or events in the general population have a limitation, because their samples included individuals with CKD. Keeping this fact in mind, links were found between FGF23 and LVH, endothelial dysfunction, and total body atherosclerosis as assessed by magnetic resonance imaging in the community [134]. Recently, an analysis of the cohort participating in the Heart and Soul Study, which included 833 patients with coronary artery disease, established FGF23 as a predictor of events in this population [135]. This study included patients with CKD, but the results

FGF23 is also being linked to severe aortic and coronary artery calcifications and is considered a marker of CV disease in patients with CKD [136, 137]. One of the mechanisms may be related to a decrease in fetuin-A. Fetuin-A is synthesized by the hepatocytes, is secreted into the blood, and accumulates in the skeleton during bone mineralization due to its high affinity for hydroxyapatite. It is considered an inhibitor of CV disease and represents the most important inhibitor of the formation of circulating hydroxyapatite [138, 139]. Another mechanism that would explain the vascular calcifications associated with FGF23 would be through hyperphosphatemia.

1,25-dihydroxivitamin D [1,25(OH)D] [118, 121, 122].

remained the same after adjusting for this variable.

lation [126].

markers [71–73].

Zittermann et al. [100] proposed various mechanisms to explain the relation between vitamin D deficiency and cardiovascular disease. One of these suggests that the matrix Gla protein—synthesized by the chondrocytes and the vascular smooth muscle and stimulated by calcitriol—is an important inhibitor of vascular calcification. They also mention the important role that inflammatory processes play in the development of adverse cardiovascular effects and the fact that interleukin 6 and tumor necrosis factor (TNF), which are stimulators of C-reactive protein, are suppressed by calcitriol, unlike interleukin 10, whose production is stimulated. The renin-angiotensin-aldosterone system, which is responsible for regulating blood pressure, electrolytes, and volemic status, is regulated by calcitriol via reduction of plasma renin activity and the angiotensin II concentration [99, 103].

In addition to these mechanisms, PTH and vitamin D are significantly involved in the osteoprotegerin/RANKL/RANK pathway, a fact that could make it the connecting link between bone tissue and cardiovascular diseases [104, 105]. Calcitriol, on the other hand, reduces expression of osteoprotegerin [106, 107].

A link between vitamin D deficiency and cardiovascular disease can be found in a number of studies, which demonstrated a 30–50% higher cardiovascular morbidity and mortality associated with reduced sun exposure caused by changes in season or latitude [108–110]. One fact that supports this thesis is that cardiovascular mortality rates are lower in the European countries with greater sun exposure and higher during the winter months [110].

Despite the negative association between vitamin D deficiency and cardiovascular disease described in multiple studies [111–114], clinical trials have failed to convincingly demonstrate a benefit of vitamin D supplements on cardiovascular (CV) health. One such study was the PRIMO trial, which showed no improvement in ventricular mass index or any other remodeling parameters by administering paricalcitol, a selective activator of vitamin D receptors, to patients with chronic renal failure [115]. However, experiments performed in vitro and in several animal models of LV pressure overload show that vitamin D supplements attenuate LV hypertrophy, reduce cardiac fibrosis, and decrease the expression of collagen, fibronectin, and transforming growth factor-β, along with an improvement of the systolic and diastolic function [116, 117].

## **3.3. FGF23**

Fibroblast growth factor 23 (FGF23) is a phosphaturic protein and an inhibitor of 1α-hydroxylase, the enzyme responsible for calcitriol synthesis. Its discovery has enabled a better understanding of chronic kidney disease-related mineral and bone disorders (CKD-MBD) [118, 119]. Recent experimental and clinical studies have confirmed the role of FGF23 in the physiology of MBD and CV disease [120]. FGF23 is produced by osteocytes and osteoblasts, and it acts on the kidneys in the proximal tubular cells, increasing renal excretion of phosphorus and decreasing 1,25-dihydroxivitamin D [1,25(OH)D] [118, 121, 122].

[100]. PTH-related peptide is produced by the vascular smooth muscle cells, which regulate the arterial smooth muscle tissue proliferation rate, producing positive chronotropic and inotropic effects, not attributable to PTH, in isolated cardiomyocytes [96]. PTH is responsible for the expression of fetal proteins in the cardiomyocytes and, if present in excess, may be related to hypertrophic growth of the myocytes [100]. In animal studies, a relation between PTH levels and a permissive role in fibroblast activation and cardiac fibrosis has been observed, possibly via transformation of growth factor 1, a promoter of cardiac fibrosis [82, 101, 102].

Zittermann et al. [100] proposed various mechanisms to explain the relation between vitamin D deficiency and cardiovascular disease. One of these suggests that the matrix Gla protein—synthesized by the chondrocytes and the vascular smooth muscle and stimulated by calcitriol—is an important inhibitor of vascular calcification. They also mention the important role that inflammatory processes play in the development of adverse cardiovascular effects and the fact that interleukin 6 and tumor necrosis factor (TNF), which are stimulators of C-reactive protein, are suppressed by calcitriol, unlike interleukin 10, whose production is stimulated. The renin-angiotensin-aldosterone system, which is responsible for regulating blood pressure, electrolytes, and volemic status, is regulated by calcitriol via reduction of

In addition to these mechanisms, PTH and vitamin D are significantly involved in the osteoprotegerin/RANKL/RANK pathway, a fact that could make it the connecting link between bone tissue and cardiovascular diseases [104, 105]. Calcitriol, on the other hand, reduces

A link between vitamin D deficiency and cardiovascular disease can be found in a number of studies, which demonstrated a 30–50% higher cardiovascular morbidity and mortality associated with reduced sun exposure caused by changes in season or latitude [108–110]. One fact that supports this thesis is that cardiovascular mortality rates are lower in the European coun-

Despite the negative association between vitamin D deficiency and cardiovascular disease described in multiple studies [111–114], clinical trials have failed to convincingly demonstrate a benefit of vitamin D supplements on cardiovascular (CV) health. One such study was the PRIMO trial, which showed no improvement in ventricular mass index or any other remodeling parameters by administering paricalcitol, a selective activator of vitamin D receptors, to patients with chronic renal failure [115]. However, experiments performed in vitro and in several animal models of LV pressure overload show that vitamin D supplements attenuate LV hypertrophy, reduce cardiac fibrosis, and decrease the expression of collagen, fibronectin, and transforming growth factor-β, along with an improvement of the systolic and diastolic

Fibroblast growth factor 23 (FGF23) is a phosphaturic protein and an inhibitor of 1α-hydroxylase, the enzyme responsible for calcitriol synthesis. Its discovery has enabled a better understanding of chronic kidney disease-related mineral and bone disorders (CKD-MBD) [118, 119].

plasma renin activity and the angiotensin II concentration [99, 103].

90 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

tries with greater sun exposure and higher during the winter months [110].

expression of osteoprotegerin [106, 107].

function [116, 117].

**3.3. FGF23**

Elevated FGF23 is observed after dietary ingestion due to a resulting increase in intestinal absorption of phosphorus after administration of PTH in experimental work with CKD [123, 124]. The rise in FGF23 associated with the resulting decrease in intestinal absorption of phosphorus, mediated by the decrease in calcitriol, contributes to maintaining adequate blood phosphate levels in the initial stages of kidney disease [125]. In CKD, there are concomitant increases in the levels of phosphorus, PTH, and FGF23, which reflects an increased production and decreased degradation, leading to their accumulation to levels much higher than those in the general population [126].

The action of FGF23 is obtained only when it is bound to the FGFR1c receptor associated with the Klotho cofactor. The Klotho protein is specifically expressed in the distal tubule of the normal kidney, but it is produced in many other tissues and organs [118, 127, 128]. The main targets of FGF23 are defined by the expression of the FGFR1c-Klotho complex. However, important actions of FGF23 on cardiomyocytes occur even in the absence of Klotho, via intracellular mechanisms that are not yet fully understood [129]. Elevated FGF23 levels imply an increase in the mortality rate adjusted for classic CV-KD factors and other traditional CKD markers [71–73].

This link between elevated serum levels of FGF23 and the occurrence of relevant clinical events was initially established in patients with kidney disease who were on hemodialysis [130, 131]. Faul et al. in a cohort study of 3000 patients demonstrated that, in the early stages of kidney disease, FGF23 is an independent risk factor for LVH [132]. The cardiac hypertrophic effects of FGF23 are mediated by FGFR-dependent activation of the calcineurin nuclear factor of the activated T-cell (NFAT) signaling cascade, but do not require Klotho as a co-receptor [133].

The available studies that evaluated FGF23 and cardiovascular changes or events in the general population have a limitation, because their samples included individuals with CKD. Keeping this fact in mind, links were found between FGF23 and LVH, endothelial dysfunction, and total body atherosclerosis as assessed by magnetic resonance imaging in the community [134]. Recently, an analysis of the cohort participating in the Heart and Soul Study, which included 833 patients with coronary artery disease, established FGF23 as a predictor of events in this population [135]. This study included patients with CKD, but the results remained the same after adjusting for this variable.

FGF23 is also being linked to severe aortic and coronary artery calcifications and is considered a marker of CV disease in patients with CKD [136, 137]. One of the mechanisms may be related to a decrease in fetuin-A. Fetuin-A is synthesized by the hepatocytes, is secreted into the blood, and accumulates in the skeleton during bone mineralization due to its high affinity for hydroxyapatite. It is considered an inhibitor of CV disease and represents the most important inhibitor of the formation of circulating hydroxyapatite [138, 139]. Another mechanism that would explain the vascular calcifications associated with FGF23 would be through hyperphosphatemia.

Scialla et al. studied the link between FGF23, P, and coronary calcification as measured by CT scan of the aorta in 1501 subjects with CKD. They concluded that FGF23 was not directly associated with calcification of the aorta and coronary arteries, but rather with phosphorus levels. This group found a link between the severity of the calcification and FGF23 and concluded that FGF23 may be a marker of surveillance and not of the genesis of vascular calcification [140].

The role of emerging factors like FGF23 and Klotho in cardiovascular risk in both the early and late stages of chronic kidney disease is not entirely perceptible. The entire process involves

Cardiovascular Risk Factors: The Old Ones and a Closer Look to the Mineral Metabolism

http://dx.doi.org/10.5772/intechopen.69323

93

Chronic kidney disease is an independent risk factor for increased cardiovascular morbidity and mortality. It has a complex pathogenesis, and traditional risk factors are not able to fully explain its high incidence and prevalence. Several substances have been identified, and they

The CKD mineral disease is another player in this complex puzzle and is one of the factors responsible for this high cardiovascular risk of this population in the early or late stages of the CKD.

Nephrology Department, Centro Hospitalar do Algarve, Algarve Biomedical Center,

[1] Zoccali C, Mallamaci F, Tripepi G. Traditional and emerging cardiovascular risk factors

[2] Yerram P, Karuparthi PR, Hesemann L, Horst J, Whaley-Connell A. Chronic kidney disease and cardiovascular risk. Journal of the American Society of Hypertension. 2007

[3] Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. American Journal

[4] Tonelli M, Karumanchi A, Thadhani R. Epidemiology and mechanisms of uremia-

[5] Zocalli C. Traditional and emerging cardiovascular and renal risk factors: An epidemio-

[6] Ayodele OE, Alebiosu CO. Burden of chronic kidney disease: An inter- national perspective.

direct and indirect mechanisms that contribute to this high cardiovascular risk.

seem to play important roles in different physiological functions.

Ana Paula Silva\*, Anabela Malho Guedes and Pedro Leão Neves

in end-stage renal disease. Kidney Int. 2003;**63**:105-110

related cardiovascular disease. Circulation. 2016;**133**:518-536

logic perspective. Kidney International. 2006;**70**:26-33

Advances in Chronic Kidney Disease. 2010;**17**:215-224

of Kidney Diseases. 2002;**39**(Suppl 2):S1-S246

\*Address all correspondence to: anapassionara@gmail.com

**4. Conclusions**

**Author details**

Faro, Portugal

**References**

May-Jun;**1**(3):178-184

### **3.4. Klotho**

The Klotho protein is a potential marker for vascular events. Suppression of the Klotho gene in animal models causes extensive aging-like phenotypes, including atherosclerosis, ectopic calcification, infertility, skin atrophy, and severe hypoglycemia [141], while its overexpression increases life span by 20–30%, in animal models [142]. The Klotho protein is present mainly in the distal tubules of the kidney and in the cerebral choroid plexus, but it can be posttranslationally processed and released into the bloodstream, with the free extracellular domain functioning as a hormone [143, 144]. Its presence in vascular tissue is still a topic of debate [145].

An important physiological property attributed to circulating Klotho is the start of a pathway that inhibits insulin and IGF1 signaling, which contributes to the integrity of the microcirculation and of a healthy endothelium [146, 147].

In chronic kidney disease, serum levels of Klotho are decreased, contributing to increased cardiovascular risk in this population. Tests have been carried out in wild-type and transgenic mice, where it was observed that KL-/- mice with chronic kidney disease (CKD) showed early calcification of the soft tissues compared to wild-type mice (KL+/+) that also had CKD. Mice with CKD that overexpress Klotho (preserved levels of Klotho) showed greater phosphaturia and, consequently, better renal function and less calcification of tissues compared to wildtype mice with CKD [148].

The role of Klotho in uremic myocardiopathy is not yet fully understood. However, in animal models, we know that ventricular hypertrophy is associated with increased expression of transient receptor potential canonical (TRPC6) channels, whose expression is regulated by different mechanisms. Recently, Xie et al. demonstrated that Klotho can inhibit the cardiac TRPC6 channels, thereby protecting the myocardium against excessive/pathological remodeling [149, 150].

The cardioprotective mechanisms of Klotho and the role of FGF23 in the cardiac fibrosis of CKD are not yet fully explained. However, some studies have demonstrated that there are several factors responsible for this complex process: (1) cardiac fibrosis and hypertrophy are associated with primary genetic Klotho deficiency or secondary deficiency associated with aging and CKD; (2) cardiac hypertrophy precedes cardiac fibrosis and is associated with left ventricular dysfunction; (3) high levels of phosphate and low serum levels of Klotho correlate with more cardiac hypertrophy and fibrosis in all the studied models; (4) even in the absence of Klotho, important actions of FGF23 on the cardiomyocytes occur by an intracellular route that is not clarified, promoting cardiac hypertrophy [151, 152].

The role of emerging factors like FGF23 and Klotho in cardiovascular risk in both the early and late stages of chronic kidney disease is not entirely perceptible. The entire process involves direct and indirect mechanisms that contribute to this high cardiovascular risk.

## **4. Conclusions**

Scialla et al. studied the link between FGF23, P, and coronary calcification as measured by CT scan of the aorta in 1501 subjects with CKD. They concluded that FGF23 was not directly associated with calcification of the aorta and coronary arteries, but rather with phosphorus levels. This group found a link between the severity of the calcification and FGF23 and concluded that FGF23 may be a marker of surveillance and not of the genesis of vascular

The Klotho protein is a potential marker for vascular events. Suppression of the Klotho gene in animal models causes extensive aging-like phenotypes, including atherosclerosis, ectopic calcification, infertility, skin atrophy, and severe hypoglycemia [141], while its overexpression increases life span by 20–30%, in animal models [142]. The Klotho protein is present mainly in the distal tubules of the kidney and in the cerebral choroid plexus, but it can be posttranslationally processed and released into the bloodstream, with the free extracellular domain functioning as a hormone [143, 144]. Its presence in vascular tissue is still a topic of

An important physiological property attributed to circulating Klotho is the start of a pathway that inhibits insulin and IGF1 signaling, which contributes to the integrity of the microcircula-

In chronic kidney disease, serum levels of Klotho are decreased, contributing to increased cardiovascular risk in this population. Tests have been carried out in wild-type and transgenic mice, where it was observed that KL-/- mice with chronic kidney disease (CKD) showed early calcification of the soft tissues compared to wild-type mice (KL+/+) that also had CKD. Mice with CKD that overexpress Klotho (preserved levels of Klotho) showed greater phosphaturia and, consequently, better renal function and less calcification of tissues compared to wild-

The role of Klotho in uremic myocardiopathy is not yet fully understood. However, in animal models, we know that ventricular hypertrophy is associated with increased expression of transient receptor potential canonical (TRPC6) channels, whose expression is regulated by different mechanisms. Recently, Xie et al. demonstrated that Klotho can inhibit the cardiac TRPC6 channels, thereby protecting the myocardium against excessive/pathological

The cardioprotective mechanisms of Klotho and the role of FGF23 in the cardiac fibrosis of CKD are not yet fully explained. However, some studies have demonstrated that there are several factors responsible for this complex process: (1) cardiac fibrosis and hypertrophy are associated with primary genetic Klotho deficiency or secondary deficiency associated with aging and CKD; (2) cardiac hypertrophy precedes cardiac fibrosis and is associated with left ventricular dysfunction; (3) high levels of phosphate and low serum levels of Klotho correlate with more cardiac hypertrophy and fibrosis in all the studied models; (4) even in the absence of Klotho, important actions of FGF23 on the cardiomyocytes occur by an intracellular route

that is not clarified, promoting cardiac hypertrophy [151, 152].

calcification [140].

**3.4. Klotho**

debate [145].

tion and of a healthy endothelium [146, 147].

92 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

type mice with CKD [148].

remodeling [149, 150].

Chronic kidney disease is an independent risk factor for increased cardiovascular morbidity and mortality. It has a complex pathogenesis, and traditional risk factors are not able to fully explain its high incidence and prevalence. Several substances have been identified, and they seem to play important roles in different physiological functions.

The CKD mineral disease is another player in this complex puzzle and is one of the factors responsible for this high cardiovascular risk of this population in the early or late stages of the CKD.

## **Author details**

Ana Paula Silva\*, Anabela Malho Guedes and Pedro Leão Neves

\*Address all correspondence to: anapassionara@gmail.com

Nephrology Department, Centro Hospitalar do Algarve, Algarve Biomedical Center, Faro, Portugal

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**Chapter 5**

**Provisional chapter**

**Cardiovascular Aspects of Patients with Chronic Kidney**

Chronic kidney disease (CKD) is a globally recognized public health concern. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. CKD causes accelerated coronary artery disease (CAD). In this chapter, we discuss the pathophysi‐ ological mechanisms that play a role in increasing CVD risk in patients with CKD. Further we delve into some commonly encountered challenges related to CVD in patients with CKD. These include revascularization challenges, contrasted induced nephropathy and alterations in traditional risk factors for CVD in renal transplant

**Keywords:** coronary artery disease, chronic kidney disease, mortality, morbidity, public

Chronic kidney disease (CKD) is recognized as a major global public health problem [1]. It is estimated that 10–25% of population from Asia, Australia, Europe and United States of

Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. These include the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular

**Cardiovascular Aspects of Patients with Chronic Kidney** 

DOI: 10.5772/intechopen.69294

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Disease and End-Stage Renal Disease**

**Disease and End-Stage Renal Disease**

Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and

Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Ali Osama Malik, Sumit Sehgal,

Ali Osama Malik, Sumit Sehgal,

http://dx.doi.org/10.5772/intechopen.69294

Chowdhury Ahsan

**Abstract**

patients.

health

**1. Introduction**

America (USA) is affected by CKD [2–6].

Chowdhury Ahsan


**Provisional chapter**

## **Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease Disease and End-Stage Renal Disease**

**Cardiovascular Aspects of Patients with Chronic Kidney** 

DOI: 10.5772/intechopen.69294

Ali Osama Malik, Sumit Sehgal, Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and Chowdhury Ahsan Hashim Hussnain Ahmed, Subodh Devabhaktuni, Edward Co, Arhama Aftab Malik, Syed Shah and Chowdhury Ahsan Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.69294

Ali Osama Malik, Sumit Sehgal,

#### **Abstract**

[149] Xie J, Yoon J, An SW, Kuro-o M, Huang CL. Soluble klotho protects against uremic cardiomyopathy independently of fibroblast growth factor 23 and phosphate. Journal of

[150] Xie J, Cha SK, An SW, Kuro-O M, Birnbaumer L, Huang CL, Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart. Nature Communications.

[151] Hu MC, Shi M, Cho HJ, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. American Society of Nephrology. 2015;**26**(6):1290-1302 [152] Floege J, Fliser D.Klotho Deficiency and the cardiomyopathy of advanced CKD. Journal

the American Society of Nephrology. 2015 May;**26**(5):1150-1160

104 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

of the American Society of Nephrology. 2015;**26**:1229-1237

2012;**3**:1238

Chronic kidney disease (CKD) is a globally recognized public health concern. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. CKD causes accelerated coronary artery disease (CAD). In this chapter, we discuss the pathophysi‐ ological mechanisms that play a role in increasing CVD risk in patients with CKD. Further we delve into some commonly encountered challenges related to CVD in patients with CKD. These include revascularization challenges, contrasted induced nephropathy and alterations in traditional risk factors for CVD in renal transplant patients.

**Keywords:** coronary artery disease, chronic kidney disease, mortality, morbidity, public health

## **1. Introduction**

Chronic kidney disease (CKD) is recognized as a major global public health problem [1]. It is estimated that 10–25% of population from Asia, Australia, Europe and United States of America (USA) is affected by CKD [2–6].

Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors. These include the Atherosclerosis Risk in Communities study (ARIC) and the Cardiovascular

Health Study [7–9]. The risk of developing congestive heart failure, atrial fibrillation, stroke, coronary artery disease (CAD) and peripheral artery disease (PAD) is increased twofold in patients with glomerular filtration rate (eGFR) < 70ml/min/1.73m<sup>2</sup> [8, 10]. Furthermore, in two separate meta‐analyses of twenty‐one studies from fourteen different countries eGFR and albuminuria were found to be independently associated with increased risk of all‐cause and cardiovascular mortality [11, 12].

**2.2. Albuminuria a marker of worse cardiovascular outcomes in CKD patients**

albuminuria have been reported in other large scale studies [11, 12].

**3. Ischemic heart disease in chronic kidney disease**

**3.1. Background**

higher in the CKD population [24].

factor for developing CVD [30].

**3.2. Revascularization in CKD patients with stable CAD**

trials, the efficacy of these agents in patients with CKD is still unclear.

Abuminuria has been proven to be a significant risk factor for all cause and CVD related mor‐ tality in patients with CKD. Pooled data from Van der Welde et al., demonstrated a significant increase in cardiovascular mortality in patients with Albumin‐to‐creatinine ratio of 10 mg/dl compared to 5 mg/dl [22]. Similar results demonstrating an association of CVD mortality with

Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease

http://dx.doi.org/10.5772/intechopen.69294

107

Cardiovascular (CV) mortality is the leading cause of death in CKD patients and the risk of CV mortality increases with decrease in eGFR. Most of the burden of CV mortality in CKD patients is secondary to ischemic heart disease or complications associated with it including congestive heart failure. The severity and incidence of CAD increases as the kidney function declines with the prevalence of multi‐vessel CAD and left main disease being significantly

Coronary arteries in CKD patients have shown to exhibit more extensive atherosclerosis [25]. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors [26, 27]. Mineralocorticoid excess, oxidative stress and cellular inflammation are linked to plaque for‐ mation and rupture in CKD patients. Vitamin D deficiency a common sequela of CKD could explain the propensity of CKD patients to develop CAD. It has been shown that patients with Vitamin D deficiency have higher risk of myocardial infarction (MI). Similarly fibroblast growth factor 23 (FGF 23) a hormone usually elevated in CKD patients, to mitigate hyper‐ phosphatemia was associated with increased CVD mortality in patients with CKD [28, 29].

In summation, the pathophysiological basis of increased CVD risk and severity in patients with CKD is due to a complex interplay of factors involving hormonal and immune mediated responses. However the risk of CAD in CKD has been well established. Hence in 2013 the American Heart Association (AHA) issued a statement to classify CKD as an independent risk

Management of patients with established CAD and CKD is challenging. Medical manage‐ ment in patients with renal dysfunction has been based on therapy shown to be beneficial in patient population without CKD. These medications include aspirin, beta‐blockers, nitrates, hydroxymethylglutaryl co‐enzyme A reductase inhibitors (statins) and angiotensin convert‐ ing enzyme inhibitors. However because of routine exclusion of CKD patients from clinical

In this chapter we discuss the acute and chronic cardiovascular impact of patients with reduced kidney function. We further delve in evaluation of coronary artery disease in patients with CKD. We also address the cardiovascular aspects of patient care in renal transplant patients including modification of traditional CVD risk factors in patients taking immuno‐ suppressive therapy.

## **2. Epidemiology**

CKD is a globally recognized public health burden [13]. USA alone deals with a population of more than 20 million people with CKD [14]. Data from other developed and developing nations confirms the rising trend of the disease. Data from China estimates this number to be close to 100 million Chinese being affected with CKD [15].

CKD has long shared its associations with CVD. The prevalence of CVD among patients with CKD has been known across trials in USA, Japan, Spain, United Kingdom and, recently, across China. Highest prevalence was found in U.K., 47.2% followed by Spain, 39.1%, U.S., 33.4%, Japan, 26.8% and China 9.8% [16–19].

United States Renal Data System (USRDS) reports from 2016 revealed the prevalence of any cardiovascular event to be twice among those with CKD compared to those without it, 68.8% vs. 34.1% respectively.

## **2.1. Linear relationship of cardiovascular mortality with EGFR**

CKD is an independent risk factor for progression to cardiovascular disease, known to con‐ tribute to cardiovascular morbidity and mortality [20]. Go et al., using longitudinal measure‐ ment of estimated eGFR, demonstrated the inverse relationship between eGFR and mortality rate secondary to cardiovascular events, below an eGFR of 60 ml/min per 1.73 m<sup>2</sup> [21]. A meta‐ analysis from 2011, comprising a grand total of 266,975 patients reported an exponential rise in mortality with eGFR below 60 ml/min per 1.73 m<sup>2</sup> [22]. (21,307,840) For cardiovascular mor‐ tality, adjusted hazard ratios at eGFR 60, 45, and 15 ml/min per 1.73 m<sup>2</sup> were 1.11 (0.93–1.32), 1.73 (1.49–2.00), and 3.08 (1.89–5.01), respectively [22].

Manjunath et al., also demonstrated eGFR as an independent risk factor for progression to CVD [23]. In a sample population of 4893, subjects with GFR 90 mL/min/1.73 m<sup>2</sup> had a 15% risk of CVD over 3 years while subjects with GFR 30 mL/min/1.73 m<sup>2</sup> had a 40% risk of CVD [23]. These findings were independent from traditional risk factors of cardiovascular diseases.

## **2.2. Albuminuria a marker of worse cardiovascular outcomes in CKD patients**

Abuminuria has been proven to be a significant risk factor for all cause and CVD related mor‐ tality in patients with CKD. Pooled data from Van der Welde et al., demonstrated a significant increase in cardiovascular mortality in patients with Albumin‐to‐creatinine ratio of 10 mg/dl compared to 5 mg/dl [22]. Similar results demonstrating an association of CVD mortality with albuminuria have been reported in other large scale studies [11, 12].

## **3. Ischemic heart disease in chronic kidney disease**

## **3.1. Background**

Health Study [7–9]. The risk of developing congestive heart failure, atrial fibrillation, stroke, coronary artery disease (CAD) and peripheral artery disease (PAD) is increased twofold in

separate meta‐analyses of twenty‐one studies from fourteen different countries eGFR and albuminuria were found to be independently associated with increased risk of all‐cause and

In this chapter we discuss the acute and chronic cardiovascular impact of patients with reduced kidney function. We further delve in evaluation of coronary artery disease in patients with CKD. We also address the cardiovascular aspects of patient care in renal transplant patients including modification of traditional CVD risk factors in patients taking immuno‐

CKD is a globally recognized public health burden [13]. USA alone deals with a population of more than 20 million people with CKD [14]. Data from other developed and developing nations confirms the rising trend of the disease. Data from China estimates this number to be

CKD has long shared its associations with CVD. The prevalence of CVD among patients with CKD has been known across trials in USA, Japan, Spain, United Kingdom and, recently, across China. Highest prevalence was found in U.K., 47.2% followed by Spain, 39.1%, U.S.,

United States Renal Data System (USRDS) reports from 2016 revealed the prevalence of any cardiovascular event to be twice among those with CKD compared to those without it, 68.8%

CKD is an independent risk factor for progression to cardiovascular disease, known to con‐ tribute to cardiovascular morbidity and mortality [20]. Go et al., using longitudinal measure‐ ment of estimated eGFR, demonstrated the inverse relationship between eGFR and mortality

analysis from 2011, comprising a grand total of 266,975 patients reported an exponential rise

Manjunath et al., also demonstrated eGFR as an independent risk factor for progression to

These findings were independent from traditional risk factors of cardiovascular diseases.

rate secondary to cardiovascular events, below an eGFR of 60 ml/min per 1.73 m<sup>2</sup>

CVD [23]. In a sample population of 4893, subjects with GFR 90 mL/min/1.73 m<sup>2</sup>

tality, adjusted hazard ratios at eGFR 60, 45, and 15 ml/min per 1.73 m<sup>2</sup>

of CVD over 3 years while subjects with GFR 30 mL/min/1.73 m<sup>2</sup>

[8, 10]. Furthermore, in two

[21]. A meta‐

had a 15% risk

were 1.11 (0.93–1.32),

had a 40% risk of CVD [23].

[22]. (21,307,840) For cardiovascular mor‐

patients with glomerular filtration rate (eGFR) < 70ml/min/1.73m<sup>2</sup>

106 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

close to 100 million Chinese being affected with CKD [15].

**2.1. Linear relationship of cardiovascular mortality with EGFR**

in mortality with eGFR below 60 ml/min per 1.73 m<sup>2</sup>

1.73 (1.49–2.00), and 3.08 (1.89–5.01), respectively [22].

33.4%, Japan, 26.8% and China 9.8% [16–19].

cardiovascular mortality [11, 12].

suppressive therapy.

**2. Epidemiology**

vs. 34.1% respectively.

Cardiovascular (CV) mortality is the leading cause of death in CKD patients and the risk of CV mortality increases with decrease in eGFR. Most of the burden of CV mortality in CKD patients is secondary to ischemic heart disease or complications associated with it including congestive heart failure. The severity and incidence of CAD increases as the kidney function declines with the prevalence of multi‐vessel CAD and left main disease being significantly higher in the CKD population [24].

Coronary arteries in CKD patients have shown to exhibit more extensive atherosclerosis [25]. Multiple studies have shown the association of CKD with cardiovascular mortality that persists after adjustment for traditional cardiovascular disease (CVD) risk factors [26, 27]. Mineralocorticoid excess, oxidative stress and cellular inflammation are linked to plaque for‐ mation and rupture in CKD patients. Vitamin D deficiency a common sequela of CKD could explain the propensity of CKD patients to develop CAD. It has been shown that patients with Vitamin D deficiency have higher risk of myocardial infarction (MI). Similarly fibroblast growth factor 23 (FGF 23) a hormone usually elevated in CKD patients, to mitigate hyper‐ phosphatemia was associated with increased CVD mortality in patients with CKD [28, 29].

In summation, the pathophysiological basis of increased CVD risk and severity in patients with CKD is due to a complex interplay of factors involving hormonal and immune mediated responses. However the risk of CAD in CKD has been well established. Hence in 2013 the American Heart Association (AHA) issued a statement to classify CKD as an independent risk factor for developing CVD [30].

## **3.2. Revascularization in CKD patients with stable CAD**

Management of patients with established CAD and CKD is challenging. Medical manage‐ ment in patients with renal dysfunction has been based on therapy shown to be beneficial in patient population without CKD. These medications include aspirin, beta‐blockers, nitrates, hydroxymethylglutaryl co‐enzyme A reductase inhibitors (statins) and angiotensin convert‐ ing enzyme inhibitors. However because of routine exclusion of CKD patients from clinical trials, the efficacy of these agents in patients with CKD is still unclear.

No robust evidence is yet available to ascertain whether CKD patients with chronic stable angina who undergo revascularization have a definite survival advantage compared to CKD patients on medical therapy alone. In the only randomized study of dialysis patients compar‐ ing invasive approach (PCI and coronary artery bypass graft surgery (CABG)) with medical therapy alone, the invasive approach had a clear survival benefit [31]. However medical therapy at that time only consisted of calcium channel blockers, and use of other agents proven to have survival advantage in patients with cardiovascular disease was not the norm. Furthermore, this study only included patients with diabetes mellitus. In another study done in 2002, PCI did not significantly improve survival [32].

and other comorbid conditions [46]. However in analysis of CREDO‐Hyoto PCI/CABG reg‐ istry Marui A et al. found CABG relative to PCI reduced risk of cardiac death, sudden death, myocardial infarction and need for revascularization in patients with left main disease or multi‐vessel CAD only [47]. In a study by Banglore et al., revascularization with Everolimus eluting stensts was compared to CABG in patients with CKD. The authors concluded that CABG was associated with higher short term risk of death, stroke and repeat revasculariza‐ tion, whereas PCI with everolimus‐eluting stent was associated with higher long‐term risk of revascularization and perhaps MI [48]. Current American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend CABG for patients with left main

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As already mentioned CKD patients are at a higher risk of CVD. Imaging plays a central role in risk stratification and assessment of severity of CAD. A range of imaging modalities have been developed to assist with diagnosis and risk stratification of CVD in patients with CKD. Myocardial perfusion imaging (MPI) is widely used for non‐invasive assessment of myocar‐ dial ischemia due to CAD [49]. MPI can be performed using single photon emission computed tomography (SPECT) as well as positron emission tomography (PET). SPECT MPI is more widely available. It can be performed with a variety of stressors such as exercise or administra‐ tion of vasodilatory agents (adenosine or regadenoson) or dobutamine. SPECT detects areas of reduced perfusion by measuring and comparing the distribution of injected radioactive trac‐ ers such as 99 technetium or 201 thallium, when at rest and after stressor/vasodilator agents. For PET MPI stress perfusion is measured in the same way as SPECT. Various agents can be used as radiotracer including H2 15 O, ammonia or rubidium. With PET absolute quantifica‐ tion of myocardial blood flow is possible. Although both SPECT and PET MPI have widely been studied for detection of CAD in general population, data regarding their use in CKD

Echocardiography plays a pivotal role in assessment of cardiac dysfunction in patients with or without renal insufficiency. Various cardiac abnormalities including left ventricular hyper‐ trophy (LVH), diastolic or systolic dysfunction are predictive of poor prognosis in CKD patients and can be rapidly diagnosed using 2 D trans‐thoracic echocardiogram (TTE). Stress echocardiography is an established technique used to investigate myocardial viability and ischemia. Patients can be stressed either pharmacologically with dobutamine or with exer‐ cise [50]. However, the sensitivity and specificity of stress echocardiography is modest in patients with CKD. In a systemic review by Sharma et al. sensitivity of stress echocardiogra‐ phy was 80% in patients with ESRD [51]. Factors limiting the role of stress echocardiography for detecting CAD in patients with CKD include LVH and blunted chronotropic response in

CT coronary angiography (CTA) has good sensitivity and specificity for detection of CAD in non‐ CKD population [54]. However, data is limited in patients with CKD. Iodinated contrast agent is required that increases the risk of contrast induced nephropathy. (contrast induced nephropathy

or multi‐vessel disease irrespective of renal function.

population in limited.

patients with CKD [52, 53].

**3.3. Non‐invasive cardiac imaging in patients with CKD**

Multiple studies have found that patients with CKD who undergo revascularization for CAD have worst outcomes compared to patients with normal kidney function [32, 33]. Patients with CKD have more cardiovascular risk factors at baseline [32]. Furthermore, CKD itself was independently associated with worst outcomes including increased all‐cause mortality and subsequent cardiac events [32].

In CKD revascularization procedures including percutanous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are complicated by risk of contrast induced nephropathy (CIN) and increased risk of bleeding due to dual antiplatelet therapy. CIN is discussed in detail in separate section.

CKD results in complex hemostatic disorder manifested by increased bleeding and thrombo‐ sis. Hence the use of antiplatelet therapy has the potential for both benefit and harm. Reduced platelet aggregation, intrinsic platelet dysfunction and abnormalities in platelet‐endothelial interactions are found in CKD and may in part account for increased bleeding risk with PCI in these patients [34–36].

On the contrary, some studies have suggested the presence of pro‐thrombotic state in CKD patients that manifest by an increase in serum fibrinogen, von Willibrand factor and reduc‐ tion in antithrombin 3 [34, 37–39]. Therefore, it is unclear whether dual antiplatelet therapy after PCI is beneficial and safe in CKD patients. Furthermore, few studies have evaluated the appropriate dosing of antithrombotic agents or anticoagulants in patients with CKD [40].

Although clinical restenosis rates are not higher compared to patients with normal renal func‐ tion, on repeated angiography restenosis rates were found to be as high as 60–81% [41, 42]. Thus, absence of symptoms of restenosis in patients with chronic renal insufficiency may lead to silent ischemia and contribute to high risk of subsequent cardiac events.

CKD patients have worse outcomes after CABG. One study found in‐hospital mortality rate to be 14.6% [43]. Another study that was done on end‐stage renal disease (ESRD) patients over course of 10 years found peri‐operative mortality to be about 14% in cardiac surgery patients [44]. Even mild renal insufficiency is associated with double in‐hospitality rates in one analysis [45]. CAD is more diffuse in patients with renal dysfunction which likely contrib‐ utes higher complication rates and worst outcomes.

Szczech et al. published a study in 2001 that showed survival benefit among patients with ESRD undergoing CABG as compared to PCI, while controlling for severity of CAD, LV dysfunction and other comorbid conditions [46]. However in analysis of CREDO‐Hyoto PCI/CABG reg‐ istry Marui A et al. found CABG relative to PCI reduced risk of cardiac death, sudden death, myocardial infarction and need for revascularization in patients with left main disease or multi‐vessel CAD only [47]. In a study by Banglore et al., revascularization with Everolimus eluting stensts was compared to CABG in patients with CKD. The authors concluded that CABG was associated with higher short term risk of death, stroke and repeat revasculariza‐ tion, whereas PCI with everolimus‐eluting stent was associated with higher long‐term risk of revascularization and perhaps MI [48]. Current American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend CABG for patients with left main or multi‐vessel disease irrespective of renal function.

## **3.3. Non‐invasive cardiac imaging in patients with CKD**

No robust evidence is yet available to ascertain whether CKD patients with chronic stable angina who undergo revascularization have a definite survival advantage compared to CKD patients on medical therapy alone. In the only randomized study of dialysis patients compar‐ ing invasive approach (PCI and coronary artery bypass graft surgery (CABG)) with medical therapy alone, the invasive approach had a clear survival benefit [31]. However medical therapy at that time only consisted of calcium channel blockers, and use of other agents proven to have survival advantage in patients with cardiovascular disease was not the norm. Furthermore, this study only included patients with diabetes mellitus. In another study done

Multiple studies have found that patients with CKD who undergo revascularization for CAD have worst outcomes compared to patients with normal kidney function [32, 33]. Patients with CKD have more cardiovascular risk factors at baseline [32]. Furthermore, CKD itself was independently associated with worst outcomes including increased all‐cause mortality and

In CKD revascularization procedures including percutanous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are complicated by risk of contrast induced nephropathy (CIN) and increased risk of bleeding due to dual antiplatelet therapy. CIN is

CKD results in complex hemostatic disorder manifested by increased bleeding and thrombo‐ sis. Hence the use of antiplatelet therapy has the potential for both benefit and harm. Reduced platelet aggregation, intrinsic platelet dysfunction and abnormalities in platelet‐endothelial interactions are found in CKD and may in part account for increased bleeding risk with PCI

On the contrary, some studies have suggested the presence of pro‐thrombotic state in CKD patients that manifest by an increase in serum fibrinogen, von Willibrand factor and reduc‐ tion in antithrombin 3 [34, 37–39]. Therefore, it is unclear whether dual antiplatelet therapy after PCI is beneficial and safe in CKD patients. Furthermore, few studies have evaluated the appropriate dosing of antithrombotic agents or anticoagulants in patients with CKD [40].

Although clinical restenosis rates are not higher compared to patients with normal renal func‐ tion, on repeated angiography restenosis rates were found to be as high as 60–81% [41, 42]. Thus, absence of symptoms of restenosis in patients with chronic renal insufficiency may lead

CKD patients have worse outcomes after CABG. One study found in‐hospital mortality rate to be 14.6% [43]. Another study that was done on end‐stage renal disease (ESRD) patients over course of 10 years found peri‐operative mortality to be about 14% in cardiac surgery patients [44]. Even mild renal insufficiency is associated with double in‐hospitality rates in one analysis [45]. CAD is more diffuse in patients with renal dysfunction which likely contrib‐

Szczech et al. published a study in 2001 that showed survival benefit among patients with ESRD undergoing CABG as compared to PCI, while controlling for severity of CAD, LV dysfunction

to silent ischemia and contribute to high risk of subsequent cardiac events.

utes higher complication rates and worst outcomes.

in 2002, PCI did not significantly improve survival [32].

108 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

subsequent cardiac events [32].

in these patients [34–36].

discussed in detail in separate section.

As already mentioned CKD patients are at a higher risk of CVD. Imaging plays a central role in risk stratification and assessment of severity of CAD. A range of imaging modalities have been developed to assist with diagnosis and risk stratification of CVD in patients with CKD.

Myocardial perfusion imaging (MPI) is widely used for non‐invasive assessment of myocar‐ dial ischemia due to CAD [49]. MPI can be performed using single photon emission computed tomography (SPECT) as well as positron emission tomography (PET). SPECT MPI is more widely available. It can be performed with a variety of stressors such as exercise or administra‐ tion of vasodilatory agents (adenosine or regadenoson) or dobutamine. SPECT detects areas of reduced perfusion by measuring and comparing the distribution of injected radioactive trac‐ ers such as 99 technetium or 201 thallium, when at rest and after stressor/vasodilator agents.

For PET MPI stress perfusion is measured in the same way as SPECT. Various agents can be used as radiotracer including H2 15 O, ammonia or rubidium. With PET absolute quantifica‐ tion of myocardial blood flow is possible. Although both SPECT and PET MPI have widely been studied for detection of CAD in general population, data regarding their use in CKD population in limited.

Echocardiography plays a pivotal role in assessment of cardiac dysfunction in patients with or without renal insufficiency. Various cardiac abnormalities including left ventricular hyper‐ trophy (LVH), diastolic or systolic dysfunction are predictive of poor prognosis in CKD patients and can be rapidly diagnosed using 2 D trans‐thoracic echocardiogram (TTE). Stress echocardiography is an established technique used to investigate myocardial viability and ischemia. Patients can be stressed either pharmacologically with dobutamine or with exer‐ cise [50]. However, the sensitivity and specificity of stress echocardiography is modest in patients with CKD. In a systemic review by Sharma et al. sensitivity of stress echocardiogra‐ phy was 80% in patients with ESRD [51]. Factors limiting the role of stress echocardiography for detecting CAD in patients with CKD include LVH and blunted chronotropic response in patients with CKD [52, 53].

CT coronary angiography (CTA) has good sensitivity and specificity for detection of CAD in non‐ CKD population [54]. However, data is limited in patients with CKD. Iodinated contrast agent is required that increases the risk of contrast induced nephropathy. (contrast induced nephropathy is discussed in separate section) Furthermore concerns exist that diffuse calcifications in CKD patients might render interpretation of CTA findings difficult. In patients on hemodialysis (HD) calcifications can occur in intima, where it contributes to luminal stenosis or medial where it is related to vascular stiffness. CTA might not be able to discern the difference. Despite these limi‐ tations some small studies have reported > 90% sensitivity of CTA to detect CAD in patients on HD [55]. However, coronary angiography was not used as gold standard in these studies.

and Troponin I (cTnI) are considered the preferred biochemical markers to detect myocar‐ dial injury and to diagnose acute myocardial infarction (AMI). Since the introduction of high sensitivity cardiac troponin (hs‐cTn) assays, more accurate detection of low levels of circulat‐

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111

However the increase in sensitivity of hs‐cTn for AMI is accompanied by decrease in specific‐ ity [68, 69]. In patients with chronic kidney disease elevated hs‐cTn concentrations are associ‐

The interpretation of serum markers for myocardial injury in patients with renal insufficiency remains controversial. Large scale trials of patients with acute coronary syndrome (ACS) have documented the importance of troponin elevations in risk stratification, prognosis and thera‐ peutic utilization. However most of these studies excluded patients with renal insufficiency. Cardinaels et al. recently showed that in patients with acute chest discomfort hs‐cTnT and hs‐ cTnI were strongly correlated with eGFR [70]. Although differences were small, the authors reported a greater correlation of hs‐cTnT with eGFR compared to hs‐cTnI. Furthermore, the association of hs‐cTnT is greater with eGFR as compared to any other cardiac parameters including coronary plaque severity, coronary calcium score and left ventricular structure [70]. In contrast to hs‐TnT, hs‐TnI has a greater association with LV mass compared to eGFR. Hence it is possible that hs‐TnT is more susceptible to renal clearance then hs‐cTnI. However, these

Furthermore, many investigators have hypothesized uremic‐induced skeletal myopathy may be responsible for increased troponins in patients with renal failure [66]. This conclu‐ sion is centered on the notion that uremia may promote re‐expression of cardiac TnT from injured or regenerating cardiac muscle fibers. Some anecdotal reports show elevated serum TnT levels in patients with skeletal muscle injury or inflammatory myopathies in the absence of any obvious myocardial ischemia [71, 72]. In marathon runners without any history of cor‐ onary artery disease cardiac TnT levels were elevated after running a marathon [73]. Hence cardiac troponin levels may be elevated in patients with renal insufficiency in the absence of AMI due to increased production from skeletal muscles and possible due to decreased renal clearance. It is imperative to evaluate troponin concentrations in patients with CKD in proper clinical context and utilization of other resources such as Electrocardiogram (EKG)

The heart and kidneys work together to manage blood pressure, electrolyte and fluid excre‐ tion, but most importantly extracellular fluid balance [74]. Cardio‐renal syndrome (CRS) is defined as a broad spectrum of diseases where both the heart and kidneys are involved in an

There are five types of CRSs. Type I, or acute CRS, is acute heart failure leading to acute kidney injury [74] Type II, or chronic CRS, occurs in the setting of chronic heart failure which leads to kidney injury [75]. Type III or acute nephrocardiac is caused by acute kidney injury

ing cardiac troponins became feasible [67].

differences are yet to be completely established.

to rule out AMI.

**5. Cardio‐renal Syndromes**

acute or chronic setting [75]

ated with reduced renal function.

Leading authors have advocated for combining functional imaging technique with anatomi‐ cal imaging technique for CAD screening in clinical practice. Although these hybrid tech‐ niques are potentially useful in general population, none have been validated in patients with CKD [56, 82]. Role of non‐invasive imaging for pre‐transplant evaluation of CAD is addressed in a separate section.

#### **3.4. Contrast Induced Nephropathy**

PCI in patients with CKD is challenging due to presence of complex calcified lesions and the very high risk of CIN. PCI in patients with advanced CKD is associated with increased risk of CIN which is independently associated with major adverse clinical events [57]. Outcomes are even worse if renal replacement therapy is required [57].

Pathophysiologically several mechanisms are involved in acute kidney injury caused by CIN. Studies have shown evidence of acute tubular necrosis (ATN). Two mechanism of ATN have been postulated. Direct nephrotoxicity of contrast agents has been documented [58, 59]. Furthermore, it has also been hypothesized that renal vasoconstriction, mediated by endothelin and prostaglandins resulting in medullary hypoxia causes ATN [60–62].

Studies have demonstrated a dose‐dependent relationship of acute kidney injury (AKI) caused by CIN [63]. The type of contrast alters the risk of CIN. The use of first generation hyperosmo‐ lar ionic agents is associated with a greater risk of CIN [64]. Prevention strategies for CIN that have been well established also apply to patients undergoing PCI. These include using minimal amount of contrast, avoiding ionic contrast and non‐steroidal anti‐inflammatory drugs (NSAIDs).

Most recently Galougahi et al. have described a case series of a unique approach toward revascularization in patients with CKD by sequential diagnostic angiography using ultra‐ low volumes of contrast followed by staged physiology and intravascular ultrasound (IVUS)‐ guided zero contrast PCI in three patients with severely calcified coronary lesions [65]. While such strategies have potential for more wider acceptance, at this time they are not practiced widely due to technical and procedural limitations.

## **4. Use of troponin concentration level in patients with chronic kidney disease**

Troponin proteins are present in both cardiac and skeletal muscle [66]. Cardiac troponin C is identicial to troponin C expressed in skeletal muscle. However cardiac troponin TnT and TnI are each derived from genes that are specific to the heart [66]. Hence troponin T (cTnT) and Troponin I (cTnI) are considered the preferred biochemical markers to detect myocar‐ dial injury and to diagnose acute myocardial infarction (AMI). Since the introduction of high sensitivity cardiac troponin (hs‐cTn) assays, more accurate detection of low levels of circulat‐ ing cardiac troponins became feasible [67].

However the increase in sensitivity of hs‐cTn for AMI is accompanied by decrease in specific‐ ity [68, 69]. In patients with chronic kidney disease elevated hs‐cTn concentrations are associ‐ ated with reduced renal function.

The interpretation of serum markers for myocardial injury in patients with renal insufficiency remains controversial. Large scale trials of patients with acute coronary syndrome (ACS) have documented the importance of troponin elevations in risk stratification, prognosis and thera‐ peutic utilization. However most of these studies excluded patients with renal insufficiency.

Cardinaels et al. recently showed that in patients with acute chest discomfort hs‐cTnT and hs‐ cTnI were strongly correlated with eGFR [70]. Although differences were small, the authors reported a greater correlation of hs‐cTnT with eGFR compared to hs‐cTnI. Furthermore, the association of hs‐cTnT is greater with eGFR as compared to any other cardiac parameters including coronary plaque severity, coronary calcium score and left ventricular structure [70]. In contrast to hs‐TnT, hs‐TnI has a greater association with LV mass compared to eGFR. Hence it is possible that hs‐TnT is more susceptible to renal clearance then hs‐cTnI. However, these differences are yet to be completely established.

Furthermore, many investigators have hypothesized uremic‐induced skeletal myopathy may be responsible for increased troponins in patients with renal failure [66]. This conclu‐ sion is centered on the notion that uremia may promote re‐expression of cardiac TnT from injured or regenerating cardiac muscle fibers. Some anecdotal reports show elevated serum TnT levels in patients with skeletal muscle injury or inflammatory myopathies in the absence of any obvious myocardial ischemia [71, 72]. In marathon runners without any history of cor‐ onary artery disease cardiac TnT levels were elevated after running a marathon [73]. Hence cardiac troponin levels may be elevated in patients with renal insufficiency in the absence of AMI due to increased production from skeletal muscles and possible due to decreased renal clearance. It is imperative to evaluate troponin concentrations in patients with CKD in proper clinical context and utilization of other resources such as Electrocardiogram (EKG) to rule out AMI.

## **5. Cardio‐renal Syndromes**

is discussed in separate section) Furthermore concerns exist that diffuse calcifications in CKD patients might render interpretation of CTA findings difficult. In patients on hemodialysis (HD) calcifications can occur in intima, where it contributes to luminal stenosis or medial where it is related to vascular stiffness. CTA might not be able to discern the difference. Despite these limi‐ tations some small studies have reported > 90% sensitivity of CTA to detect CAD in patients on HD [55]. However, coronary angiography was not used as gold standard in these studies.

Leading authors have advocated for combining functional imaging technique with anatomi‐ cal imaging technique for CAD screening in clinical practice. Although these hybrid tech‐ niques are potentially useful in general population, none have been validated in patients with CKD [56, 82]. Role of non‐invasive imaging for pre‐transplant evaluation of CAD is addressed

PCI in patients with CKD is challenging due to presence of complex calcified lesions and the very high risk of CIN. PCI in patients with advanced CKD is associated with increased risk of CIN which is independently associated with major adverse clinical events [57]. Outcomes are

Pathophysiologically several mechanisms are involved in acute kidney injury caused by CIN. Studies have shown evidence of acute tubular necrosis (ATN). Two mechanism of ATN have been postulated. Direct nephrotoxicity of contrast agents has been documented [58, 59]. Furthermore, it has also been hypothesized that renal vasoconstriction, mediated by endothelin

Studies have demonstrated a dose‐dependent relationship of acute kidney injury (AKI) caused by CIN [63]. The type of contrast alters the risk of CIN. The use of first generation hyperosmo‐ lar ionic agents is associated with a greater risk of CIN [64]. Prevention strategies for CIN that have been well established also apply to patients undergoing PCI. These include using minimal amount of contrast, avoiding ionic contrast and non‐steroidal anti‐inflammatory drugs (NSAIDs). Most recently Galougahi et al. have described a case series of a unique approach toward revascularization in patients with CKD by sequential diagnostic angiography using ultra‐ low volumes of contrast followed by staged physiology and intravascular ultrasound (IVUS)‐ guided zero contrast PCI in three patients with severely calcified coronary lesions [65]. While such strategies have potential for more wider acceptance, at this time they are not practiced

**4. Use of troponin concentration level in patients with chronic kidney** 

Troponin proteins are present in both cardiac and skeletal muscle [66]. Cardiac troponin C is identicial to troponin C expressed in skeletal muscle. However cardiac troponin TnT and TnI are each derived from genes that are specific to the heart [66]. Hence troponin T (cTnT)

in a separate section.

**disease**

**3.4. Contrast Induced Nephropathy**

even worse if renal replacement therapy is required [57].

110 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

widely due to technical and procedural limitations.

and prostaglandins resulting in medullary hypoxia causes ATN [60–62].

The heart and kidneys work together to manage blood pressure, electrolyte and fluid excre‐ tion, but most importantly extracellular fluid balance [74]. Cardio‐renal syndrome (CRS) is defined as a broad spectrum of diseases where both the heart and kidneys are involved in an acute or chronic setting [75]

There are five types of CRSs. Type I, or acute CRS, is acute heart failure leading to acute kidney injury [74] Type II, or chronic CRS, occurs in the setting of chronic heart failure which leads to kidney injury [75]. Type III or acute nephrocardiac is caused by acute kidney injury


**Table 1.** Classification of cardio‐renal syndromes.

leading to acute heart failure, example Uremic cardiomyopathy [75]. Type IV, or chronic nephrocardiac, occurs with chronic kidney disease which causes heart failure for example diastolic heart failure and kidney failure [75]. Lastly, is type V which is secondary to systemic disease leading to heart and kidney failure [75]. **Table 1** summarizes the five types of CRSs.

Management of patients with acute decompensated heart failure and worsening renal func‐ tion can be challenging. A randomized control trial compared the effect of venovenous ultra‐ filtration with intravenous diuretics on renal function with acute decompensated heart failure and worsening renal function [76]. This study found that there was no significant difference between diuretics and ultrafiltration in weight loss, mortality or the rate of re‐hospitalization for acute decompensated heart failure during a 60 day follow‐up.

## **6. CAD evaluation before kidney transplant**

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) and in those after kidney transplant [77, 78]. Based on Medicare billing claims incidence of myocardial infarction have ranged from 8.7 to 16.7% by 3 years after kidney transplant listing and from 4.7 to 11.1% after kidney transplanta‐ tion [79]. Cardiovascular disease accounts for 30% of the overall mortality especially in the peri‐transplantation period [80]. So, the preoperative cardiovascular risk assessment is of high importance before the kidney transplant surgery as these patients are closely followed up for over the 3 years and events are reported to the United Network for Organ Sharing (UNOS).

**Figure 1** summarizes a clinical approach to preoperative cardiovascular risk assessment before kidney transplantation.

**Figure 1.** Pre‐operative cardiovascular risk assessment before kidney transplant.

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Cardiovascular Aspects of Patients with Chronic Kidney Disease and End-Stage Renal Disease http://dx.doi.org/10.5772/intechopen.69294 113

**Figure 1.** Pre‐operative cardiovascular risk assessment before kidney transplant.

leading to acute heart failure, example Uremic cardiomyopathy [75]. Type IV, or chronic nephrocardiac, occurs with chronic kidney disease which causes heart failure for example diastolic heart failure and kidney failure [75]. Lastly, is type V which is secondary to systemic disease leading to heart and kidney failure [75]. **Table 1** summarizes the five types of CRSs. Management of patients with acute decompensated heart failure and worsening renal func‐ tion can be challenging. A randomized control trial compared the effect of venovenous ultra‐ filtration with intravenous diuretics on renal function with acute decompensated heart failure and worsening renal function [76]. This study found that there was no significant difference between diuretics and ultrafiltration in weight loss, mortality or the rate of re‐hospitalization

**Cardiorenal type Inciting event Secondary event Example**

Type III Acute kidney injury Acute cardiac disease (heart

112 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Type IV Chronic kidney disease Decreased cardiac output,

Type V Systemic disease Both kidney and heart

**Table 1.** Classification of cardio‐renal syndromes.

Type I Acute heart failure Acute kidney injury Acute coronary syndrome

edema)

Type II Chronic heart failure Progressive kidney disease Chronic heart failure leading to

failure, arrhythmia, pulmonary

Increased blood pressure leading

to cardiac hypertrophy

dysfunction and disease

leading to decreased cardiac output and acute kidney injury

decreased cardiac output

Acute kidney failure (drug induced, glomerulonephritis)

Chronic kidney disease due to chronic hypertension or diabetic nephropathy

diabetes mellitus, sepsis, lupus

Cardiovascular disease is the leading cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) and in those after kidney transplant [77, 78]. Based on Medicare billing claims incidence of myocardial infarction have ranged from 8.7 to 16.7% by 3 years after kidney transplant listing and from 4.7 to 11.1% after kidney transplanta‐ tion [79]. Cardiovascular disease accounts for 30% of the overall mortality especially in the peri‐transplantation period [80]. So, the preoperative cardiovascular risk assessment is of high importance before the kidney transplant surgery as these patients are closely followed up for over the 3 years and events are reported to the United Network for Organ

**Figure 1** summarizes a clinical approach to preoperative cardiovascular risk assessment

for acute decompensated heart failure during a 60 day follow‐up.

**6. CAD evaluation before kidney transplant**

Sharing (UNOS).

before kidney transplantation.

## *Step 1: Assess for presence of active cardiac condition:*

Patients with active cardiac condition should be ruled out by detailed history and physical examination. Active cardiac conditions include‐ unstable coronary syndromes (e.g., unstable angina, severe angina, or recent MI), decompensated heart failure, significant arrhythmias, and severe valvular disease. The presence of one or more of these conditions is associated with high rates of perioperative cardiovascular morbidity and mortality and may require delay or cancellation of surgery.

*Step 5: Revascularization*

functional grafts.

cular diseases.

cardiovascular event [86].

**7.2. Left ventricle hypertrophy**

of stable ischemic heart disease.

risk factors will be discussed.

**7.1. Non‐traditional risk factors**

**7. Cardiovascular risk in renal transplant patients**

Revascularization is done either with PCI with stent or CABG after assessment of extent of obstructive CAD and risk factors like diabetes as per the ACC/AHA guidelines for management

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Renal transplant (RT) has dramatically improved the survival and quality of life for success‐ ful recipients. Despite advancements in surgical methods and medical management of RT patients, cardiovascular disease (CVD) remains the leading cause of death in patients with

The risk of CVD improves after RT when compared to patients with end‐stage renal disease (ESRD) awaiting transplantation. However, mortality due to CVD is ten times higher in renal

The increased risk of CVD cannot be explained by traditional risk factors alone.Non‐tradi‐

Traditional CVD risk factors include Hypertension, Diabetes Mellitus, Dyslipidemia, Tobacco use, and Obesity. In this section the effect of immunosuppressive agents on these traditional

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to endothelial dysfunction, electrolyte imbalances (calcium

A retrospective study using database from Données Informatisées et Validées en Transplantation (DIVAT) evaluated 244 RT patients post‐transplant for 1 year for ST‐segment elevation myocardial infarction (STEMI), non‐ST‐segment elevation myocardial infarction (NSTEMI), new onset atrial fibrillation or ventricular fibrillation, and death from cardiovas‐

The results revealed that a past medical history of cardiovascular disease (Hazard Ratio (HR) = 2.06, p = 0.03), left ventricular hypertrophy (HR = 2.04, p = 0.04) and abnormal myo‐ cardial perfusion imaging (HR = 2.18, p = 0.05) were associated with a higher risk of early

LVH is a common co‐morbidity observed in chronic kidney disease (CKD) and end‐stage renal disease (ESRD) patients [87]. Multiple factors have been implicated as the cause of LVH

and phosphorous), anemia and variations in the plasma volume following dialysis.

transplant recipients than the age and sex‐matched general population [83, 84].

tional risk factors in RT patient population also play a pivotal role [85].

#### *Step 2: Assess for presence of risk factors*

After excluding active cardiac condition, presence of risk factors for CAD should be assessed. Traditional Framingham risk score has modest to moderate ability to predict long‐term coronary events among kidney transplantation patients. Risk stratification based on 2007 Lisbon conference [81] strategy improved the sensitivity and specificity for the identifica‐ tion of CAD (sensitivity, 94% vs. 77%; specificity, 33% vs. 24%) when compared to ACC/ AHA recommended CAD risk stratification strategy The risk factors for CAD Aeemed rel‐ evant to transplantation candidates in the Lisbon Conference report include diabetes mellitus, prior cardiovascular disease, >1 year on dialysis, left ventricular hypertrophy, age > 60 years, smoking, hypertension, and dyslipidemia.

Currently, the preoperative assessment is done based on the ACC/AHA scientific statement [78]. As per this "Noninvasive stress testing may be considered in kidney transplantation candidates with no active cardiac conditions based on the presence of multiple coronary artery disease (CAD) risk factors regardless of functional status. Relevant risk factors among transplantation candidates include diabetes mellitus, prior cardiovascular disease, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hyperten‐ sion, and dyslipidemia. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers 3 or more as reasonable (Class IIb; Level of Evidence C)."

#### *Step 3: Non‐invasive testing*

Most common non‐invasive stress testing modalities include dobutamine stress echocar‐ diogram (DSE) and MPI. The diagnostic accuracy of these tests varies with sensitivity rang‐ ing from 0.29 to 0.92 (MPI) 0.44–0.89 (DSE) and specificity of around 0.67–0.89 (MPI) and 0.71–0.94 (DSE) [78]. MPI accuracy can be effected by presence of balanced ischemia result‐ ing in more false negative results. Recently, coronary computed tomography angiography (CCTA) was shown to be a reliable test with high sensitivity (93%) and a high negative pre‐ dictive value (97%) for diagnosing obstructive CAD before kidney transplantation. Hybrid imaging techniques like combining CCTA and SPECT have a sensitivity and specificity of 67 and 86% [82]

#### *Step 4: Coronary angiography*

Based on the noninvasive testing, coronary angiography is performed as needed to determine the presence and extent of obstructive CAD.

#### *Step 5: Revascularization*

*Step 1: Assess for presence of active cardiac condition:*

114 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

delay or cancellation of surgery.

*Step 2: Assess for presence of risk factors*

smoking, hypertension, and dyslipidemia.

IIb; Level of Evidence C)." *Step 3: Non‐invasive testing*

67 and 86% [82]

*Step 4: Coronary angiography*

the presence and extent of obstructive CAD.

Patients with active cardiac condition should be ruled out by detailed history and physical examination. Active cardiac conditions include‐ unstable coronary syndromes (e.g., unstable angina, severe angina, or recent MI), decompensated heart failure, significant arrhythmias, and severe valvular disease. The presence of one or more of these conditions is associated with high rates of perioperative cardiovascular morbidity and mortality and may require

After excluding active cardiac condition, presence of risk factors for CAD should be assessed. Traditional Framingham risk score has modest to moderate ability to predict long‐term coronary events among kidney transplantation patients. Risk stratification based on 2007 Lisbon conference [81] strategy improved the sensitivity and specificity for the identifica‐ tion of CAD (sensitivity, 94% vs. 77%; specificity, 33% vs. 24%) when compared to ACC/ AHA recommended CAD risk stratification strategy The risk factors for CAD Aeemed rel‐ evant to transplantation candidates in the Lisbon Conference report include diabetes mellitus, prior cardiovascular disease, >1 year on dialysis, left ventricular hypertrophy, age > 60 years,

Currently, the preoperative assessment is done based on the ACC/AHA scientific statement [78]. As per this "Noninvasive stress testing may be considered in kidney transplantation candidates with no active cardiac conditions based on the presence of multiple coronary artery disease (CAD) risk factors regardless of functional status. Relevant risk factors among transplantation candidates include diabetes mellitus, prior cardiovascular disease, more than 1 year on dialysis, left ventricular hypertrophy, age greater than 60 years, smoking, hyperten‐ sion, and dyslipidemia. The specific number of risk factors that should be used to prompt testing remains to be determined, but the committee considers 3 or more as reasonable (Class

Most common non‐invasive stress testing modalities include dobutamine stress echocar‐ diogram (DSE) and MPI. The diagnostic accuracy of these tests varies with sensitivity rang‐ ing from 0.29 to 0.92 (MPI) 0.44–0.89 (DSE) and specificity of around 0.67–0.89 (MPI) and 0.71–0.94 (DSE) [78]. MPI accuracy can be effected by presence of balanced ischemia result‐ ing in more false negative results. Recently, coronary computed tomography angiography (CCTA) was shown to be a reliable test with high sensitivity (93%) and a high negative pre‐ dictive value (97%) for diagnosing obstructive CAD before kidney transplantation. Hybrid imaging techniques like combining CCTA and SPECT have a sensitivity and specificity of

Based on the noninvasive testing, coronary angiography is performed as needed to determine

Revascularization is done either with PCI with stent or CABG after assessment of extent of obstructive CAD and risk factors like diabetes as per the ACC/AHA guidelines for management of stable ischemic heart disease.

## **7. Cardiovascular risk in renal transplant patients**

Renal transplant (RT) has dramatically improved the survival and quality of life for success‐ ful recipients. Despite advancements in surgical methods and medical management of RT patients, cardiovascular disease (CVD) remains the leading cause of death in patients with functional grafts.

The risk of CVD improves after RT when compared to patients with end‐stage renal disease (ESRD) awaiting transplantation. However, mortality due to CVD is ten times higher in renal transplant recipients than the age and sex‐matched general population [83, 84].

The increased risk of CVD cannot be explained by traditional risk factors alone.Non‐tradi‐ tional risk factors in RT patient population also play a pivotal role [85].

Traditional CVD risk factors include Hypertension, Diabetes Mellitus, Dyslipidemia, Tobacco use, and Obesity. In this section the effect of immunosuppressive agents on these traditional risk factors will be discussed.

## **7.1. Non‐traditional risk factors**

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to endothelial dysfunction, electrolyte imbalances (calcium and phosphorous), anemia and variations in the plasma volume following dialysis.

A retrospective study using database from Données Informatisées et Validées en Transplantation (DIVAT) evaluated 244 RT patients post‐transplant for 1 year for ST‐segment elevation myocardial infarction (STEMI), non‐ST‐segment elevation myocardial infarction (NSTEMI), new onset atrial fibrillation or ventricular fibrillation, and death from cardiovas‐ cular diseases.

The results revealed that a past medical history of cardiovascular disease (Hazard Ratio (HR) = 2.06, p = 0.03), left ventricular hypertrophy (HR = 2.04, p = 0.04) and abnormal myo‐ cardial perfusion imaging (HR = 2.18, p = 0.05) were associated with a higher risk of early cardiovascular event [86].

## **7.2. Left ventricle hypertrophy**

LVH is a common co‐morbidity observed in chronic kidney disease (CKD) and end‐stage renal disease (ESRD) patients [87]. Multiple factors have been implicated as the cause of LVH including over‐activation of the sympathetic nervous system, volume overload, hypertension, inhibition of nitric oxide, arterial stiffness, diabetes, dyslipidemia, endothelial dysfunction, and anemia of chronic disease. Electrocardiographic (ECG) evidence of LVH in the first year after RT was found to be an independent risk factor for death and subsequent congestive heart failure [88]. Persistent or de novo LVH is also a strong independent risk factor for death after 5 years, confirming the continuing importance of LVH even in the late post‐transplant period [88].

survival and increased risk of cardiovascular events [91]. These findings were similar to CKD

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117

According to the follow‐up data from the ALERT study, anemia is a predictor of graft loss but not associated with an increased incidence of cardiovascular morbidity and mortality or

No immunosuppressive drug has been directly associated with cardiovascular events. However, immunosuppressive drugs impact the traditional risk factors and play a crucial role.

According to the historical literature, corticosteroids were believed to cause elevated blood pressure by water and salt retention via an effect on the mineralocorticoid receptor. However, recent data points that blockade of NO formation by inhibition of both inducible and endo‐ thelial nitric oxide synthase (eNOS), inhibition of transmembrane arginine transport and

Anti‐proliferative agents were thought to worsen hypertension in RT patients. However recent studies in patients with systemic lupus erythematosus suggests an improved blood

Cyclosporine monotherapy induces hypertension to the same extent as corticosteroids [94]. The mechanism by which cyclosporine and tacrolimus increase blood pressure is complex. One proposed mechanism is that cyclosporine stimulates transmembrane influxes of calcium, thereby leading to vascular smooth muscle cell contraction and vasoconstriction.

inhibition of the synthesis of the NOS cofactor BH4 play a prominent role [93].

pressure control with the use of mycophenolate mofetil.

RT patients are usually on a combination of following maintenance medications:

*Antiproliferative agents: Mycophenolate Mofetil and Azathioprine.*

*Calcineurin inhibitors: Tacrolimus and Cyclosporine.*

*mTOR inhibitors: Sirolimus and Everolimus.*

patients without transplant as previously described.

all‐cause mortality in RT patients [92].

**7.7. Immunosuppressive therapy**

*Corticosteroids: Prednisone.*

**8. Hypertension**

**8.1. Corticosteroids**

**8.2. Antiproliferative agents**

**8.3. Calcineurin inhibitors**

**7.6. Anemia**

The presence of LVH is a important prognostic factor for CVD mortality and morbidity in RT patients. Whether a successful renal transplantation can reverse LVH still remains a debatable issue [87].

## **7.3. Over‐activation of the sympathetic nervous system**

To entertain the hypothesis that development of LVH may be connected to excessive activa‐ tion of the sympathetic nervous system, the effect of pre‐transplant bilateral native nephrec‐ tomy on left ventricular mass and function has been evaluated. A study group of 32 patients who had undergone pre‐transplant bilateral native nephrectomy were compared to 32 control group patients and evaluated with echocardiography and/or cardiac magnetic resonance (CMR) [89].

After a 90‐month follow‐up, bilateral native nephrectomy before transplantation was associ‐ ated with a lower left ventricular mass index (LVMI; p = 0.001), left atrial volume index (LAVI; p = 0.004), and a lower grade (grade I) of left ventricular diastolic dysfunction [89]. In compar‐ ison with controls, the study group had lower systolic blood pressure (p = 0.04) and required a fewer number of anti‐hypertensive medications (p = 0.001) [89].

## **7.4. Inflammatory state**

Pro‐inflammatory markers have also been studied in RT patient population. Neopterin is syn‐ thesized by macrophages upon stimulation by interferon‐gamma. Serum neopterin is a marker of a pro‐inflammatory state in RT patients. Clinical trial data has revealed that Neopterin is associated with cardiovascular events and all‐cause mortality in renal transplant patients.

The Assessment of LEscol in Renal Transplant (ALERT) trial prospectively analyzed RT patients with stable graft for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all‐cause mortality.The long‐term follow‐up suggests that neopterin‐to‐creatinine ratio is significantly associated with MACE (p = 0.009) and all‐cause mortality (p = 0.002) [90].

## **7.5. Proteinuria**

A prospective trial of 90 RT patients with normal graft function in the post‐transplantation period (3–5 years) investigated the association between proteinuria and graft/patient survival and to determine whether proteinuria may be a predictor for cardiovascular disease. High‐ grade (≥500 mg/24 hours) proteinuria in RT patients is strongly associated with poor graft survival and increased risk of cardiovascular events [91]. These findings were similar to CKD patients without transplant as previously described.

#### **7.6. Anemia**

including over‐activation of the sympathetic nervous system, volume overload, hypertension, inhibition of nitric oxide, arterial stiffness, diabetes, dyslipidemia, endothelial dysfunction, and anemia of chronic disease. Electrocardiographic (ECG) evidence of LVH in the first year after RT was found to be an independent risk factor for death and subsequent congestive heart failure [88]. Persistent or de novo LVH is also a strong independent risk factor for death after 5 years, confirming the continuing importance of LVH even in the late post‐transplant

The presence of LVH is a important prognostic factor for CVD mortality and morbidity in RT patients. Whether a successful renal transplantation can reverse LVH still remains a debatable

To entertain the hypothesis that development of LVH may be connected to excessive activa‐ tion of the sympathetic nervous system, the effect of pre‐transplant bilateral native nephrec‐ tomy on left ventricular mass and function has been evaluated. A study group of 32 patients who had undergone pre‐transplant bilateral native nephrectomy were compared to 32 control group patients and evaluated with echocardiography and/or cardiac magnetic resonance

After a 90‐month follow‐up, bilateral native nephrectomy before transplantation was associ‐ ated with a lower left ventricular mass index (LVMI; p = 0.001), left atrial volume index (LAVI; p = 0.004), and a lower grade (grade I) of left ventricular diastolic dysfunction [89]. In compar‐ ison with controls, the study group had lower systolic blood pressure (p = 0.04) and required

Pro‐inflammatory markers have also been studied in RT patient population. Neopterin is syn‐ thesized by macrophages upon stimulation by interferon‐gamma. Serum neopterin is a marker of a pro‐inflammatory state in RT patients. Clinical trial data has revealed that Neopterin is associated with cardiovascular events and all‐cause mortality in renal transplant patients.

The Assessment of LEscol in Renal Transplant (ALERT) trial prospectively analyzed RT patients with stable graft for an association between serum neopterin and subsequent clinical events: graft loss, major cardiovascular events (MACE) and all‐cause mortality.The long‐term follow‐up suggests that neopterin‐to‐creatinine ratio is significantly associated with MACE

A prospective trial of 90 RT patients with normal graft function in the post‐transplantation period (3–5 years) investigated the association between proteinuria and graft/patient survival and to determine whether proteinuria may be a predictor for cardiovascular disease. High‐ grade (≥500 mg/24 hours) proteinuria in RT patients is strongly associated with poor graft

**7.3. Over‐activation of the sympathetic nervous system**

116 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

a fewer number of anti‐hypertensive medications (p = 0.001) [89].

(p = 0.009) and all‐cause mortality (p = 0.002) [90].

period [88].

issue [87].

(CMR) [89].

**7.4. Inflammatory state**

**7.5. Proteinuria**

According to the follow‐up data from the ALERT study, anemia is a predictor of graft loss but not associated with an increased incidence of cardiovascular morbidity and mortality or all‐cause mortality in RT patients [92].

## **7.7. Immunosuppressive therapy**

RT patients are usually on a combination of following maintenance medications:

*Corticosteroids: Prednisone.*

*Antiproliferative agents: Mycophenolate Mofetil and Azathioprine.*

*Calcineurin inhibitors: Tacrolimus and Cyclosporine.*

*mTOR inhibitors: Sirolimus and Everolimus.*

No immunosuppressive drug has been directly associated with cardiovascular events. However, immunosuppressive drugs impact the traditional risk factors and play a crucial role.

## **8. Hypertension**

#### **8.1. Corticosteroids**

According to the historical literature, corticosteroids were believed to cause elevated blood pressure by water and salt retention via an effect on the mineralocorticoid receptor. However, recent data points that blockade of NO formation by inhibition of both inducible and endo‐ thelial nitric oxide synthase (eNOS), inhibition of transmembrane arginine transport and inhibition of the synthesis of the NOS cofactor BH4 play a prominent role [93].

#### **8.2. Antiproliferative agents**

Anti‐proliferative agents were thought to worsen hypertension in RT patients. However recent studies in patients with systemic lupus erythematosus suggests an improved blood pressure control with the use of mycophenolate mofetil.

#### **8.3. Calcineurin inhibitors**

Cyclosporine monotherapy induces hypertension to the same extent as corticosteroids [94]. The mechanism by which cyclosporine and tacrolimus increase blood pressure is complex. One proposed mechanism is that cyclosporine stimulates transmembrane influxes of calcium, thereby leading to vascular smooth muscle cell contraction and vasoconstriction. Other proposed mechanisms include increased production of endothelin 1 (ET‐1), transform‐ ing growth factor (TGF), renin, and inhibition of NO production by multiple pathways.

and impaired glucose tolerance. Additionally, transplant related risk factors also play a role: immunosuppressive medications, HLA mismatch, donor gender, type of underlying renal

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119

The implications of PTDM in patient outcomes are not well established, but data from the USRDS/UNOS have shown that PTDM increases the risk of post‐transplant myocardial

Corticosteroids lead to development of PTDM by enhancing insulin resistance. PTDM is

There is no data suggesting that mycophenolate mofetil or azathioprine play a role in devel‐

RT patients receiving calcineurin inhibitors have a higher incidence of PTDM. The etiology is impairment in pancreatic beta‐cell secretory function [104]. Dose reduction has been shown to reverse diabetes in majority of the affected patients. The incidence of PTDM with tacrolimus is postulated to be as high as 20%. The higher incidence of PTDM with tacrolimus versus cyclosporine is believed to be due to stronger potency of tacrolimus in calcineurin inhibition

Tacrolimus leads to PTDM in a dose‐dependent manner. It leads to complete reversible inhi‐ bition of the insulin gene transcription with no acute effects on insulin secretion or the glucose uptake by insulin. Therefore, in majority of patients, PTDM is reversible after reducing the

There is no data suggesting that sirolimus or everolimus plays a role in development of PTDM.

Corticosteroids negatively impact blood pressure, lipid profile, and glucose metabolism. Randomized trials have shown that corticosteroid withdrawal or corticosteroid‐free immu‐

nosuppression improves hypertension, dyslipidemia, and glucose metabolism [106].

**11. Management of immunosuppressive agents in controlling** 

disease and viral infections (HCV and CMV) [102].

reversible by cessation of corticosteroids.

dose of tacrolimus and withdrawing corticosteroids.

**10.2. Antiproliferative agents**

**10.3. Calcineurin inhibitors**

than cyclosporine [105].

**10.4. mTOR inhibitors**

**risk factors**

**11.1. Corticosteroids**

infarction [103].

**10.1. Corticosteroids**

opment of PTDM.

Recent data suggests that tacrolimus results in less renal vasoconstriction than cyclosporine. RT patients being treated with tacrolimus and equivalent dosages of corticosteroids require fewer anti‐hypertensive medications than patients being treated with cyclosporine [95].

## **9. Dyslipidemia**

#### **9.1. Corticosteroids**

Corticosteroids increase total cholesterol, low‐density lipoprotein (LDL), high‐ density lipo‐ protein (HDL), and hepatic synthesis of very low‐density lipoprotein (VLDL) [96]. Corti‐ costeroids lead to decreased LDL receptor synthesis and subsequent expression, thereby leading to reduced uptake and degradation of LDL [97].

## **9.2. Calcineurin inhibitors**

Cyclosporine increases total cholesterol, LDL, and VLDL but decreases HDL. Cyclosporine decreases the activity of lipoprotein lipase (LPL) leading to hypertriglyceridemia. It also impairs the clearance of LDL by a similar mechanism to corticosteroids [98].

When comparing patients on tacrolimus versus cyclosporine, tacrolimus‐treated patients have lower total cholesterol, LDL, and triglycerides. The levels of HDL are comparable. In a randomized, prospective trial evaluating RT patients with conversion from cyclosporine to tacrolimus, total cholesterol improved significantly by a mean of 0.5 mmol/L, LDL by 0.35 mmol/L and triglycerides by 0.4 mmol/L. These results were sustained up to 2 years after conversion [99].

#### **9.3. mTOR inhibitors**

Sirolimus is notorious for causing hyperlipidemia; increasing VLDL and LDL. One hypothesis is that sirolimus increases hepatic production of triglycerides and secretion of VLDL [100]. In clini‐ cal trials evaluating serum lipid profile, the addition of sirolimus 10 milligrams to cyclosporine and corticosteroids for 6 weeks increased both total cholesterol and LDL by 50% and triglycer‐ ides by almost 100%. The effects were fully reversible after discontinuation of sirolimus [100].

## **10. Diabetes mellitus**

Post‐transplantation diabetes mellitus (PTDM) has evolved into a concerning challenge in RT patients. Approximately one‐third of nondiabetic kidney transplant recipients develop persistent impaired glucose metabolism by 6 months post‐transplantation [101]. Risk factors for PTDM include age, obesity, African American race and Hispanic ethnicity, family history and impaired glucose tolerance. Additionally, transplant related risk factors also play a role: immunosuppressive medications, HLA mismatch, donor gender, type of underlying renal disease and viral infections (HCV and CMV) [102].

The implications of PTDM in patient outcomes are not well established, but data from the USRDS/UNOS have shown that PTDM increases the risk of post‐transplant myocardial infarction [103].

## **10.1. Corticosteroids**

Other proposed mechanisms include increased production of endothelin 1 (ET‐1), transform‐ ing growth factor (TGF), renin, and inhibition of NO production by multiple pathways.

Recent data suggests that tacrolimus results in less renal vasoconstriction than cyclosporine. RT patients being treated with tacrolimus and equivalent dosages of corticosteroids require fewer anti‐hypertensive medications than patients being treated with cyclosporine [95].

Corticosteroids increase total cholesterol, low‐density lipoprotein (LDL), high‐ density lipo‐ protein (HDL), and hepatic synthesis of very low‐density lipoprotein (VLDL) [96]. Corti‐ costeroids lead to decreased LDL receptor synthesis and subsequent expression, thereby

Cyclosporine increases total cholesterol, LDL, and VLDL but decreases HDL. Cyclosporine decreases the activity of lipoprotein lipase (LPL) leading to hypertriglyceridemia. It also

When comparing patients on tacrolimus versus cyclosporine, tacrolimus‐treated patients have lower total cholesterol, LDL, and triglycerides. The levels of HDL are comparable. In a randomized, prospective trial evaluating RT patients with conversion from cyclosporine to tacrolimus, total cholesterol improved significantly by a mean of 0.5 mmol/L, LDL by 0.35 mmol/L and triglycerides by 0.4 mmol/L. These results were sustained up to 2 years after

Sirolimus is notorious for causing hyperlipidemia; increasing VLDL and LDL. One hypothesis is that sirolimus increases hepatic production of triglycerides and secretion of VLDL [100]. In clini‐ cal trials evaluating serum lipid profile, the addition of sirolimus 10 milligrams to cyclosporine and corticosteroids for 6 weeks increased both total cholesterol and LDL by 50% and triglycer‐ ides by almost 100%. The effects were fully reversible after discontinuation of sirolimus [100].

Post‐transplantation diabetes mellitus (PTDM) has evolved into a concerning challenge in RT patients. Approximately one‐third of nondiabetic kidney transplant recipients develop persistent impaired glucose metabolism by 6 months post‐transplantation [101]. Risk factors for PTDM include age, obesity, African American race and Hispanic ethnicity, family history

impairs the clearance of LDL by a similar mechanism to corticosteroids [98].

leading to reduced uptake and degradation of LDL [97].

118 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**9. Dyslipidemia**

**9.1. Corticosteroids**

**9.2. Calcineurin inhibitors**

conversion [99].

**9.3. mTOR inhibitors**

**10. Diabetes mellitus**

Corticosteroids lead to development of PTDM by enhancing insulin resistance. PTDM is reversible by cessation of corticosteroids.

#### **10.2. Antiproliferative agents**

There is no data suggesting that mycophenolate mofetil or azathioprine play a role in devel‐ opment of PTDM.

## **10.3. Calcineurin inhibitors**

RT patients receiving calcineurin inhibitors have a higher incidence of PTDM. The etiology is impairment in pancreatic beta‐cell secretory function [104]. Dose reduction has been shown to reverse diabetes in majority of the affected patients. The incidence of PTDM with tacrolimus is postulated to be as high as 20%. The higher incidence of PTDM with tacrolimus versus cyclosporine is believed to be due to stronger potency of tacrolimus in calcineurin inhibition than cyclosporine [105].

Tacrolimus leads to PTDM in a dose‐dependent manner. It leads to complete reversible inhi‐ bition of the insulin gene transcription with no acute effects on insulin secretion or the glucose uptake by insulin. Therefore, in majority of patients, PTDM is reversible after reducing the dose of tacrolimus and withdrawing corticosteroids.

#### **10.4. mTOR inhibitors**

There is no data suggesting that sirolimus or everolimus plays a role in development of PTDM.

## **11. Management of immunosuppressive agents in controlling risk factors**

#### **11.1. Corticosteroids**

Corticosteroids negatively impact blood pressure, lipid profile, and glucose metabolism. Randomized trials have shown that corticosteroid withdrawal or corticosteroid‐free immu‐ nosuppression improves hypertension, dyslipidemia, and glucose metabolism [106].

## **11.2. Calcineurin inhibitors**

In patients receiving cyclosporine combined with mycophenolate mofetil, a 50% reduction in cyclosporine dose or complete cyclosporine withdrawal from a mycophenolate mofetil or sirolimus‐based regimen results in fewer anti‐hypertensive medications [106]. Tacrolimus increases the risk of PTDM more than cyclosporine, therefore, switching from tacrolimus to cyclosporine may lead to improvement in PTDM.

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[3] Chadban SJ. et al. Prevalence of kidney damage in Australian adults: The AusDiab kid‐ ney study. Journal of the American Society of Nephrology. 2003;**14**(7 Suppl 2):S131‐S138

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[6] Imran S. et al. Burden of chronic kidney disease in an urban city of Pakistan, a cross‐sec‐

[7] Manjunath G. et al. Level of kidney function as a risk factor for atherosclerotic cardio‐ vascular outcomes in the community. Journal of the American College of Cardiology.

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[9] Shlipak MG. et al. Chronic renal insufficiency and cardiovascular events in the elderly: Findings from the Cardiovascular Health Study. The American Journal of Geriatric

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## **12. Conclusion**

Renal transplantation is the single most effective intervention for reducing CV risk in appro‐ priately selected patients with ESRD. Even though renal transplant has significantly improved survival for successful recipients, CVD remains the leading cause of death in patients with functional grafts [107].

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to left ventricular hypertrophy, over‐activation of the sympa‐ thetic nervous system, pro‐inflammatory state, and proteinuria.

Post‐transplantation, patients are maintained on a regimen of immunosuppressive medica‐ tions. Even though immunosuppressive drugs have not been directly associated with car‐ diovascular events, they play pivotal role in risk associated with traditional risk factors of hypertension, dyslipidemia, and diabetes.

Strategies targeting transplant‐specific CV risk factors should include optimization of renal function, limiting risk of rejection, avoidance of PTDM and anticipation of CV side effects of immunosuppression.

## **Author details**

Ali Osama Malik1 , Sumit Sehgal2 , Hashim Hussnain Ahmed<sup>3</sup> , Subodh Devabhaktuni2 , Edward Co1 , Arhama Aftab Malik5 , Syed Shah4 and Chowdhury Ahsan2 \*

\*Address all correspondence to: chahsan92@yahoo.com

1 Department of Internal Medicine, University of Nevada, School of Medicine, Reno, Nevada

2 Department of Cardiovascular Medicine, University of Nevada, School of Medicine, Reno, Nevada

3 Department of Surgery, Shaukat Khanum Memorial Cancer and Research Center, Pakistan

4 Kidney Specialist of Southern Nevada, Nevada, USA

5 Aga Khan University, Karachi, Pakistan

## **References**

**11.2. Calcineurin inhibitors**

**12. Conclusion**

functional grafts [107].

immunosuppression.

**Author details**

Ali Osama Malik1

Edward Co1

Nevada

cyclosporine may lead to improvement in PTDM.

120 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

thetic nervous system, pro‐inflammatory state, and proteinuria.

hypertension, dyslipidemia, and diabetes.

, Sumit Sehgal2

\*Address all correspondence to: chahsan92@yahoo.com

4 Kidney Specialist of Southern Nevada, Nevada, USA

5 Aga Khan University, Karachi, Pakistan

, Arhama Aftab Malik5

In patients receiving cyclosporine combined with mycophenolate mofetil, a 50% reduction in cyclosporine dose or complete cyclosporine withdrawal from a mycophenolate mofetil or sirolimus‐based regimen results in fewer anti‐hypertensive medications [106]. Tacrolimus increases the risk of PTDM more than cyclosporine, therefore, switching from tacrolimus to

Renal transplantation is the single most effective intervention for reducing CV risk in appro‐ priately selected patients with ESRD. Even though renal transplant has significantly improved survival for successful recipients, CVD remains the leading cause of death in patients with

In addition to traditional CVD risk factors, RT patients develop specific risk factors related to ESRD including but not limited to left ventricular hypertrophy, over‐activation of the sympa‐

Post‐transplantation, patients are maintained on a regimen of immunosuppressive medica‐ tions. Even though immunosuppressive drugs have not been directly associated with car‐ diovascular events, they play pivotal role in risk associated with traditional risk factors of

Strategies targeting transplant‐specific CV risk factors should include optimization of renal function, limiting risk of rejection, avoidance of PTDM and anticipation of CV side effects of

, Hashim Hussnain Ahmed<sup>3</sup>

and Chowdhury Ahsan2

, Syed Shah4

1 Department of Internal Medicine, University of Nevada, School of Medicine, Reno, Nevada 2 Department of Cardiovascular Medicine, University of Nevada, School of Medicine, Reno,

3 Department of Surgery, Shaukat Khanum Memorial Cancer and Research Center, Pakistan

, Subodh Devabhaktuni2

\*

,


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**Inflammation and CKD**

