**Inflammation and CKD**

[101] Valderhaug TG. et al. Fasting plasma glucose and glycosylated hemoglobin in the screen‐ ing for diabetes mellitus after renal transplantation. Transplantation. 2009;**88**(3):429‐434

[102] Sharif A, Baboolal K. Complications associated with new‐onset diabetes after kidney

[103] Jardine AG. et al. Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: Post‐hoc subgroup analyses of the ALERT Study. American

[104] Nam JH. et al. Beta‐Cell dysfunction rather than insulin resistance is the main con‐ tributing factor for the development of postrenal transplantation diabetes mellitus.

[105] Pirsch JD. et al. A comparison of tacrolimus (FK506) and cyclosporine for immunosup‐ pression after cadaveric renal transplantation. FK506 kidney transplant study group.

[106] Marcen R. Immunosuppressive drugs in kidney transplantation: Impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs.

[107] Stoumpos S, Jardine AG, Mark PB. Cardiovascular morbidity and mortality after kid‐

ney transplantation. Transplant International. 2015;**28**(1):10‐21

transplantation. Nature Reviews Nephrology. 2011;**8**(1):34‐42

Journal of Transplantation. 2004;**4**(6):988‐995

128 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Transplantation. 2001;**71**(10):1417‐1423

Transplantation. 1997;**63**(7):977‐983

2009;**69**(16):2227‐2243

**Chapter 6**

**Provisional chapter**

**Motto:** *"All disease begins in the gut." (Hippocrates)*

**Inflammation and Chronic Kidney Disease: Current**

**Inflammation and Chronic Kidney Disease: Current** 

Despite being a "silent epidemic" disease, chronic kidney disease (CKD) is considered one of the major causes of mortality, together with its main complication, the cardiovascular disease, which contributes to the poor prognosis of these patients. Inflammation has been recognized as an essential part of CKD and is closely linked to cardiovascular complications. The identification of novel biomarkers using omics technologies is rapidly advancing and could improve the early detection in renal diseases. Omics approaches, including proteomics, could provide novel insights into disease mechanisms, identifying at the same time accurate inflammatory biomarker panels with an essential role in disease monitoring and follow-up. Recent advances highlight the gut microbiota as an important source of inflammation in kidney diseases. An increasing body of evidence reveals the cross talk between microbiota and host in CKD; in addition, gut dysbiosis may represent an underappreciated cause of inflammation and subsequently could lead to malnutrition, accelerated cardiovascular disease and CKD progression. This chapter discusses the relationship between inflammation and CKD and highlights the novel approaches regarding microbiota involvement in CKD pathol-

ogy, as well as their potential to facilitate improving the quality of life. **Keywords:** chronic kidney disease, inflammation, gut microbiota, omics

DOI: 10.5772/intechopen.72716

© 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.

Chronic kidney disease (CKD) is defined, according to KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney

**Approaches and Recent Advances**

**Approaches and Recent Advances**

Simona Mihai, Elena Codrici, Ionela Daniela Popescu,

Ionela Daniela Popescu, Ana-Maria Enciu, Laura Georgiana Necula, Gabriela Anton and

Ana-Maria Enciu, Laura Georgiana Necula,

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Simona Mihai, Elena Codrici,

http://dx.doi.org/10.5772/intechopen.72716

Gabriela Anton and Cristiana Tanase

Cristiana Tanase

**Abstract**

**1. Introduction**

#### **Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances**

DOI: 10.5772/intechopen.72716

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

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.72716

**Motto:** *"All disease begins in the gut." (Hippocrates)*

#### **Abstract**

Despite being a "silent epidemic" disease, chronic kidney disease (CKD) is considered one of the major causes of mortality, together with its main complication, the cardiovascular disease, which contributes to the poor prognosis of these patients. Inflammation has been recognized as an essential part of CKD and is closely linked to cardiovascular complications. The identification of novel biomarkers using omics technologies is rapidly advancing and could improve the early detection in renal diseases. Omics approaches, including proteomics, could provide novel insights into disease mechanisms, identifying at the same time accurate inflammatory biomarker panels with an essential role in disease monitoring and follow-up. Recent advances highlight the gut microbiota as an important source of inflammation in kidney diseases. An increasing body of evidence reveals the cross talk between microbiota and host in CKD; in addition, gut dysbiosis may represent an underappreciated cause of inflammation and subsequently could lead to malnutrition, accelerated cardiovascular disease and CKD progression. This chapter discusses the relationship between inflammation and CKD and highlights the novel approaches regarding microbiota involvement in CKD pathology, as well as their potential to facilitate improving the quality of life.

**Keywords:** chronic kidney disease, inflammation, gut microbiota, omics

## **1. Introduction**

Chronic kidney disease (CKD) is defined, according to KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney

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

© 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.

Disease–Mineral and Bone Disorder (CKD-MBD), as "abnormalities of kidney structure or function, present for more than 3 months, with implications for health." CKD is classified based on pathological cause, glomerular filtration rate category (from G1, normal, to G5, kidney failure), and albuminuria category (from A1, <30 mg/g, to A3 > 300 mg/g) [1]. It will inexorably lead to end-stage renal disease, unless managed as to address treatment of the underlying condition, diagnosing and treating the pathologic manifestations and timely planning for longterm renal replacement therapy. A recent systematic review and metaanalysis of observational studies revealed that CKD has an estimated global prevalence between 11 and 13%, with the majority of cases in stage 3 [2]. The complexity of CKD pathogenesis is underlined by a plethora of risk factors: genetic and epigenetic age [3], low birth weight, socioeconomic status, obesity [1], smoking and/or hypoxia [4], and vascular factors, induced by atherosclerosis [5], hypertension [6], and diabetes mellitus [7]. Furthermore, the *complications* of this disease also impact beyond the kidney, with cardiovascular burden (such as coronary artery disease, congestive heart failure, arrhythmias, and sudden cardiac death) as a major mark [8]. CKD associates also with enhanced formation of atherosclerotic plaques [9]. Other complications include endocrine dysfunctions involving hormones that control calcium [10] and phosphate balance [11], vitamin D metabolism, and, consequently, bone mineralization defects [12]. Hemodialysis patients are further at risk for cardiovascular complications, such as vascular overload leading to arterial stiffness [13] or, apparently paradoxical, ischemia induced by repeated episodes of hypovolemic hypoperfusion during hemodialysis [9].

disease (ESRD), which shifts the perception of inflammation as no longer a new, but rather a traditional risk factor for CKD morbidity and mortality [14, 21]. A challenging theory regarding the direct effect of inflammation on the progression of both CKD and cardiovascular disease came out with the assumption of association between markers of inflammation, changes in GFR and nutrition habits in elderly individuals. It was found that the deterioration in renal function (alteration of GFR, urea and creatinine) was associated with an increasing number of markers of inflammation and thrombosis [22]. Regardless of a genetic background, CKD is a condition that accelerates premature aging through diverse mechanisms in the internal milieu, counting DNA damage, inflammation, low Klotho expression, redox perturbations, toxicity, and local signaling of growth factors [23]. It is generally known that there is a heterogeneous distribution of intrarenal vasculature in normal conditions, and only medulla is under hypoxic conditions. In order to bypass energy depri-

the complex processes, including hormones, autocoids, and vasoactive substances: medullipin, prostaglandins, endothelins, nitric oxide, angiotensin II, kinins, and adenosine. A state of sustained inflammation could surely alter the microvascular feedback to its regulators and could activate the reaction of an array of tubular toxins, including reactive oxygen species (ROS), generating further renal failure [24]. The highly reactive ROS could alter different structures and functional pathways in cells, and, as a repercussion, a vicious circle arises, in which the inflammatory cells are stimulated by cell damage caused by ROS, giving birth to a state of oxidative stress. The common oxidant "imbalance" theory is remarkably completed with recent advances regarding the cross talk between oxidants and antioxidants; the reasoning for antioxidant therapies consists thus in repairing the imbalances in the redox environment of cells [25]. The old theory suggesting the oxidative stress as a "unifying concept of cardiovascular disease in uremia" [26] is continuously enriched, and novel molecules, belonging to the Paraoxonase family, are suggested as potential biomarkers. Paraoxonase1 seems to have a protective effect against lipoprotein oxidation and its expression is decreased in CKD patients, being a marker for antioxidant status [27]. The development of specific redox proteomic techniques will facilitate the implementation of new preventive and therapeutic strategies to fight against atherosclerosis and other metabolic diseases [28].

In comparison with the wellestablished clinical markers, proteomic biomarkers could offer an accurate and earlier detection of renal pathology. Although the "breaking point" could be various in different patients, in some populations, the circulating creatinine levels fall into normal ranges despite loss of more than 50% of renal function, so supplementary biomarkers of renal function are desired. Recent studies conclude that a cross talk between inflammation, bone, vasculature, and renal function exists in CKD. In early stage 2 of CKD, an increased expression of a panel of proteomic biomarkers was observed, including IL6, TNFα, osteoprotegerin, osteocalcin, osteopontin, and FGF23, which, at a first glance, highlights the hope of improving the management of patients with CKD starting with early stages, which is an area to focus research in the near future [29]. Another study evaluating the association between kidney function, albuminuria, and biomarkers of inflammation in a large cohort of CKD patients showed that plasma levels of IL1β, IL1RA, IL6, TNFα, hsCRP, and fibrinogen were higher among participants with lower levels of estimated glomerular filtration rate (GFR). Moreover, inflammation score was higher among patients with lower estimated GFR and higher urine albumin to creatinine ratio (UACR). These results demonstrated that biomarkers of inflammation were

parts of the kidneys, an avalanche of mediators is involved to regulate

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

133

vation in the deficient pO2

Inflammation has been recognized as an essential part of chronic kidney disease (CKD) since the late 1990s and is now considered a wellestablished risk factor for this pathology [14], as well as for other renal pathologies. In fact, inflammation is now considered a key player in different major pathologies such as cardiovascular disease [15], neurodegeneration [16], or cancer progression and survival [17]. Chronic systemic inflammation, sometimes referred to as lowgrade chronic inflammation, is characterized by 2–3 fold increase of circulating inflammatory mediators (such as interleukins 1, 6 tumor necrosis factor, and their soluble receptors), slow developing, persistent and of multifactorial origin, sometimes difficult to identify [18]. Recent findings associate chronic systemic inflammation with alteration of gut microbiota, which is in permanent cross talk with the immune system. This cross talk is essential for maintenance of a tolerant immune response toward commensal flora and elimination of pathogens [19]. Intestinal dysbiosis is detrimental for health in ways overpassing the intestinal environment, from production of toxic metabolites, overconsumption of energy, and molecular mimicry of host proteins [20]. This chapter will present an uptodate findings relating to chronic systemic inflammation and CKD, with emphasis on gut dysmicrobism involvement and whether intervention on gut microbiota could be proven beneficial for the outcome of this fatal disease.

## **2. Inflammation and its impact on CKD progression: an update**

Persistent, lowgrade inflammation is considered crucial component of CKD, having a huge contribution to the development of all-cause mortality related to renal disease. There has been an ascending growth of interest regarding the role of inflammation in CKD and endstage renal disease (ESRD), which shifts the perception of inflammation as no longer a new, but rather a traditional risk factor for CKD morbidity and mortality [14, 21]. A challenging theory regarding the direct effect of inflammation on the progression of both CKD and cardiovascular disease came out with the assumption of association between markers of inflammation, changes in GFR and nutrition habits in elderly individuals. It was found that the deterioration in renal function (alteration of GFR, urea and creatinine) was associated with an increasing number of markers of inflammation and thrombosis [22]. Regardless of a genetic background, CKD is a condition that accelerates premature aging through diverse mechanisms in the internal milieu, counting DNA damage, inflammation, low Klotho expression, redox perturbations, toxicity, and local signaling of growth factors [23]. It is generally known that there is a heterogeneous distribution of intrarenal vasculature in normal conditions, and only medulla is under hypoxic conditions. In order to bypass energy deprivation in the deficient pO2 parts of the kidneys, an avalanche of mediators is involved to regulate the complex processes, including hormones, autocoids, and vasoactive substances: medullipin, prostaglandins, endothelins, nitric oxide, angiotensin II, kinins, and adenosine. A state of sustained inflammation could surely alter the microvascular feedback to its regulators and could activate the reaction of an array of tubular toxins, including reactive oxygen species (ROS), generating further renal failure [24]. The highly reactive ROS could alter different structures and functional pathways in cells, and, as a repercussion, a vicious circle arises, in which the inflammatory cells are stimulated by cell damage caused by ROS, giving birth to a state of oxidative stress. The common oxidant "imbalance" theory is remarkably completed with recent advances regarding the cross talk between oxidants and antioxidants; the reasoning for antioxidant therapies consists thus in repairing the imbalances in the redox environment of cells [25]. The old theory suggesting the oxidative stress as a "unifying concept of cardiovascular disease in uremia" [26] is continuously enriched, and novel molecules, belonging to the Paraoxonase family, are suggested as potential biomarkers. Paraoxonase1 seems to have a protective effect against lipoprotein oxidation and its expression is decreased in CKD patients, being a marker for antioxidant status [27]. The development of specific redox proteomic techniques will facilitate the implementation of new preventive and therapeutic strategies to fight against atherosclerosis and other metabolic diseases [28].

Disease–Mineral and Bone Disorder (CKD-MBD), as "abnormalities of kidney structure or function, present for more than 3 months, with implications for health." CKD is classified based on pathological cause, glomerular filtration rate category (from G1, normal, to G5, kidney failure), and albuminuria category (from A1, <30 mg/g, to A3 > 300 mg/g) [1]. It will inexorably lead to end-stage renal disease, unless managed as to address treatment of the underlying condition, diagnosing and treating the pathologic manifestations and timely planning for longterm renal replacement therapy. A recent systematic review and metaanalysis of observational studies revealed that CKD has an estimated global prevalence between 11 and 13%, with the majority of cases in stage 3 [2]. The complexity of CKD pathogenesis is underlined by a plethora of risk factors: genetic and epigenetic age [3], low birth weight, socioeconomic status, obesity [1], smoking and/or hypoxia [4], and vascular factors, induced by atherosclerosis [5], hypertension [6], and diabetes mellitus [7]. Furthermore, the *complications* of this disease also impact beyond the kidney, with cardiovascular burden (such as coronary artery disease, congestive heart failure, arrhythmias, and sudden cardiac death) as a major mark [8]. CKD associates also with enhanced formation of atherosclerotic plaques [9]. Other complications include endocrine dysfunctions involving hormones that control calcium [10] and phosphate balance [11], vitamin D metabolism, and, consequently, bone mineralization defects [12]. Hemodialysis patients are further at risk for cardiovascular complications, such as vascular overload leading to arterial stiffness [13] or, apparently paradoxical, ischemia induced by repeated episodes of hypovolemic hypoperfusion during hemodialysis [9]. Inflammation has been recognized as an essential part of chronic kidney disease (CKD) since the late 1990s and is now considered a wellestablished risk factor for this pathology [14], as well as for other renal pathologies. In fact, inflammation is now considered a key player in different major pathologies such as cardiovascular disease [15], neurodegeneration [16], or cancer progression and survival [17]. Chronic systemic inflammation, sometimes referred to as lowgrade chronic inflammation, is characterized by 2–3 fold increase of circulating inflammatory mediators (such as interleukins 1, 6 tumor necrosis factor, and their soluble receptors), slow developing, persistent and of multifactorial origin, sometimes difficult to identify [18]. Recent findings associate chronic systemic inflammation with alteration of gut microbiota, which is in permanent cross talk with the immune system. This cross talk is essential for maintenance of a tolerant immune response toward commensal flora and elimination of pathogens [19]. Intestinal dysbiosis is detrimental for health in ways overpassing the intestinal environment, from production of toxic metabolites, overconsumption of energy, and molecular mimicry of host proteins [20]. This chapter will present an uptodate findings relating to chronic systemic inflammation and CKD, with emphasis on gut dysmicrobism involvement and whether intervention on gut microbiota could be proven beneficial for the outcome of this fatal disease.

132 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**2. Inflammation and its impact on CKD progression: an update**

Persistent, lowgrade inflammation is considered crucial component of CKD, having a huge contribution to the development of all-cause mortality related to renal disease. There has been an ascending growth of interest regarding the role of inflammation in CKD and endstage renal In comparison with the wellestablished clinical markers, proteomic biomarkers could offer an accurate and earlier detection of renal pathology. Although the "breaking point" could be various in different patients, in some populations, the circulating creatinine levels fall into normal ranges despite loss of more than 50% of renal function, so supplementary biomarkers of renal function are desired. Recent studies conclude that a cross talk between inflammation, bone, vasculature, and renal function exists in CKD. In early stage 2 of CKD, an increased expression of a panel of proteomic biomarkers was observed, including IL6, TNFα, osteoprotegerin, osteocalcin, osteopontin, and FGF23, which, at a first glance, highlights the hope of improving the management of patients with CKD starting with early stages, which is an area to focus research in the near future [29]. Another study evaluating the association between kidney function, albuminuria, and biomarkers of inflammation in a large cohort of CKD patients showed that plasma levels of IL1β, IL1RA, IL6, TNFα, hsCRP, and fibrinogen were higher among participants with lower levels of estimated glomerular filtration rate (GFR). Moreover, inflammation score was higher among patients with lower estimated GFR and higher urine albumin to creatinine ratio (UACR). These results demonstrated that biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria [30]. The erythrocyte sedimentation rate, a nonspecific measure of inflammation, has been shown to be predictive of endstage renal disease in adolescents [31]. The level of proinflammatory cytokine IL2 was elevated in hemodialysis patients with uremic pruritus (a common tormenting symptom among these patients) when compared to hemodialysis patient controls without pruritus [32]. The results obtained from several researches suggest that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) plays an important role in kidney injury associated with inflammation and promotes acute and chronic kidney diseases [33]. There are several studies testing different nanoconjugates that could prevent TWEAKinduced cell death and inflammatory signaling in different cell types, including renal tubular cells [34]. The results obtained from a study investigating hemodialysis patients showed that the group of patients with a specific pattern of high proinflammatory cytokines (IL1, IL6, and TNFα) had increased mortality when compared to patients with a pattern of high Tcell regulatory or antiinflammatory parameters (IL2, IL4, IL5, IL12, CH50, and Tcell number) [35].

could add a peculiar signature to the gut microbiota composition, and intestinal dysbiosis itself

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

135

In summary, persistent lowgrade inflammation has been recognized as an important component of CKD scenario, playing major roles in the pathophysiology of the disease, with a major imprint on its complications. Nevertheless, further investigations are necessary to decipher

Cardiovascular disease represents one of the main determinants of CKD's poor prognosis, since early stages of CKD are significantly correlated with increased risk of subsequent coronary heart disease [41]. In agreement with several clinical studies, approximately 50% of patients with CKD have a rising mortality due to the cardiovascular complications, such as advanced calcific arterial and valvular disease; however, the mechanisms that involves the accelerated calcification in CKD continue to be questionable, thus no specific therapies have

The current CKD guidelines are recommending the screening for vascular calcification (VC), for the reason that VC represents a cardiovascular risk factor, and it is correlated with an increased morbidity and mortality in CKD group, culminating in CKD stage 5. Vascular calcification is now considered an active process that involves many proteins, as possible candidate markers [43]. In CKD individuals, several studies have highlighted various circulating biomarkers that could play important roles in extraskeletal calcification and mineral metabolism alterations, which are considered characteristics of CKDmineral bone disorder (CKDMBD) [44]. As a result, these findings have revealed that CKDMBD comprises laboratory and bone abnormalities and vascular calcification and has deleterious consequences on clinical outcomes; however, these processes are interconnected and they have to be studied in association with cardiovascular diseases [1].

Cardiovascular calcification represents though an exceptional marker of chronic inflammatory status in CKD, strongly correlated with morbidity and mortality. Curiously, CKD accelerates the atherosclerosis evolution and it has been showed that CKD produces increasing vascular inflammation and calcification. Recent advances highlighted the potential involvement of matrix vesicles (secreted by macrophages), as key molecules in the alternative processes independent of osteogenic differentiation [45]. Deciphering the association between these mechanisms and signaling pathways could bring novel insights into the mechanistics of calcification and could possibly move forward to new therapeutic strategies aiming at cardiovascular disease in CKD [46]. These findings are in concordance with the genetics, and it was shown that 40–50% of coronary calcification cases could be linked to genetic predisposition, considering that several loci were linked to coronary arterial calcification [47]. The involvement of single polymorphisms located at 9p21 locus near the cyclin genes was proposed as a genetic mechanism of this pathology; the concerned genes could be generally associated with cellular senescence and inflammation, although the accurate causative DNA sequences continue to be uncertain [48]. Recent evidence

could thus interfere with the inflammatory mechanisms in CKD population.

the role of inflammation in CKD population, particularly in the early stages.

**diseases in CKD**

emerged to target the disease prevention [42].

**3. The role of inflammation in the development of cardiovascular** 

Availability of omics multiplex technology offered the opportunity of shifting the analysis of single individual marker toward assessing cytokine panels [36]. It was described an inflammatory panel, consisting of proinflammatory cytokines IL1, IL6, and TNFα with antiinflammatory ones IL2, IL4, IL5, IL12, CH50, as well, with a significant impact on CKD patients' survival [35]. Recently, significant attention has been granted to the potential role of adipokines in CKD, such as proinflammatory leptin, apelin, omentin, visfatin, resistin, and antiinflammatory adiponectin. Based on the data from the National Health and Nutrition Examination Survey (NHANES), it was shown that CKD is correlated with increased leptin levels [37]. Moreover, adiponectin expression in ESRD patients was also significantly increased compared to healthy individuals [14].

Atherosclerosis is now considered a chronic inflammatory disease and, in turn, cardiovascular disease is a major complication of CKD. Thus, a vicious circle is created between inflammation and CKD. Atherosclerosis is accelerated in CKD by complex mechanisms involving a cross talk between lymphocyte T helper type 1 and subendothelial macrophages as antigen presenting cells. The triggers of this cellular response are alteration of lipid metabolism and subendothelial deposit of plasma lipoproteins. Locally recruited lymphocytes react to autoantigens from the apolipoprotein B100 protein of LDL, generating an inflammatory response [38]. Within the predialysis CKD patients, the prevalence of inflammation is increasing and represents a critical indicator of patient health and future outcome. In ESRD, the process of hemodialysis itself may contribute to the proinflammatory state, and different types of dialysis membrane could determine an inflammatory response. However, hemodialysis does not represent the only source of inflammation, since the predialysis CKD patients already manifest a certain inflammatory state [39]. A persistent inflammatory state in CKD is not only linked to cardiovascular complications but is also one of the key players in the development of malnutrition/proteinenergy wasting, having as consequence the malnutritioninflammationcachexia syndrome in CKD/ESRD patients. It was also described, in a cohort of dialysis patients, that circulating levels of IL1 and IL6 could suppress the PTH secretion, which, in turn, may reflect the malnutritioninflammationcachexia syndrome, rather than the low bone turnover disease [40]. The pathophysiology of inflammation could be different with regard to different racial, ethnic, or genetic features. Recent studies specify that dietary habits could add a peculiar signature to the gut microbiota composition, and intestinal dysbiosis itself could thus interfere with the inflammatory mechanisms in CKD population.

In summary, persistent lowgrade inflammation has been recognized as an important component of CKD scenario, playing major roles in the pathophysiology of the disease, with a major imprint on its complications. Nevertheless, further investigations are necessary to decipher the role of inflammation in CKD population, particularly in the early stages.

## **3. The role of inflammation in the development of cardiovascular diseases in CKD**

inversely associated with measures of kidney function and positively with albuminuria [30]. The erythrocyte sedimentation rate, a nonspecific measure of inflammation, has been shown to be predictive of endstage renal disease in adolescents [31]. The level of proinflammatory cytokine IL2 was elevated in hemodialysis patients with uremic pruritus (a common tormenting symptom among these patients) when compared to hemodialysis patient controls without pruritus [32]. The results obtained from several researches suggest that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) plays an important role in kidney injury associated with inflammation and promotes acute and chronic kidney diseases [33]. There are several studies testing different nanoconjugates that could prevent TWEAKinduced cell death and inflammatory signaling in different cell types, including renal tubular cells [34]. The results obtained from a study investigating hemodialysis patients showed that the group of patients with a specific pattern of high proinflammatory cytokines (IL1, IL6, and TNFα) had increased mortality when compared to patients with a pattern of high Tcell regulatory or antiinflammatory

Availability of omics multiplex technology offered the opportunity of shifting the analysis of single individual marker toward assessing cytokine panels [36]. It was described an inflammatory panel, consisting of proinflammatory cytokines IL1, IL6, and TNFα with antiinflammatory ones IL2, IL4, IL5, IL12, CH50, as well, with a significant impact on CKD patients' survival [35]. Recently, significant attention has been granted to the potential role of adipokines in CKD, such as proinflammatory leptin, apelin, omentin, visfatin, resistin, and antiinflammatory adiponectin. Based on the data from the National Health and Nutrition Examination Survey (NHANES), it was shown that CKD is correlated with increased leptin levels [37]. Moreover, adiponectin expression in ESRD patients was also sig-

Atherosclerosis is now considered a chronic inflammatory disease and, in turn, cardiovascular disease is a major complication of CKD. Thus, a vicious circle is created between inflammation and CKD. Atherosclerosis is accelerated in CKD by complex mechanisms involving a cross talk between lymphocyte T helper type 1 and subendothelial macrophages as antigen presenting cells. The triggers of this cellular response are alteration of lipid metabolism and subendothelial deposit of plasma lipoproteins. Locally recruited lymphocytes react to autoantigens from the apolipoprotein B100 protein of LDL, generating an inflammatory response [38]. Within the predialysis CKD patients, the prevalence of inflammation is increasing and represents a critical indicator of patient health and future outcome. In ESRD, the process of hemodialysis itself may contribute to the proinflammatory state, and different types of dialysis membrane could determine an inflammatory response. However, hemodialysis does not represent the only source of inflammation, since the predialysis CKD patients already manifest a certain inflammatory state [39]. A persistent inflammatory state in CKD is not only linked to cardiovascular complications but is also one of the key players in the development of malnutrition/proteinenergy wasting, having as consequence the malnutritioninflammationcachexia syndrome in CKD/ESRD patients. It was also described, in a cohort of dialysis patients, that circulating levels of IL1 and IL6 could suppress the PTH secretion, which, in turn, may reflect the malnutritioninflammationcachexia syndrome, rather than the low bone turnover disease [40]. The pathophysiology of inflammation could be different with regard to different racial, ethnic, or genetic features. Recent studies specify that dietary habits

parameters (IL2, IL4, IL5, IL12, CH50, and Tcell number) [35].

134 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

nificantly increased compared to healthy individuals [14].

Cardiovascular disease represents one of the main determinants of CKD's poor prognosis, since early stages of CKD are significantly correlated with increased risk of subsequent coronary heart disease [41]. In agreement with several clinical studies, approximately 50% of patients with CKD have a rising mortality due to the cardiovascular complications, such as advanced calcific arterial and valvular disease; however, the mechanisms that involves the accelerated calcification in CKD continue to be questionable, thus no specific therapies have emerged to target the disease prevention [42].

The current CKD guidelines are recommending the screening for vascular calcification (VC), for the reason that VC represents a cardiovascular risk factor, and it is correlated with an increased morbidity and mortality in CKD group, culminating in CKD stage 5. Vascular calcification is now considered an active process that involves many proteins, as possible candidate markers [43]. In CKD individuals, several studies have highlighted various circulating biomarkers that could play important roles in extraskeletal calcification and mineral metabolism alterations, which are considered characteristics of CKDmineral bone disorder (CKDMBD) [44]. As a result, these findings have revealed that CKDMBD comprises laboratory and bone abnormalities and vascular calcification and has deleterious consequences on clinical outcomes; however, these processes are interconnected and they have to be studied in association with cardiovascular diseases [1].

Cardiovascular calcification represents though an exceptional marker of chronic inflammatory status in CKD, strongly correlated with morbidity and mortality. Curiously, CKD accelerates the atherosclerosis evolution and it has been showed that CKD produces increasing vascular inflammation and calcification. Recent advances highlighted the potential involvement of matrix vesicles (secreted by macrophages), as key molecules in the alternative processes independent of osteogenic differentiation [45]. Deciphering the association between these mechanisms and signaling pathways could bring novel insights into the mechanistics of calcification and could possibly move forward to new therapeutic strategies aiming at cardiovascular disease in CKD [46]. These findings are in concordance with the genetics, and it was shown that 40–50% of coronary calcification cases could be linked to genetic predisposition, considering that several loci were linked to coronary arterial calcification [47]. The involvement of single polymorphisms located at 9p21 locus near the cyclin genes was proposed as a genetic mechanism of this pathology; the concerned genes could be generally associated with cellular senescence and inflammation, although the accurate causative DNA sequences continue to be uncertain [48]. Recent evidence suggests that the overlap between CKD and cardiovascular disease is due, on one hand, to the dynamic cross talk between these organs, resulting in cardio-renal syndrome, increasingly recognized [49] and, on the other hand, it could be linked to the common etiologies of these major diseases (hypertension and diabetes mellitus). It has also been investigated as a possible common disorder of the kidneys and heart whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ; nevertheless, a complete picture of the mechanisms implicated in these processes is still missing [49]. The highly reactive oxygen species (ROS) present the potential of disrupting different structural and functional pathways in cells. Therefore, the inflammatory cells are activated by cell damage produced by ROS; thus, a vicious circle of chronic disturbance is constantly perpetuated. The oxidant imbalance theory comprises several important pathways and cell metabolism also has been under the surveillance of the cross talk between oxidants and antioxidants. The role of oxidative stress in the pathogenesis of CKD relies though on the hypothesis that antioxidant therapies could target and reconstruct the disturbances in the redox environment of cells [50]. Different therapeutic strategies have been considered to decrease oxidative stress (OS) in models of CKD and cardiovascular disease, proposing a low oxidant intake in different dietary approaches. Oxidative stress and inflammation increase with aging, and these conditions are related to kidney failure in its early stages, as well. There are evidences that a diet supplemented with oxidants could produce increased serum levels of OS and inflammatory mediators in both normal aging and in CKD. It is mentioned that dietary intervention could offer novel therapeutic strategies by reducing OS and inflammation in patients with CKD and in aging population with decreased kidney function [51].

also an accelerated development in the last years, being able to rapidly separate analytes in a highly reproducible manner [55]. Also, matrixassisted laser desorption/ionization (MALDI) platform has moved the boundaries above, being able to assess tissue specimens with high resolution in order to discriminate individual cells. This approach can provide detailed information related to CKD and the potential to detect specific biomarkers. Recent evidence suggests that MALDI could generate molecular signatures of primary and secondary kidney injury, with one particular signal, identified as serine/threonineprotein kinase MRCK gamma, being overexpressed in the glomeruli of primary membranous nephropathy (MN). These findings could be potential future targets for the further stratification of these patients [56]. Other studies emphasize the role of omics technologies, including MALDI to generate molecular signatures capable to distinguish between normal kidney and pathological kidney, with specific signals representing potential indicators of CKD development [57]. Kidney and Urinary Pathway Knowledge Base (KUPKB) represents an open source to explore multi-omics data and to generate new *in silico* theories using a novel approach based on semantic web technologies [58]. Moreover, CKDdb represents the most comprehensive molecular information resource in characterizing CKD-related experiments and model systems, potentially useful in the design of disease models, thus avoiding the chal-

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

137

lenges related with handling and integration of heterogeneous enormous data [59].

**5. Gut microbiota as a source of inflammation in CKD:** 

the field of personalized medicine [60].

**a bidirectional relationship**

The emerging knowledge generated by the application of omics (genomics, proteomics, and metabolomics) in major diseases, including CKD, could provide new insights into the pathophysiology of the disease by identifying novel biomarkers that could improve, in real time, the early diagnostics, monitoring, and prognostics; thus, omics will provide a major impact in

Accumulating evidence over the recent years has highlighted that chronic inflammation represents a nontraditional risk factor in CKD population and was revealed that gastrointestinal tract is a major player in systemic inflammation occurring in CKD [61]. The gut microbiota preserves the symbiotic relationship with the host in normal conditions and is essential for regulation of local and systemic immunity [62], although its imbalance has latterly been related with several diseases [63]. Alteration in the functions or signaling pathways of the commensal flora contributes to the pathogenesis of diverse diseases, including chronic inflammation and renal disorders, as well; gut bacterial DNA fragments have been detected in the blood of both predialysis CKD and chronic hemodialysis patients [64]. The decisive role of the biochemical milieu in shaping the gut microbiota, in terms of structure, composition, and function, which could promote a proinflammatory activity, was also described and it could simultaneously restrict the beneficial effects offered by a balanced microbiota. Such conditions could lead to an altered status, targeting inflammation, uremic toxicity, and other complications inside the CKD patients [65]. The interactions are bidirectional: on the one hand, uremia negatively interferes with the microbiota, altering the composition and metabolism and, on the other hand, the microbiota dysbiosis releases compounds that are normally excreted by the kidneys

Due to the circulating nature of many inflammatory mediators (cytokines and immune cells), it is tempting to hypothesize that the immune system could have crucial roles in organ interactions and could mediate the reciprocal dysfunction that is experienced in cardio-renal syndromes.

## **4. Omics technologies and clinical relevance of proteomic biomarkers in renal diseases: rolling proteomics into clinics**

Over the last decade, there has been an increasing progression of omics approaches, accompanied by remarkable improvement of methodologies and analytical instruments, based on the concept that a thorough characterization of a complex system, providing novel perceptions into functional pathways and regulatory networks, could be deciphered in frame of these omics. In the light of recent advances in bioinformatics and biostatistics on state-of-the-art platforms, the access of scientists in correlating the experimentally observed data regarding the fundamental biochemical and pathological mechanisms was facilitated [52, 53]. Proteomic biomarkers in kidney disease may represent, along with classical markers serum creatinine and urinary albumin, valuable tools in clinical diagnosis due to their accurate potential for clinical implementation. Moreover, proteomic biomarkers could also be useful in characterizing the most suitable therapeutic targets in a given patient or disease setting [54].

The huge step forward was accomplished by coupling liquid chromatography with mass spectrometry, enabling untargeted protein identification. Additionally, capillary electrophoresis had also an accelerated development in the last years, being able to rapidly separate analytes in a highly reproducible manner [55]. Also, matrixassisted laser desorption/ionization (MALDI) platform has moved the boundaries above, being able to assess tissue specimens with high resolution in order to discriminate individual cells. This approach can provide detailed information related to CKD and the potential to detect specific biomarkers. Recent evidence suggests that MALDI could generate molecular signatures of primary and secondary kidney injury, with one particular signal, identified as serine/threonineprotein kinase MRCK gamma, being overexpressed in the glomeruli of primary membranous nephropathy (MN). These findings could be potential future targets for the further stratification of these patients [56]. Other studies emphasize the role of omics technologies, including MALDI to generate molecular signatures capable to distinguish between normal kidney and pathological kidney, with specific signals representing potential indicators of CKD development [57]. Kidney and Urinary Pathway Knowledge Base (KUPKB) represents an open source to explore multi-omics data and to generate new *in silico* theories using a novel approach based on semantic web technologies [58]. Moreover, CKDdb represents the most comprehensive molecular information resource in characterizing CKD-related experiments and model systems, potentially useful in the design of disease models, thus avoiding the challenges related with handling and integration of heterogeneous enormous data [59].

The emerging knowledge generated by the application of omics (genomics, proteomics, and metabolomics) in major diseases, including CKD, could provide new insights into the pathophysiology of the disease by identifying novel biomarkers that could improve, in real time, the early diagnostics, monitoring, and prognostics; thus, omics will provide a major impact in the field of personalized medicine [60].

## **5. Gut microbiota as a source of inflammation in CKD: a bidirectional relationship**

suggests that the overlap between CKD and cardiovascular disease is due, on one hand, to the dynamic cross talk between these organs, resulting in cardio-renal syndrome, increasingly recognized [49] and, on the other hand, it could be linked to the common etiologies of these major diseases (hypertension and diabetes mellitus). It has also been investigated as a possible common disorder of the kidneys and heart whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ; nevertheless, a complete picture of the mechanisms implicated in these processes is still missing [49]. The highly reactive oxygen species (ROS) present the potential of disrupting different structural and functional pathways in cells. Therefore, the inflammatory cells are activated by cell damage produced by ROS; thus, a vicious circle of chronic disturbance is constantly perpetuated. The oxidant imbalance theory comprises several important pathways and cell metabolism also has been under the surveillance of the cross talk between oxidants and antioxidants. The role of oxidative stress in the pathogenesis of CKD relies though on the hypothesis that antioxidant therapies could target and reconstruct the disturbances in the redox environment of cells [50]. Different therapeutic strategies have been considered to decrease oxidative stress (OS) in models of CKD and cardiovascular disease, proposing a low oxidant intake in different dietary approaches. Oxidative stress and inflammation increase with aging, and these conditions are related to kidney failure in its early stages, as well. There are evidences that a diet supplemented with oxidants could produce increased serum levels of OS and inflammatory mediators in both normal aging and in CKD. It is mentioned that dietary intervention could offer novel therapeutic strategies by reducing OS and inflammation

136 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

in patients with CKD and in aging population with decreased kidney function [51].

**4. Omics technologies and clinical relevance of proteomic biomarkers in renal diseases: rolling proteomics into clinics**

Due to the circulating nature of many inflammatory mediators (cytokines and immune cells), it is tempting to hypothesize that the immune system could have crucial roles in organ interactions and could mediate the reciprocal dysfunction that is experienced in cardio-renal syndromes.

Over the last decade, there has been an increasing progression of omics approaches, accompanied by remarkable improvement of methodologies and analytical instruments, based on the concept that a thorough characterization of a complex system, providing novel perceptions into functional pathways and regulatory networks, could be deciphered in frame of these omics. In the light of recent advances in bioinformatics and biostatistics on state-of-the-art platforms, the access of scientists in correlating the experimentally observed data regarding the fundamental biochemical and pathological mechanisms was facilitated [52, 53]. Proteomic biomarkers in kidney disease may represent, along with classical markers serum creatinine and urinary albumin, valuable tools in clinical diagnosis due to their accurate potential for clinical implementation. Moreover, proteomic biomarkers could also be useful in character-

izing the most suitable therapeutic targets in a given patient or disease setting [54].

The huge step forward was accomplished by coupling liquid chromatography with mass spectrometry, enabling untargeted protein identification. Additionally, capillary electrophoresis had Accumulating evidence over the recent years has highlighted that chronic inflammation represents a nontraditional risk factor in CKD population and was revealed that gastrointestinal tract is a major player in systemic inflammation occurring in CKD [61]. The gut microbiota preserves the symbiotic relationship with the host in normal conditions and is essential for regulation of local and systemic immunity [62], although its imbalance has latterly been related with several diseases [63]. Alteration in the functions or signaling pathways of the commensal flora contributes to the pathogenesis of diverse diseases, including chronic inflammation and renal disorders, as well; gut bacterial DNA fragments have been detected in the blood of both predialysis CKD and chronic hemodialysis patients [64]. The decisive role of the biochemical milieu in shaping the gut microbiota, in terms of structure, composition, and function, which could promote a proinflammatory activity, was also described and it could simultaneously restrict the beneficial effects offered by a balanced microbiota. Such conditions could lead to an altered status, targeting inflammation, uremic toxicity, and other complications inside the CKD patients [65]. The interactions are bidirectional: on the one hand, uremia negatively interferes with the microbiota, altering the composition and metabolism and, on the other hand, the microbiota dysbiosis releases compounds that are normally excreted by the kidneys but could be considered as potential uremic toxins, both conditions further leading to a toxin avalanche exposure, due to the disruption of the epithelial barrier with an increased intestinal permeability, often referred to as "leaky gut," a condition that has been reported in CKD [66].

In conclusion, accumulating evidence recognizes that dietary fiber may reverse gut dysbiosis and abolish microinflammation, being in agreement with epidemiological evidence suggesting correlations between higher dietary fiber intake, better kidney function, and lower inflammation, at least in the general population. Many researchers accept that supporting intestinal health and restoring the integrity of the gut wall will represent one of the most important

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

139

**6. Restoring microbiota balance: the exploration of novel therapeutic** 

**Figure 1.** The crosstalk between CKD and inflammation in correlation with microbiota dysbiosis modulation.

Intestinal inflammation and gut microbiota dysbiosis, as well, are now recognized as important contributors in chronic inflammation and other CKD complications, thus explaining the guttherapeutic novel avenues taken into consideration in designing CKD interventions [61] . The microbiota can be considered as a recently discovered "organ," being involved in many pathological axes, in relation with almost every organ, including kidneys; there are different metabolites derived from microbiota dysbiosis engaged in distinct physiology pathways linking to renal dysfunction [72]. The bidirectional relationship between gut microbiota and CKD is noted in many studies, and the effect of CKD on gut structure, leading further to dysbiosis (**Figure 1**) is also mentioned. The abundance of specific bacterial groups are dominated by Bacteroides, Prevotella, or Ruminococcus in normal individual gut microbiota [73], and these enterotypes are markedly correlated with long-term diets, especially the proteins and

goals in improving the quality of life within CKD individuals.

**avenues in renal diseases**

Uremia status seems to impair the intestinal barrier function and promotes inflammation throughout the gastrointestinal tract. A prospective, observational study reported the baseline concentration of indoxyl sulfate, a uremic toxin that could have a predictive power in CKD progression [67]. Other uremic toxins, p-cresol sulfate and trimethylamine N-oxide (TMAO), were assessed in relation to kidney function (estimated GFR), and the results conclude that the elevated expression was associated to an increased risk for all-cause mortality in ESRD patients. [68]. Uremia represents a condition that accompanies kidney failure and CKD. Uremic toxins originated in, or inserted into, the body via the intestine, such as glycation metabolites, phenols, indoles, all may play important roles in CKD pathophysiology. Consequently, it is biologically plausible, but not well accepted, that a crucial player in the toxic scenario of the CKD resides in the gut microbiota [69].

Deciphering the role of gut microbiota in CKD progression needs a complex comprehension regarding its composition, function, and homeostasis within each individual. As expected, the gut microbiota composition shows great variations, representing a unique signature with each individual harboring, consisting mainly of Gramnegative Bacteroidetes and the Grampositive lowGC Firmicutes [68]. Gut dysbiosis in CKD was correlated with an increase in pathogenic flora compared to symbiotic flora, which, along with enhanced intestinal permeability, increases absorption of endotoxins with harmful consequences in the organism. The gut-derived uremic toxins, along with an expanded permeability of the intestinal barrier, have been correlated with an increased inflammatory state and oxidative stress, which are constant features of advanced CKD, with a major impact on its complications [65]. The dysbiotic intestinal microflora could be correlated to the intestinal wall edema and ischemia, as well as to a defective colonic epithelial barrier [65]. Recent evidences suggested that several circulating metabolites derived from gut microbiota metabolism could be related to systemic immunoinflammatory response and kidney damage. It has been shown that shortchain fatty acids (SCFAs), which are metabolites essentially derived from dietary fiber fermentation in the gut, are significant players in modulation of immunity, blood pressure, glucose, and lipid metabolism. In addition, SCFAs also "modulate different cell signal transduction processes via Gprotein–coupled receptors and act as epigenetic regulators by the inhibition of histone deacetylase and as potential mediators involved in the autophagy pathway." Though controversial, the SCFAs may be regarded as potential therapeutic targets and seem to represent the link between kidney damage and inflammatory response [70]. Gut inflammation is prevalent in CKD and is subsequently involved in systemic inflammation by disruption in the epithelial tight junction, leading to endotoxin and bacterial translocation; this state is associated with a defective Nrf2 pathway. On the basis that Nrf2 represents a protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, oral administration of Nrf2 activator (study conducted on rats) has reestablished the epithelial tight junction protein expression, alleviating arterial hypertension and rehabilitating the markers of kidney function [71].

In conclusion, accumulating evidence recognizes that dietary fiber may reverse gut dysbiosis and abolish microinflammation, being in agreement with epidemiological evidence suggesting correlations between higher dietary fiber intake, better kidney function, and lower inflammation, at least in the general population. Many researchers accept that supporting intestinal health and restoring the integrity of the gut wall will represent one of the most important goals in improving the quality of life within CKD individuals.

but could be considered as potential uremic toxins, both conditions further leading to a toxin avalanche exposure, due to the disruption of the epithelial barrier with an increased intestinal permeability, often referred to as "leaky gut," a condition that has been reported in CKD [66]. Uremia status seems to impair the intestinal barrier function and promotes inflammation throughout the gastrointestinal tract. A prospective, observational study reported the baseline concentration of indoxyl sulfate, a uremic toxin that could have a predictive power in CKD progression [67]. Other uremic toxins, p-cresol sulfate and trimethylamine N-oxide (TMAO), were assessed in relation to kidney function (estimated GFR), and the results conclude that the elevated expression was associated to an increased risk for all-cause mortality in ESRD patients. [68]. Uremia represents a condition that accompanies kidney failure and CKD. Uremic toxins originated in, or inserted into, the body via the intestine, such as glycation metabolites, phenols, indoles, all may play important roles in CKD pathophysiology. Consequently, it is biologically plausible, but not well accepted, that a crucial player in the

Deciphering the role of gut microbiota in CKD progression needs a complex comprehension regarding its composition, function, and homeostasis within each individual. As expected, the gut microbiota composition shows great variations, representing a unique signature with each individual harboring, consisting mainly of Gramnegative Bacteroidetes and the Grampositive lowGC Firmicutes [68]. Gut dysbiosis in CKD was correlated with an increase in pathogenic flora compared to symbiotic flora, which, along with enhanced intestinal permeability, increases absorption of endotoxins with harmful consequences in the organism. The gut-derived uremic toxins, along with an expanded permeability of the intestinal barrier, have been correlated with an increased inflammatory state and oxidative stress, which are constant features of advanced CKD, with a major impact on its complications [65]. The dysbiotic intestinal microflora could be correlated to the intestinal wall edema and ischemia, as well as to a defective colonic epithelial barrier [65]. Recent evidences suggested that several circulating metabolites derived from gut microbiota metabolism could be related to systemic immunoinflammatory response and kidney damage. It has been shown that shortchain fatty acids (SCFAs), which are metabolites essentially derived from dietary fiber fermentation in the gut, are significant players in modulation of immunity, blood pressure, glucose, and lipid metabolism. In addition, SCFAs also "modulate different cell signal transduction processes via Gprotein–coupled receptors and act as epigenetic regulators by the inhibition of histone deacetylase and as potential mediators involved in the autophagy pathway." Though controversial, the SCFAs may be regarded as potential therapeutic targets and seem to represent the link between kidney damage and inflammatory response [70]. Gut inflammation is prevalent in CKD and is subsequently involved in systemic inflammation by disruption in the epithelial tight junction, leading to endotoxin and bacterial translocation; this state is associated with a defective Nrf2 pathway. On the basis that Nrf2 represents a protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, oral administration of Nrf2 activator (study conducted on rats) has reestablished the epithelial tight junction protein expression, alleviating arterial hypertension and

toxic scenario of the CKD resides in the gut microbiota [69].

138 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

rehabilitating the markers of kidney function [71].

## **6. Restoring microbiota balance: the exploration of novel therapeutic avenues in renal diseases**

Intestinal inflammation and gut microbiota dysbiosis, as well, are now recognized as important contributors in chronic inflammation and other CKD complications, thus explaining the guttherapeutic novel avenues taken into consideration in designing CKD interventions [61] .

The microbiota can be considered as a recently discovered "organ," being involved in many pathological axes, in relation with almost every organ, including kidneys; there are different metabolites derived from microbiota dysbiosis engaged in distinct physiology pathways linking to renal dysfunction [72]. The bidirectional relationship between gut microbiota and CKD is noted in many studies, and the effect of CKD on gut structure, leading further to dysbiosis (**Figure 1**) is also mentioned. The abundance of specific bacterial groups are dominated by Bacteroides, Prevotella, or Ruminococcus in normal individual gut microbiota [73], and these enterotypes are markedly correlated with long-term diets, especially the proteins and

**Figure 1.** The crosstalk between CKD and inflammation in correlation with microbiota dysbiosis modulation.

animalfat level (Bacteroides) versus carbohydrates (Prevotella) [74]. On the other side, the gut microbiota in CKD patients is altered, particularly with a decreased amount of Lactobacillaceae and Prevotellaceae families, and with an increased amount (more than 100 times higher) of Enterobacteria and Enterococci, species that are normally found in lower concentrations in healthy individuals [65]. The "supplementary organ" has also an important contribution to digestion, using two different catabolic pathways: saccharolytic (fermentation), with a high prevalence of Bifidobacteria and Lactobacilli, having shortchain fatty acids as end products, and the second, proteolytic (putrefaction) pathway, involving some species within Clostridium, Bacteroides, Enterobacterium, Bifidobacterium, and Lactobacillus [75] that leads to short or branchedchain fatty acids and other cometabolites, considered as microbial uremic toxins [76]. Another controversial mechanism linked to microbial dysbiosis in CKD patients involves the elevated gastrointestinal urea secretion, leading to important amounts of ammonia, which, in turn, contribute to the disturbance in the commensal bacteria [77]; therefore, targeting the gut microbiota composition could represent a promising approach in CKD monitoring and followup. Hence, it is considered that a balanced microbiota is mainly saccharolytic and therefore diet itself owns a beneficial role in modulating the gut microbiota composition [78].

Key mechanisms to preserve the gut microbiota balance are considered to include special diets, such as Mediterranean diet, (detailed in **Table 1**) enriched in nondigestible carbohydrates, subject to fermentation by gut microbiota, with low quantities of proteins or fats [75]. It was also revealed that dietary content and their metabolites, such as advanced glycated end products (AGEs), types of uremic toxin resulted in the glycation process, could be closely linked to CKD. Promising therapeutic targets based on nutrition approaches include uremic toxin absorbents and inhibitors of AGEs or the receptor for AGEs. Also specific types of amino acids (dserine) or fatty acids (palmitate) have been indicated to be related with CKD progression, but they are preliminary results and further studies are needed to confirm their efficacy [79]. It is worth mentioning that dietary interventions could increase the quality of life in CKD patients, though their certain effects on mortality, cardiovascular events, and ESRD remain unclear [80]. The significance of a proper diet was settled in large retrospective cohort studies, which evidenced that the mortality occurrence in predialysis patients that were under dietitian surveillance decreased 19% compared with the patients not under any dietary treat. The conclusion that emerged is that a nutritional care in early stages of CKD could have a better prognosis on survival; however, randomized clinical trials are needed to prove this hypothesis [81].

Another area of potential beneficent therapies in CKD patients relies on the administration of prebiotics and probiotics, and the combination of both therapies into "synbiotic" preparations [81].

> and the suspicion whether these bacteria will resist in the uremic habitat remain questionable [84]. A multinational trial involving patients with CKD stage 3 and 4 has described that half year treatment with proprietary formulation of *S. thermophilus*, *L. acidophilus*, and *B. longum* over has induced a significant decline in urea nitrogen circulating levels and has also enhanced the quality of life scores in these patients. It still remains unclear whether the described interventions may alter the integrity of gut tight junction barrier; thus, more studies are needed to

**Dietary type Diet summary Effects on CKD References**

PROTECTIVE: potentially restoring microbiota balance, ameliorating CKD conditions, slow down disease

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

the burden of uremic toxins; attention must be paid to serum

modulates microbiota metabolism and the high fiber intake of vegan diet may have favorable effects on

PROTECTIVE: decreased risk of

PROTECTIVE: inversely associated

DETRIMENTAL: increased risk of

DETRIMENTAL: independently associated with mortality in persons

DETRIMENTAL: directly associated

DETRIMENTAL: rapid kidney

DETRIMENTAL: increased risk of

[78, 91, 92]

141

http://dx.doi.org/10.5772/intechopen.72716

[93, 94]

[93]

[95, 96]

[97]

[96]

[98] [97]

[97]

[99]

[100–103]

progression.

potassium levels.

intestinal microbiota.

rapid eGFR decline.

rapid eGFR decline.

with CKD.

with CKD.

with CKD.

function decline.

ESRD and mortality.

unrefined grains, fruits and vegetables, nuts, olive oil, fish, and a moderate consumption of red wine, dairy products, and

**Vegetarian diet** Fruits and vegetables, olive oil ADDITIONAL BENEFITS: reduce

**Vegan diet** Fruits and vegetables, olive oil POSITIVE: the addition of inulin

approach to hypertension

egg, milk, and deep-fried

low in fruit and vegetables, grains, and fibers

Rice, pork, and vegetables, and

High intake of fruit, soy milk, egg, milk, and deep-fried products, with cadmium contamination in parts of the

Guidelines for Americans

sweetened beverages

low intake of wheat

food supply

(DGA)

**Table 1.** Different dietary patterns assessed in association with CKD.

**DAL diet** Diet enriched in dietary acid load

**Mediterranean diet** Carbohydrates, basically

**DASH diet** Consistent with a dietary

**Modern dietary pattern** High intake of fruit, soy milk,

**Western diet** Excessively rich in protein and

**Southern diet** Fried foods, organ meats,

**DGA diet** Diet based on Dietary

**Modern dietary pattern, with increased cadmium** 

**intake**

products

red meats

enlarge the knowledge in this area [85].

*Probiotics* are defined as "live microorganisms that when administered in adequate amounts confer a health benefit on the host" [82]. Probiotics consist of living bacteria, which can reshape gut microbiota, with impact on the inflammatory status, and are mainly represented by Bifidobacteria species, Lactobacilli, and Streptococci. A study on mice revealed that treatment with Lactobacillus acidophilus could have the potential to attenuate the development of atherosclerotic lesions in mice by reducing the oxidative stress and the inflammatory response [83]. However, the optimal dose of the bacteria essential to obtain an impeccable engraftment


**Table 1.** Different dietary patterns assessed in association with CKD.

animalfat level (Bacteroides) versus carbohydrates (Prevotella) [74]. On the other side, the gut microbiota in CKD patients is altered, particularly with a decreased amount of Lactobacillaceae and Prevotellaceae families, and with an increased amount (more than 100 times higher) of Enterobacteria and Enterococci, species that are normally found in lower concentrations in healthy individuals [65]. The "supplementary organ" has also an important contribution to digestion, using two different catabolic pathways: saccharolytic (fermentation), with a high prevalence of Bifidobacteria and Lactobacilli, having shortchain fatty acids as end products, and the second, proteolytic (putrefaction) pathway, involving some species within Clostridium, Bacteroides, Enterobacterium, Bifidobacterium, and Lactobacillus [75] that leads to short or branchedchain fatty acids and other cometabolites, considered as microbial uremic toxins [76]. Another controversial mechanism linked to microbial dysbiosis in CKD patients involves the elevated gastrointestinal urea secretion, leading to important amounts of ammonia, which, in turn, contribute to the disturbance in the commensal bacteria [77]; therefore, targeting the gut microbiota composition could represent a promising approach in CKD monitoring and followup. Hence, it is considered that a balanced microbiota is mainly saccharolytic and therefore diet

140 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

itself owns a beneficial role in modulating the gut microbiota composition [78].

Key mechanisms to preserve the gut microbiota balance are considered to include special diets, such as Mediterranean diet, (detailed in **Table 1**) enriched in nondigestible carbohydrates, subject to fermentation by gut microbiota, with low quantities of proteins or fats [75]. It was also revealed that dietary content and their metabolites, such as advanced glycated end products (AGEs), types of uremic toxin resulted in the glycation process, could be closely linked to CKD. Promising therapeutic targets based on nutrition approaches include uremic toxin absorbents and inhibitors of AGEs or the receptor for AGEs. Also specific types of amino acids (dserine) or fatty acids (palmitate) have been indicated to be related with CKD progression, but they are preliminary results and further studies are needed to confirm their efficacy [79]. It is worth mentioning that dietary interventions could increase the quality of life in CKD patients, though their certain effects on mortality, cardiovascular events, and ESRD remain unclear [80]. The significance of a proper diet was settled in large retrospective cohort studies, which evidenced that the mortality occurrence in predialysis patients that were under dietitian surveillance decreased 19% compared with the patients not under any dietary treat. The conclusion that emerged is that a nutritional care in early stages of CKD could have a better prognosis on survival; however, randomized clinical trials are needed to prove this hypothesis [81].

Another area of potential beneficent therapies in CKD patients relies on the administration of prebiotics and probiotics, and the combination of both therapies into "synbiotic"

*Probiotics* are defined as "live microorganisms that when administered in adequate amounts confer a health benefit on the host" [82]. Probiotics consist of living bacteria, which can reshape gut microbiota, with impact on the inflammatory status, and are mainly represented by Bifidobacteria species, Lactobacilli, and Streptococci. A study on mice revealed that treatment with Lactobacillus acidophilus could have the potential to attenuate the development of atherosclerotic lesions in mice by reducing the oxidative stress and the inflammatory response [83]. However, the optimal dose of the bacteria essential to obtain an impeccable engraftment

preparations [81].

and the suspicion whether these bacteria will resist in the uremic habitat remain questionable [84]. A multinational trial involving patients with CKD stage 3 and 4 has described that half year treatment with proprietary formulation of *S. thermophilus*, *L. acidophilus*, and *B. longum* over has induced a significant decline in urea nitrogen circulating levels and has also enhanced the quality of life scores in these patients. It still remains unclear whether the described interventions may alter the integrity of gut tight junction barrier; thus, more studies are needed to enlarge the knowledge in this area [85].

*Prebiotics*, specialized plant fibers that promote the growth of healthy bacteria in the gut, have also an important role in preventing CKD progression [84]. The candidate prebiotics comprise inulin, fructo-oligosaccharides, galacto-oligosaccharides, soya-oligosaccharides, xylo-oligosaccharides, and pyrodextrins and have potential in promoting the growth of Bifidobacteria and *Lactobacilli* species [86]. Recent evidence indicates that prebiotic oligofructose-enriched inulin (pinulin) improves metabolic function, reduces inflammation, and mediates also weight loss [79]. Other prebiotic studies have described the role of supplements containing fructo-oligosaccharides (FOS) and/or inulin and their potential role in modulating the gut microbiota [75]. Prebiotic supplementation with FOS was correlated with a decline in proteolytic metabolites; thus, potential prebiotics such as AXOS could significantly imbalance the protein/carbohydrate fermentation ratio, resulting in alterations in the profile of fermentation metabolites, but the modifications related to microbiota composition remain ambiguous [87, 88].

biomarkers in order to enhance all types of alterations that characterize such a complex and

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

143

A variety of novel interventions have been recently proposed to target inflammation in CKD, and it seems that, in the near future, the conventional biomarkers could be proficiently improved, or even replaced with novel ones; however, confirmation of their efficacy, sensitivity, and specificity will definitely require randomized controlled and adequately interventional clinical trials.

Growing evidence indicates that gut microbiota can be considered as a recently discovered "organ," being involved in different pathological axes, in relation with almost every organ, including kidneys. Recent advances indicate that gut dysbiosis confers unexpected health risks. The gutkidney axis has imposed itself in the renal diseases scenario as a novel therapeutic avenue with great potential in the forthcoming future. Emerging evidences highlight the possible correlation between dysbiosis and a wide range of diseases. The gut microbiota imbalance represents though the plausible missing link between nutrition and health, focusing on CKD. Alterations in gut microbiota and a myriad of host responses have been involved in CKD prognosis, high risk of cardiovascular complications, uremic toxicity, and inflammation. There is a vicious circle in CKD, in which, on one hand, toxic gut microbiota metabolites are the major circulating uremic toxins and, on the other hand, their aggregation deteriorates gut dysbiosis and promotes CKD progression. This novel promising field of research could lead, in the near future, to the design of remarkably personalized nutritional procedures, in order to design the most convenient dietary

All authors contributed equally to this work. This work was partially supported by the grants

, Ionela Daniela Popescu1

1 BiochemistryProteomics Department, Victor Babes National Institute of Pathology,

2 Cellular and Molecular Medicine Department, Carol Davila University of Medicine and

3 Molecular Virology Department, Stefan S. Nicolau Institute of Virology, Bucharest, Romania

and Cristiana Tanase1,4

, Gabriela Anton<sup>3</sup>

4 Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania

\*Address all correspondence to: simona.mihai21@gmail.com

, AnaMaria Enciu1,2,

insidious disease.

strategy for each individual.

**Acknowledgements**

**Author details**

Laura Georgiana Necula<sup>3</sup>

Pharmacy, Bucharest, Romania

Bucharest, Romania

Simona Mihai<sup>1</sup>

COP A 1.2.3., ID: P\_40\_197/2016 and PN 16.22.05.03.

\*, Elena Codrici<sup>1</sup>

*Synbiotics* represent the dual approach of combining a probiotic with a prebiotic and were the subject of several studies. The Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY) Study was a singlecenter, doubleblind, placebocontrolled, randomized crossover trial that tested the effects of synbiotics in CKD patients with moderate to severe stages [89]. In this study, preliminary results highlighted that administration of synbiotic therapy did result in appreciable decreasing in circulating levels of nephrovascular uremic toxins, being accompanied by a significant modulation of the stool microbiome (especially with enhancement of Bifidobacterium and deficiency of Ruminococcaceae) in CKD patients, not under antibiotics prescription [89]. The gut microbiota alteration in CKD produces the release of indoxyl sulfate and p-cresyl sulfate, which represent key uremic nephrovascular toxins. Emerging evidence reveals that gut microbiota modulation through diet supplementation with pre and/probiotics could have an important role in inhibiting the generation of key nephrovascular toxins [90].

Considering the potential of all these preparations in shifting the uremic toxin expression and also in delaying the CKD progression, the exploration of these novel therapeutic avenues could provide vital insights into this inoffensive nutritional therapy.

## **7. Conclusions and future endeavors**

Persistent, lowgrade inflammation has been recently accepted as a potential hallmark of CKD, playing an essential role in its pathophysiology and being involved as well in the cardiovascular complications and all-cause poor prognosis in these patients. There has been an ascending growth of interest regarding the role of inflammation in CKD and endstage renal disease, which shifts the perception of inflammation as no longer a new, but rather a traditional risk factor for CKD morbidity and mortality.

The increasing evidence regarding the tight cross talk between inflammation and kidney function became pathophysiologically relevant in patients with CKD, due to the development of proteomics, genomics, and other omics, and the advancements in state-of-the-art technologies for identification of novel biomarkers in renal diseases. The complex mechanisms in CKD development and progression would require not a single marker, but assessment of a panel of biomarkers in order to enhance all types of alterations that characterize such a complex and insidious disease.

A variety of novel interventions have been recently proposed to target inflammation in CKD, and it seems that, in the near future, the conventional biomarkers could be proficiently improved, or even replaced with novel ones; however, confirmation of their efficacy, sensitivity, and specificity will definitely require randomized controlled and adequately interventional clinical trials.

Growing evidence indicates that gut microbiota can be considered as a recently discovered "organ," being involved in different pathological axes, in relation with almost every organ, including kidneys. Recent advances indicate that gut dysbiosis confers unexpected health risks. The gutkidney axis has imposed itself in the renal diseases scenario as a novel therapeutic avenue with great potential in the forthcoming future. Emerging evidences highlight the possible correlation between dysbiosis and a wide range of diseases. The gut microbiota imbalance represents though the plausible missing link between nutrition and health, focusing on CKD. Alterations in gut microbiota and a myriad of host responses have been involved in CKD prognosis, high risk of cardiovascular complications, uremic toxicity, and inflammation. There is a vicious circle in CKD, in which, on one hand, toxic gut microbiota metabolites are the major circulating uremic toxins and, on the other hand, their aggregation deteriorates gut dysbiosis and promotes CKD progression.

This novel promising field of research could lead, in the near future, to the design of remarkably personalized nutritional procedures, in order to design the most convenient dietary strategy for each individual.

## **Acknowledgements**

*Prebiotics*, specialized plant fibers that promote the growth of healthy bacteria in the gut, have also an important role in preventing CKD progression [84]. The candidate prebiotics comprise inulin, fructo-oligosaccharides, galacto-oligosaccharides, soya-oligosaccharides, xylo-oligosaccharides, and pyrodextrins and have potential in promoting the growth of Bifidobacteria and *Lactobacilli* species [86]. Recent evidence indicates that prebiotic oligofructose-enriched inulin (pinulin) improves metabolic function, reduces inflammation, and mediates also weight loss [79]. Other prebiotic studies have described the role of supplements containing fructo-oligosaccharides (FOS) and/or inulin and their potential role in modulating the gut microbiota [75]. Prebiotic supplementation with FOS was correlated with a decline in proteolytic metabolites; thus, potential prebiotics such as AXOS could significantly imbalance the protein/carbohydrate fermentation ratio, resulting in alterations in the profile of fermentation metabolites, but

*Synbiotics* represent the dual approach of combining a probiotic with a prebiotic and were the subject of several studies. The Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY) Study was a singlecenter, doubleblind, placebocontrolled, randomized crossover trial that tested the effects of synbiotics in CKD patients with moderate to severe stages [89]. In this study, preliminary results highlighted that administration of synbiotic therapy did result in appreciable decreasing in circulating levels of nephrovascular uremic toxins, being accompanied by a significant modulation of the stool microbiome (especially with enhancement of Bifidobacterium and deficiency of Ruminococcaceae) in CKD patients, not under antibiotics prescription [89]. The gut microbiota alteration in CKD produces the release of indoxyl sulfate and p-cresyl sulfate, which represent key uremic nephrovascular toxins. Emerging evidence reveals that gut microbiota modulation through diet supplementation with pre and/probiotics could have an important role in inhibiting the generation of key nephrovascular toxins [90].

Considering the potential of all these preparations in shifting the uremic toxin expression and also in delaying the CKD progression, the exploration of these novel therapeutic avenues

Persistent, lowgrade inflammation has been recently accepted as a potential hallmark of CKD, playing an essential role in its pathophysiology and being involved as well in the cardiovascular complications and all-cause poor prognosis in these patients. There has been an ascending growth of interest regarding the role of inflammation in CKD and endstage renal disease, which shifts the perception of inflammation as no longer a new, but rather a tradi-

The increasing evidence regarding the tight cross talk between inflammation and kidney function became pathophysiologically relevant in patients with CKD, due to the development of proteomics, genomics, and other omics, and the advancements in state-of-the-art technologies for identification of novel biomarkers in renal diseases. The complex mechanisms in CKD development and progression would require not a single marker, but assessment of a panel of

could provide vital insights into this inoffensive nutritional therapy.

**7. Conclusions and future endeavors**

tional risk factor for CKD morbidity and mortality.

the modifications related to microbiota composition remain ambiguous [87, 88].

142 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

All authors contributed equally to this work. This work was partially supported by the grants COP A 1.2.3., ID: P\_40\_197/2016 and PN 16.22.05.03.

## **Author details**

Simona Mihai<sup>1</sup> \*, Elena Codrici<sup>1</sup> , Ionela Daniela Popescu1 , AnaMaria Enciu1,2, Laura Georgiana Necula<sup>3</sup> , Gabriela Anton<sup>3</sup> and Cristiana Tanase1,4

\*Address all correspondence to: simona.mihai21@gmail.com

1 BiochemistryProteomics Department, Victor Babes National Institute of Pathology, Bucharest, Romania

2 Cellular and Molecular Medicine Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

3 Molecular Virology Department, Stefan S. Nicolau Institute of Virology, Bucharest, Romania

4 Faculty of Medicine, Titu Maiorescu University, Bucharest, Romania

## **References**

[1] Isakova T, Nickolas TL, Denburg M, Yarlagadda S, Weiner DE, Gutierrez OM, et al. KDOQI US Commentary on the 2017 KDIGO clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKDMBD). American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation. 2017;**70**(6):737751. [Epub 2017/09/25]

[13] Czyzewski L, Wyzgal J, Czyzewska E, Sierdzinski J, Szarpak L. Contribution of volume overload to the arterial stiffness of hemodialysis patients. Renal Failure. 2017;**39**(1):333

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

145

[14] Akchurin OM, Kaskel F. Update on inflammation in chronic kidney disease. Blood

[15] Golia E, Limongelli G, Natale F, Fimiani F, Maddaloni V, Pariggiano I, et al. Inflammation and cardiovascular disease: From pathogenesis to therapeutic target. Current Athero-

[16] Sankowski R, Mader S, ValdesFerrer SI. Systemic inflammation and the brain: Novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration.

[17] Roxburgh CS, McMillan DC. Cancer and systemic inflammation: Treat the tumour and treat the host. British Journal of Cancer. 2014;**110**(6):14091412. Epub 2014/02/20 [18] Calcada D, Vianello D, Giampieri E, Sala C, Castellani G, de Graaf A, et al. The role of lowgrade inflammation and metabolic flexibility in aging and nutritional modulation thereof: A systems biology approach. Mechanisms of Ageing and Development.

[19] Koh JH, Kim WU. Dysregulation of gut microbiota and chronic inflammatory disease: From epithelial defense to host immunity. Experimental & Molecular Medicine.

[20] Chassaing B, Gewirtz AT. Gut microbiota, lowgrade inflammation, and metabolic syn-

[21] Kochi M, Kohagura K, Shiohira Y, Iseki K, Ohya Y. Chronic kidney disease, inflammation, and cardiovascular disease risk in rheumatoid arthritis. Journal of Cardiology.

[22] Fried L, Solomon C, Shlipak M, Seliger S, StehmanBreen C, Bleyer AJ, et al. Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. Journal of the American Society of Nephrology: JASN. 2004;**15**(12):31843191. Epub 2004/12/08 [23] Stenvinkel P, Larsson TE. Chronic kidney disease: A clinical model of premature aging. American Journal of Kidney Diseases: The Official Journal of the National Kidney

[24] Qian Q. Inflammation: A key contributor to the genesis and progression of chronic kidney disease. Contributions to Nephrology. 2017;**191**:7283. Epub 2017/09/15

[25] Small DM, Gobe GC. Oxidative stress and antioxidant therapy in chronic kidney and cardiovascular disease. Biochemistry, Genetics and Molecular Biology. May 22, 2013.

[26] Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: Oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney International.

339. Epub 2017/01/26

Purification. 2015;**39**(13):8492. Epub 2015/02/11

sclerosis Reports. 2014;**16**(9):435. Epub 2014/07/20

2014;**136-137**:13847. Epub 2014/01/28

2017;**49**(5):e337. Epub 2017/05/27

2017. Epub 2017/10/04

ISBN: 9789535111238

2002;**62**(5):15241538. Epub 2002/10/10

Frontiers in Cellular Neuroscience. 2015;**9**:28. Epub 2015/02/24

drome. Toxicologic Pathology. 2014;**42**(1):4953. Epub 2013/11/29

Foundation. 2013;**62**(2):339351. Epub 2013/01/30


[13] Czyzewski L, Wyzgal J, Czyzewska E, Sierdzinski J, Szarpak L. Contribution of volume overload to the arterial stiffness of hemodialysis patients. Renal Failure. 2017;**39**(1):333 339. Epub 2017/01/26

**References**

[1] Isakova T, Nickolas TL, Denburg M, Yarlagadda S, Weiner DE, Gutierrez OM, et al. KDOQI US Commentary on the 2017 KDIGO clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKDMBD). American Journal of Kidney Diseases: The Official Journal

[2] Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease—A systematic review and metaanalysis. PLoS One.

[3] Smyth LJ, Duffy S, Maxwell AP, McKnight AJ. Genetic and epigenetic factors influencing chronic kidney disease. American Journal of Physiology. Renal Physiology.

[4] Fu Q, Colgan SP, Shelley CS. Hypoxia: The force that drives chronic kidney disease.

[5] Vassallo D, Kalra PA. Progress in the treatment of atherosclerotic renovascular disease: The conceptual journey and the unanswered questions. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant AssociationEuropean Renal

[6] Griffin KA. Hypertensive kidney injury and the progression of chronic kidney disease.

[7] Spoto B, Pisano A, Zoccali C. Insulin resistance in chronic kidney disease: A systematic review. American Journal of Physiology. Renal Physiology. 2016;**311**(6):F1087FF108.

[8] Di Lullo L, House A, Gorini A, Santoboni A, Russo D, Ronco C. Chronic kidney disease and cardiovascular complications. Heart Failure Reviews. 2015;**20**(3):259272. Epub 2014/10/26

[9] Honore PM, Jacobs R, De Waele E, Van Gorp V, De Regt J, JoannesBoyau O, et al. A fresh look into the pathophysiology of ischemia-induced complications in patients with chronic kidney disease undergoing hemodialysis. International Journal of Nephrology

[10] Hill Gallant KM, Spiegel DM. Calcium balance in chronic kidney disease. Current

[11] Toussaint ND, Holt SG. Is serum phosphate a useful target in patients with chronic kidney disease and what is the role for dietary phosphate restriction? Nephrology.

[12] Pimentel A, UrenaTorres P, Zillikens MC, Bover J, CohenSolal M. Fractures in patients with CKDdiagnosis, treatment, and prevention: A review by members of the European Calcified Tissue Society and the European Renal Association of Nephrology Dialysis

of the National Kidney Foundation. 2017;**70**(6):737751. [Epub 2017/09/25]

Clinical Medicine & Research. 2016;**14**(1):1539. Epub 2016/02/06

Association. 2016;**31**(10):15951605. Epub 2015/07/19

Hypertension. 2017;**70**(4):687694. Epub 2017/08/02

and Renovascular Disease. 2015;**8**:2528. Epub 2015/03/21

Osteoporosis Reports. 2017;**15**(3):214221. Epub 2017/05/06

and Transplantation. Kidney International. 2017. Epub 2017/10/02

2017;**22**(Suppl 2):3641. Epub 2017/04/22

Epub 2016/10/22

2016;**11**(7):e0158765. Epub 2016/07/08

144 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2014;**307**(7):F757F776. Epub 2014/08/01


[27] Scholze A, Jankowski J, PedrazaChaverri J, Evenepoel P.Oxidative stress in chronic kidney disease. Oxidative Medicine and Cellular Longevity. 2016;**2016**:8375186. Epub 2016/09/01

[41] GlubaBrzozka A, MichalskaKasiczak M, Franczyk B, Nocun M, Toth P, Banach M, et al. Markers of increased atherosclerotic risk in patients with chronic kidney disease: A

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

147

[42] Aikawa E, Aikawa M, Libby P, Figueiredo JL, Rusanescu G, Iwamoto Y, et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic

[43] Ford ML, Smith ER, Tomlinson LA, Chatterjee PK, Rajkumar C, Holt SG. FGF23 and osteoprotegerin are independently associated with myocardial damage in chronic kidney disease stages 3 and 4. Another link between chronic kidney diseasemineral bone disorder and the heart. Nephrology, Dialysis, Transplantation. 2012;**27**(2):727733. Epub 2011/07/14

[44] Liabeuf S, Okazaki H, Desjardins L, Fliser D, Goldsmith D, Covic A, et al. Vascular calcification in chronic kidney disease: Are biomarkers useful for probing the pathobiology and the health risks of this process in the clinical scenario? Nephrology, Dialysis,

[45] Rogers M, Goettsch C, Aikawa E. Medial and intimal calcification in chronic kidney disease: Stressing the contributions. Journal of the American Heart Association.

[46] Rutsch F, Nitschke Y, Terkeltaub R. Genetics in arterial calcification: Pieces of a puzzle and cogs in a wheel. Circulation Research. 2011;**109**(5):578592. Epub 2011/08/20 [47] Hofmann Bowman MA, McNally EM. Genetic pathways of vascular calcification. Trends

[48] Evrard S, Delanaye P, Kamel S, Cristol JP, Cavalier E, SSJWGOV calcifications . Vascular calcification: From pathophysiology to biomarkers. Clinica Chimica Acta. 2015;**438**:401

[49] Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, et al. Cardiorenal syndromes: Report from the consensus conference of the acute dialysis quality

[50] Gomes P, Simao S, Silva E, Pinto V, Amaral JS, Afonso J, et al. Aging increases oxidative stress and renal expression of oxidant and antioxidant enzymes that are associated with an increased trend in systolic blood pressure. Oxidative Medicine and Cellular

[51] Vlassara H, Torreggiani M, Post JB, Zheng F, Uribarri J, Striker GE. Role of oxidants/ inflammation in declining renal function in chronic kidney disease and normal aging.

[52] Hanna MH, Dalla Gassa A, Mayer G, Zaza G, Brophy PD, Gesualdo L, et al. The nephrologist of tomorrow: Towards a kidneyomic future. Pediatric Nephrology. 2017;**32**(3):393-

[53] Popescu ID, Codrici E, Albulescu L, Mihai S, Enciu AM, Albulescu R, et al. Potential serum biomarkers for glioblastoma diagnostic assessed by proteomic approaches.

initiative. European Heart Journal. 2010;**31**(6):703711. Epub 2009/12/29

Kidney International. Supplement. 2009;**114**:S311. Epub 2009/12/01

preliminary study. Lipids in Health and Disease. 2016;**15**:22. Epub 2016/02/05

renal disease. Circulation. 2009;**119**(13):17851794. Epub 2009/03/25

Transplantation. 2014;**29**(7):12751284. Epub 2013/09/07

in Cardiovascular Medicine. 2012;**22**(4):9398. Epub 2012/10/09

Longevity. 2009;**2**(3):138145. Epub 2010/07/02

Proteome Science. 2014;**12**(1):47. Epub 2014/10/10

2013;**2**(5):e000481. Epub 2013/09/26

414. Epub 2014/09/23

404. Epub 2016/03/11


[41] GlubaBrzozka A, MichalskaKasiczak M, Franczyk B, Nocun M, Toth P, Banach M, et al. Markers of increased atherosclerotic risk in patients with chronic kidney disease: A preliminary study. Lipids in Health and Disease. 2016;**15**:22. Epub 2016/02/05

[27] Scholze A, Jankowski J, PedrazaChaverri J, Evenepoel P.Oxidative stress in chronic kidney disease. Oxidative Medicine and Cellular Longevity. 2016;**2016**:8375186. Epub 2016/09/01

[28] Short JD, Downs K, Tavakoli S, Asmis R. Protein thiol redox signaling in monocytes and macrophages. Antioxidants & Redox Signaling. 2016;**25**(15):816835. Epub 2016/06/12 [29] Mihai S, Codrici E, Popescu ID, Enciu AM, Rusu E, Zilisteanu D, et al. Proteomic biomarkers panel: New insights in chronic kidney disease. Disease Markers. 2016;**2016**:3185232.

[30] Gupta J, Mitra N, Kanetsky PA, Devaney J, Wing MR, Reilly M, et al. Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC. Clinical Journal of the American Society of Nephrology: CJASN. 2012;**7**(12):1938

[31] Sundin PO, Udumyan R, Sjostrom P, Montgomery S. Predictors in adolescence of ESRD in middleaged men. American Journal of Kidney Diseases: The Official Journal of the

[32] Fallahzadeh MK, Roozbeh J, Geramizadeh B, Namazi MR. Interleukin2 serum levels are elevated in patients with uremic pruritus: A novel finding with practical implications.

[33] Sanz AB, Izquierdo MC, SanchezNino MD, Ucero AC, Egido J, RuizOrtega M, et al. TWEAK and the progression of renal disease: Clinical translation. Nephrology, Dialysis,

[34] Ucero AC, Berzal S, OcanaSalceda C, Sancho M, Orzaez M, Messeguer A, et al. A polymeric nanomedicine diminishes inflammatory events in renal tubular cells. PLoS One.

[35] Cohen SD, Phillips TM, Khetpal P, Kimmel PL. Cytokine patterns and survival in haemodialysis patients. Nephrology, Dialysis, Transplantation. 2010;**25**(4):12391243. Epub 2009/12/17

[36] PistolTanase C, Raducan E, Dima SO, Albulescu L, Alina I, Marius P, et al. Assessment of soluble angiogenic markers in pancreatic cancer. Biomarkers in Medicine. 2008;**2**(5):447

[37] Shankar A, Syamala S, Xiao J, Muntner P. Relationship between plasma leptin level and chronic kidney disease. International Journal of Nephrology. 2012;**2012**:269532. Epub

[38] Gistera A, Hansson GK. The immunology of atherosclerosis. Nature Reviews. Nephrology.

[39] Dungey M, Hull KL, Smith AC, Burton JO, Bishop NC. Inflammatory factors and exercise in chronic kidney disease. International Journal of Endocrinology. 2013;**2013**:569831.

[40] Feroze U, Molnar MZ, Dukkipati R, Kovesdy CP, KalantarZadeh K. Insights into nutritional and inflammatory aspects of low parathyroid hormone in dialysis patients.

Journal of Renal Nutrition. 2011;**21**(1):100104. Epub 2011/01/05

Nephrology, Dialysis, Transplantation. 2011;**26**(10):33383344. Epub 2011/03/05

National Kidney Foundation. 2014;**64**(5):723729. Epub 2014/08/16

Transplantation. 2014;**29**(Suppl 1):i54i62. Epub 2014/02/05

Epub 2016/09/27

1946. Epub 2012/10/02

146 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2013;**8**(1):e51992. Epub 2013/01/10

2017;**13**(6):368380. Epub 2017/04/11

455. Epub 2008/10/01

2012/06/06

Epub 2013/06/06


[54] Mischak H, Delles C, Vlahou A, Vanholder R. Proteomic biomarkers in kidney disease: Issues in development and implementation. Nature Reviews. Nephrology. 2015; **11**(4):221232. Epub 2015/02/04

[68] Al Khodor S, Shatat IF. Gut microbiome and kidney disease: A bidirectional relation-

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

149

[69] Vitetta L, Gobe G. Uremia and chronic kidney disease: The role of the gut microflora and therapies with pro and prebiotics. Molecular Nutrition & Food Research. 2013;**57**(5):824

[70] Huang W, Zhou L, Guo H, Xu Y, Xu Y. The role of shortchain fatty acids in kidney injury induced by gutderived inflammatory response. Metabolism, Clinical and Experimental.

[71] Lau WL, Liu SM, Pahlevan S, Yuan J, Khazaeli M, Ni Z, et al. Role of Nrf2 dysfunction in uremiaassociated intestinal inflammation and epithelial barrier disruption. Digestive

[72] Briskey D, Tucker P, Johnson DW, Coombes JS. The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development. Clinical and

[73] Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;**473**(7346):174180. Epub 2011/04/22 [74] Wu GD, Chen J, Hoffmann C, Bittinger K, Chen YY, Keilbaugh SA, et al. Linking longterm dietary patterns with gut microbial enterotypes. Science. 2011;**334**(6052):105108.

[75] Scott KP, Gratz SW, Sheridan PO, Flint HJ, Duncan SH. The influence of diet on the gut

[76] Evenepoel P, Meijers BK, Bammens BR, Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney International. Supplement. 2009;**114**:S12S19. Epub 2009/12/01

[77] Koppe L, Mafra D, Fouque D.Probiotics and chronic kidney disease. Kidney International.

[78] Montemurno E, Cosola C, Dalfino G, Daidone G, De Angelis M, Gobbetti M, et al. What would you like to eat, Mr CKD microbiota? A Mediterranean diet, please! Kidney &

[79] Hasegawa S, Jao TM, Inagi R. Dietary metabolites and chronic kidney disease. Nutrients.

[80] Palmer SC, Maggo JK, Campbell KL, Craig JC, Johnson DW, Sutanto B, et al. Dietary interventions for adults with chronic kidney disease. The Cochrane Database of Systematic

[81] Rysz J, Franczyk B, CialkowskaRysz A, GlubaBrzozka A. The effect of diet on the survival of patients with chronic kidney disease. Nutrients. 2017;**9**(5). pii: E495, Epub

[82] Mutsaers HA, Engelke UF, Wilmer MJ, Wetzels JF, Wevers RA, van den Heuvel LP, et al. Optimized metabolomic approach to identify uremic solutes in plasma of stage 3-4

chronic kidney disease patients. PLoS One. 2013;**8**(8):e71199. Epub 2013/08/13

microbiota. Pharmacological Research. 2013;**69**(1):5260. Epub 2012/11/14

Blood Pressure Research. 2014;**39**(23):114123. Epub 2014/08/15

ship. Pediatric Nephrology. 2017;**32**(6):921931. Epub 2016/05/01

Diseases and Sciences. 2015;**60**(5):12151222. Epub 2014/11/17

Experimental Nephrology. 2017;**21**(1):715. Epub 2016/03/12

832. Epub 2013/03/02

Epub 2011/09/03

2017/05/16

2015;**88**(5):958966. Epub 2015/09/17

2017;**9**(4). pii: E358, Epub 2017/04/05

Reviews. 2017;**4**:CD011998. Epub 2017/04/24

2017;**68**:2030. Epub 2017/02/12


[68] Al Khodor S, Shatat IF. Gut microbiome and kidney disease: A bidirectional relationship. Pediatric Nephrology. 2017;**32**(6):921931. Epub 2016/05/01

[54] Mischak H, Delles C, Vlahou A, Vanholder R. Proteomic biomarkers in kidney disease: Issues in development and implementation. Nature Reviews. Nephrology. 2015;

[55] Albalat A, Franke J, Gonzalez J, Mischak H, Zurbig P. Urinary proteomics based on capillary electrophoresis coupled to mass spectrometry in kidney disease. Methods in

[56] Smith A, L'Imperio V, Ajello E, Ferrario F, Mosele N, Stella M, et al. The putative role of MALDIMSI in the study of membranous nephropathy. Biochimica et Biophysica Acta.

[57] Smith A, L'Imperio V, De Sio G, Ferrario F, Scalia C, Dell'Antonio G, et al. α1Antitrypsin detected by MALDI imaging in the study of glomerulonephritis: Its relevance in chronic

[58] Klein J, Jupp S, Moulos P, Fernandez M, BuffinMeyer B, Casemayou A, et al. The KUPKB: A novel web application to access multiomics data on kidney disease. FASEB

[59] Fernandes M, Husi H. Establishment of a integrative multi-omics expression database CKDdb in the context of chronic kidney disease (CKD). Scientific Reports. 2017;**7**:40367.

[60] Joshi MS, Montgomery KA, Giannone PJ, Bauer JA, Hanna MH. Renal injury in neonates: Use of "omics" for developing precision medicine in neonatology. Pediatric Research.

[61] Lau WL, KalantarZadeh K, Vaziri ND. The gut as a source of inflammation in chronic

[62] Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. Journal of the American Society of Nephrology: JASN. 2014;**25**(4):657670. Epub

[63] Cigarran Guldris S, Gonzalez Parra E, Cases Amenos A. Microbiota intestinal en la enfermedad renal cronica (Gut microbiota in chronic kidney disease. Nefrologia).

[64] Wang F, Jiang H, Shi K, Ren Y, Zhang P, Cheng S. Gut bacterial translocation is associated with microinflammation in endstage renal disease patients. Nephrology. 2012;

[65] Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, De Santis TZ, et al. Chronic kidney disease alters intestinal microbial flora. Kidney International. 2013;**83**(2):308315. Epub 2012/09/21

[66] Evenepoel P, Poesen R, Meijers B. The gutkidney axis. Pediatric Nephrology. 2016;

[67] Wu IW, Hsu KH, Lee CC, Sun CY, Hsu HJ, Tsai CJ, et al. pCresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrology, Dialysis,

kidney disease progression. Proteomics. 2016;**16**(1112):17591766

kidney disease. Nephron. 2015;**130**(2):9298. Epub 2015/05/15

**11**(4):221232. Epub 2015/02/04

148 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

2017;**1865**(7):865874. Epub 2016/11/29

Journal. 2012;**26**(5):21452153. Epub 2012/02/22

2017;**81**(12):271276. Epub 2016/10/11

2017;**37**(1):919. Epub 2016/08/25

**17**(8):733738. Epub 2012/07/24

**32**(11):20052014. Epub 2016/11/17

Transplantation. 2011;**26**(3):938947. Epub 2010/10/05

Epub 2017/01/13

2013/11/16

Molecular Biology. 2013;**919**:203213. Epub 2012/09/15


[83] Chen L, Liu W, Li Y, Luo S, Liu Q, Zhong Y, et al. Lactobacillus acidophilus ATCC 4356 attenuates the atherosclerotic progression through modulation of oxidative stress and inflammatory process. International Immunopharmacology. 2013;**17**(1):108115. Epub 2013/06/12

[95] Asghari G, Yuzbashian E, Mirmiran P, Azizi F. The association between dietary approaches to stop hypertension and incidence of chronic kidney disease in adults: The Tehran lipid and glucose study. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal

Inflammation and Chronic Kidney Disease: Current Approaches and Recent Advances

http://dx.doi.org/10.5772/intechopen.72716

151

[96] Lin J, Fung TT, Hu FB, Curhan GC. Association of dietary patterns with albuminuria and kidney function decline in older white women: A subgroup analysis from the Nurses' Health Study. American Journal of Kidney Diseases: The Official Journal of the

[97] Shi Z, Taylor AW, Riley M, Byles J, Liu J, Noakes M. Association between dietary patterns, cadmium intake and chronic kidney disease among adults. Clinical Nutrition.

[98] Gutierrez OM, Muntner P, Rizk DV, McClellan WM, Warnock DG, Newby PK, et al. Dietary patterns and risk of death and progression to ESRD in individuals with CKD: A cohort study. American Journal of Kidney Diseases: The Official Journal of the National

[99] Foster MC, Hwang SJ, Massaro JM, Jacques PF, Fox CS, Chu AY. Lifestyle factors and indices of kidney function in the Framingham Heart Study. American Journal of

[100] Banerjee T, Crews DC, Wesson DE, Tilea AM, Saran R, RiosBurrows N, et al. High dietary acid load predicts ESRD among adults with CKD. Journal of the American

[101] Kanda E, Ai M, Kuriyama R, Yoshida M, Shiigai T. Dietary acid intake and kidney disease progression in the elderly. American Journal of Nephrology. 2014;**39**(2):145152.

[102] Scialla JJ, Appel LJ, Astor BC, Miller ER, 3rd, Beddhu S, Woodward M, et al. Net endogenous acid production is associated with a faster decline in GFR in African Americans.

[103] Tyson CC, Lin PH, Corsino L, Batch BC, Allen J, Sapp S, et al. Shortterm effects of the DASH diet in adults with moderate chronic kidney disease: A pilot feeding study.

Society of Nephrology: JASN. 2015;**26**(7):16931700. Epub 2015/02/14

Association. 2017;**32**(Suppl\_2):ii224ii30. Epub 2017/02/16

Kidney Foundation. 2014;**64**(2):204213. Epub 2014/04/01

Kidney International. 2012;**82**(1):106112. Epub 2012/04/06

Clinical Kidney Journal. 2016;**9**(4):592598. Epub 2016/08/02

Nephrology. 2015;**41**(45):267274. Epub 2015/05/23

2017. Epub 2017/01/18

Epub 2014/02/12

National Kidney Foundation. 2011;**57**(2):245254. Epub 2011/01/22


[95] Asghari G, Yuzbashian E, Mirmiran P, Azizi F. The association between dietary approaches to stop hypertension and incidence of chronic kidney disease in adults: The Tehran lipid and glucose study. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association. 2017;**32**(Suppl\_2):ii224ii30. Epub 2017/02/16

[83] Chen L, Liu W, Li Y, Luo S, Liu Q, Zhong Y, et al. Lactobacillus acidophilus ATCC 4356 attenuates the atherosclerotic progression through modulation of oxidative stress and inflammatory process. International Immunopharmacology. 2013;**17**(1):108115. Epub 2013/06/12 [84] Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D. Gut microbiome in chronic kidney disease: Challenges and opportunities. Translational Research. 2017;**179**:2437. Epub

[85] Ranganathan N, Ranganathan P, Friedman EA, Joseph A, Delano B, Goldfarb DS, et al. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Advances in Therapy. 2010;**27**(9):634647. Epub

[86] Devuyst O, Beaujean V, Crabbe J. Effects of environmental conditions on mitochondrialrich cell density and chloride transport in toad skin. Pflügers Archiv/European Journal

[87] De Preter V, Vanhoutte T, Huys G, Swings J, De Vuyst L, Rutgeerts P, et al. Effects of Lactobacillus casei Shirota, Bifidobacterium breve, and oligofructoseenriched inulin on colonic nitrogenprotein metabolism in healthy humans. American Journal of Physiology.

Gastrointestinal and Liver Physiology. 2007;**292**(1):G358G368. Epub 2006/09/23

bial ecosystem. Microbial Biotechnology. 2009;**2**(1):101113. Epub 2009/01/01

[88] Sanchez JI, Marzorati M, Grootaert C, Baran M, Van Craeyveld V, Courtin CM, et al. Arabinoxylanoligosaccharides (AXOS) affect the protein/carbohydrate fermentation balance and microbial population dynamics of the simulator of human intestinal micro-

[89] Rossi M, Johnson DW, Morrison M, Pascoe EM, Coombes JS, Forbes JM, et al. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): A randomized trial. Clinical Journal of the American Society of Nephrology: CJASN. 2016;**11**(2):223231.

[90] Rossi M, Johnson DW, Morrison M, Pascoe E, Coombes JS, Forbes JM, et al. SYNbiotics easing renal failure by improving gut microbiologY (SYNERGY): A protocol of placebocontrolled randomised crossover trial. BMC Nephrology. 2014;**15**:106. Epub 2014/07/06

[91] Romagnolo DF, Selmin OI. Mediterranean diet and prevention of chronic diseases.

[92] Huang X, JimenezMoleon JJ, Lindholm B, Cederholm T, Arnlov J, Riserus U, et al. Mediterranean diet, kidney function, and mortality in men with CKD. Clinical Journal of the American Society of Nephrology: CJASN. 2013;**8**(9):15481555. Epub 2013/06/08

[93] Cupisti A, D'Alessandro C, Gesualdo L, Cosola C, Gallieni M, Egidi MF, et al. Nontraditional aspects of renal diets: Focus on fiber, alkali and vitamin K1 intake. Nutrients.

[94] Chauveau P, Combe C, Fouque D, Aparicio M. Vegetarianism: Advantages and drawbacks in patients with chronic kidney diseases. Journal of Renal Nutrition: The Official Journal of the Council on Renal Nutrition of the National Kidney Foundation.

of Physiology. 1991;**417**(6):577581. Epub 1991/02/01

150 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Nutrition Today. 2017;**52**(5):208222. Epub 2017/10/21

2016/05/18

2010/08/20

Epub 2016/01/17

2017;**9**(5). Epub 2017/05/05

2013;**23**(6):399405. Epub 2013/09/28


**Chapter 7**

**Provisional chapter**

**Inflammation in Nonimmune-Mediated Chronic Kidney**

Regardless of its etiology, chronic kidney disease (CKD) is characterized by proteinuria, serum creatinine retention, glomerulosclerosis (GS), and tubulointerstitial damage. Notably, the last one has been correlated more closely with the evolution to kidney failure than the extent of glomerular injury. Tubulointerstitial inflammation comprises the activation of tubular epithelial cells, which release inflammatory mediators and chemokines promoting the influx of leukocytes in the renal parenchyma and the activation/proliferation of resident fibroblasts, leading to excessive production of extracellular matrix (EM), fibrosis, and renal function loss. Therefore, inflammation exerts a key role in the pathogenesis of CKD, although the mechanisms by which this process is activated and perpetuated, even when the initial insult is not immune-mediated, such as in the hypertensive nephrosclerosis, in the diabetic nephropathy, and in the crystal-induced renal disease, remain unclear. This chapter provides an overview on inflammation and CKD development not related to autoimmunity or caused by presence of foreign antigens. Cellular and molecular mechanisms involved in different pathways and its potential therapeutic targets to detain the progression of inflammation and fibrosis in CKD are

**Inflammation in Nonimmune-Mediated Chronic Kidney** 

DOI: 10.5772/intechopen.70611

© 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.

Chronic kidney disease (CKD) is considered a global health problem that motivates life science researchers and physicians to investigate the mechanisms beyond its development, and to seek for new therapeutic strategies to detain the evolution of renal function loss [1].

**Keywords:** chronic kidney disease, inflammation, immune system, innate immunity,

Camilla Fanelli, Ayman Noreddin and Ane Nunes

also presented ahead as a contribution in this book.

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Camilla Fanelli, Ayman Noreddin and

http://dx.doi.org/10.5772/intechopen.70611

**Disease**

Ane Nunes

**Abstract**

adaptive immunity

**1. Introduction**

**Disease**

**Provisional chapter**

## **Inflammation in Nonimmune-Mediated Chronic Kidney Disease Disease**

**Inflammation in Nonimmune-Mediated Chronic Kidney** 

DOI: 10.5772/intechopen.70611

Camilla Fanelli, Ayman Noreddin and Ane Nunes Ane Nunes

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.70611

Camilla Fanelli, Ayman Noreddin and

#### **Abstract**

Regardless of its etiology, chronic kidney disease (CKD) is characterized by proteinuria, serum creatinine retention, glomerulosclerosis (GS), and tubulointerstitial damage. Notably, the last one has been correlated more closely with the evolution to kidney failure than the extent of glomerular injury. Tubulointerstitial inflammation comprises the activation of tubular epithelial cells, which release inflammatory mediators and chemokines promoting the influx of leukocytes in the renal parenchyma and the activation/proliferation of resident fibroblasts, leading to excessive production of extracellular matrix (EM), fibrosis, and renal function loss. Therefore, inflammation exerts a key role in the pathogenesis of CKD, although the mechanisms by which this process is activated and perpetuated, even when the initial insult is not immune-mediated, such as in the hypertensive nephrosclerosis, in the diabetic nephropathy, and in the crystal-induced renal disease, remain unclear. This chapter provides an overview on inflammation and CKD development not related to autoimmunity or caused by presence of foreign antigens. Cellular and molecular mechanisms involved in different pathways and its potential therapeutic targets to detain the progression of inflammation and fibrosis in CKD are also presented ahead as a contribution in this book.

**Keywords:** chronic kidney disease, inflammation, immune system, innate immunity, adaptive immunity

## **1. Introduction**

Chronic kidney disease (CKD) is considered a global health problem that motivates life science researchers and physicians to investigate the mechanisms beyond its development, and to seek for new therapeutic strategies to detain the evolution of renal function loss [1].

© 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.

Progressive CKD may be initiated by several conditions of different etiological basis; however, in almost all cases, renal disease progresses with the development of a chronic and self-sustained inflammatory reaction, which involves both innate and adaptive arms of immune response and leads to kidney fibrosis. Reasons why inflammation parallels CKD progression even when the initial renal injury does not involve autoimmune disorders or infection episodes remain unclear [2]. In the following sections, we are going to discuss some epidemiological data on CKD in the United States (US) and in the World, as well as briefly review the pathophysiological mechanisms involved in CKD development and progression, with special attention to the participation of inflammatory components in this process.

blood flow blocking agents. Bladder and/or ureteral obstruction, in turn, can occur due to anatomic alterations, prostate hypertrophy, and cancer, or by the presence of kidney/ureteral stones. AKI can be additionally caused by some specific health conditions such as the multiple myeloma or the tubular necrosis, which can result from the administration of nephrotoxic drugs and compounds. In general, these conditions reduce the GFR, promoting a sharp decrease of renal function, that can be transitory; if the renal blood hypoperfusion or the obstruction of the urinary tract is rapidly corrected, or permanent, if the regular renal blood flow and the urinary output are not restored. There are actually growing evidence that, even when an AKI episode is properly solved, and there is a complete reestablishment of renal function, the patients should be closely followed for a long period, since this population is

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

155

Although acute renal lesions may lead to the development of progressive kidney insufficiency, the two main causes of CKD are still diabetes and hypertension [3–6]. Such insidious diseases are, together, responsible for up to two-thirds of the cases of CKD in the American population [3–5]. If poorly or inefficiently controlled, both diabetes and hypertension may cause significant damage to human body, especially when it is exposed to these conditions for a long period. Many organs and systems can be affected, such as the blood vessels, the central nervous system (CNS), the eyes and, finally, the kidneys [2, 10]. The exact pathophysiological mechanisms through which sustained high serum glucose concentration and blood pressure lead to renal injury have not yet been fully elucidated. Proposed theories and mechanisms based on experimental studies, clinical trials, and medical observation will be

The third more common cause of CKD in the US is a group of autoimmune disorders, generally designated by Glomerulonephritis (GN) [3–5]. There are a number of different kinds of GN, which differ one from the other by the type of local renal infiltrating cells, by the presence and subtyping of autoantibodies, by the accumulation of complement system components, by the specific antigens that starts the renal local immune response, and also by some differential clinical and laboratorial features, including proteinuria, hematuria, and edema [12]. Although GN is an important cause of CKD, the molecular and cellular mechanisms involved in their onset and progression are beyond the scope of this revision, since GN is considered

In a less extent, inherited diseases like different forms of polycystic kidney disease (PKD) and genetic syndromes, such as Von Hippel-Lindau, Alport's, and Bartter's can also lead to CKD, as well as congenital malformations of the urinary system and repeated urinary tract infec-

Regardless of the nature of the initial renal insult, CKD is characterized by proteinuria, serum urea and creatinine retention, blood pressure rising, and imbalance in renal perfusion, which lead to the development of glomerular hypertension and hypertrophy,

more prone to manifest CKD in the future [10, 11].

discussed further on.

tions (UTI) [3–6, 13].

an immune-mediated kidney condition.

**3. Overview of CKD pathophysiology**

## **2. Chronic kidney disease and inflammation: definition and numbers**

CKD is a general term used to define a group of heterogeneous disorders that structurally compromise the kidneys, resulting in reduction or insufficiency of renal function. CKD is one of the major degenerative conditions that lead to progressive disability, and is the ninth cause of death in the US [3]. Every year, kidney disease kills more people than breast or prostate cancer. According to the National Kidney Foundation, CKD assumed epidemic proportions in the last decades and meets all the required criteria to be considered as a major public health concern [3–8]. The 2016 Annual Data Report of the US Renal Data System (USRDS) showed that around 26 millions of American adults have some degree of kidney disease, of which, more than 661,000 have end-stage renal disease (ESRD), defined by the requirement of renal replacement therapy (RRT) for life-saving [4, 5]. Accordingly, there were 468,000 Americans on dialysis and approximately 193,000 individuals living with a transplanted kidney, in the last year [5].

This reality is also true for the other countries around the world. The Bulletin of the World Health Organization estimated the global number of patients receiving RRT to be higher than 1.4 million, with incidence of growing by around 8% annually [6]. This high prevalence and mortality, allied to the elevated costs of treating this growing epidemic represents a big burden on healthcare systems worldwide, especially in low and middle income countries, where long term dialysis is financially unaffordable [7–9]. This dramatic scenario motivates the medical community to intensify the efforts in preventing kidney injury and to improve the early detection of this condition. Moreover, scientific investigation to elucidate the pathophysiological mechanisms involved in the evolution of chronic nephropathies is of paramount importance to the development of more effective therapeutic strategies to slow or even stop the progression of CKD.

Gradual renal function deterioration is generally caused by an initial kidney injury, which acutely or chronically affects both the glomerular filtration rate (GFR) and/or the tubular reabsorption/excretion [2, 10]. The decrease of renal blood flow and the blockage of the urinary tract are the main causes of acute kidney injury (AKI). Kidneys' hypoperfusion can be caused by hypovolemia, septic shock, bleeding, hypotension, or due to renal ischemia, caused by abnormal vasoconstriction, or by the presence of blood clots, arteriosclerosis or other renal blood flow blocking agents. Bladder and/or ureteral obstruction, in turn, can occur due to anatomic alterations, prostate hypertrophy, and cancer, or by the presence of kidney/ureteral stones. AKI can be additionally caused by some specific health conditions such as the multiple myeloma or the tubular necrosis, which can result from the administration of nephrotoxic drugs and compounds. In general, these conditions reduce the GFR, promoting a sharp decrease of renal function, that can be transitory; if the renal blood hypoperfusion or the obstruction of the urinary tract is rapidly corrected, or permanent, if the regular renal blood flow and the urinary output are not restored. There are actually growing evidence that, even when an AKI episode is properly solved, and there is a complete reestablishment of renal function, the patients should be closely followed for a long period, since this population is more prone to manifest CKD in the future [10, 11].

Although acute renal lesions may lead to the development of progressive kidney insufficiency, the two main causes of CKD are still diabetes and hypertension [3–6]. Such insidious diseases are, together, responsible for up to two-thirds of the cases of CKD in the American population [3–5]. If poorly or inefficiently controlled, both diabetes and hypertension may cause significant damage to human body, especially when it is exposed to these conditions for a long period. Many organs and systems can be affected, such as the blood vessels, the central nervous system (CNS), the eyes and, finally, the kidneys [2, 10]. The exact pathophysiological mechanisms through which sustained high serum glucose concentration and blood pressure lead to renal injury have not yet been fully elucidated. Proposed theories and mechanisms based on experimental studies, clinical trials, and medical observation will be discussed further on.

The third more common cause of CKD in the US is a group of autoimmune disorders, generally designated by Glomerulonephritis (GN) [3–5]. There are a number of different kinds of GN, which differ one from the other by the type of local renal infiltrating cells, by the presence and subtyping of autoantibodies, by the accumulation of complement system components, by the specific antigens that starts the renal local immune response, and also by some differential clinical and laboratorial features, including proteinuria, hematuria, and edema [12]. Although GN is an important cause of CKD, the molecular and cellular mechanisms involved in their onset and progression are beyond the scope of this revision, since GN is considered an immune-mediated kidney condition.

In a less extent, inherited diseases like different forms of polycystic kidney disease (PKD) and genetic syndromes, such as Von Hippel-Lindau, Alport's, and Bartter's can also lead to CKD, as well as congenital malformations of the urinary system and repeated urinary tract infections (UTI) [3–6, 13].

## **3. Overview of CKD pathophysiology**

Progressive CKD may be initiated by several conditions of different etiological basis; however, in almost all cases, renal disease progresses with the development of a chronic and self-sustained inflammatory reaction, which involves both innate and adaptive arms of immune response and leads to kidney fibrosis. Reasons why inflammation parallels CKD progression even when the initial renal injury does not involve autoimmune disorders or infection episodes remain unclear [2]. In the following sections, we are going to discuss some epidemiological data on CKD in the United States (US) and in the World, as well as briefly review the pathophysiological mechanisms involved in CKD development and progression, with special attention to the participation of inflammatory components in this

154 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**2. Chronic kidney disease and inflammation: definition and numbers**

CKD is a general term used to define a group of heterogeneous disorders that structurally compromise the kidneys, resulting in reduction or insufficiency of renal function. CKD is one of the major degenerative conditions that lead to progressive disability, and is the ninth cause of death in the US [3]. Every year, kidney disease kills more people than breast or prostate cancer. According to the National Kidney Foundation, CKD assumed epidemic proportions in the last decades and meets all the required criteria to be considered as a major public health concern [3–8]. The 2016 Annual Data Report of the US Renal Data System (USRDS) showed that around 26 millions of American adults have some degree of kidney disease, of which, more than 661,000 have end-stage renal disease (ESRD), defined by the requirement of renal replacement therapy (RRT) for life-saving [4, 5]. Accordingly, there were 468,000 Americans on dialysis and approximately 193,000 individuals living with a transplanted kidney, in the

This reality is also true for the other countries around the world. The Bulletin of the World Health Organization estimated the global number of patients receiving RRT to be higher than 1.4 million, with incidence of growing by around 8% annually [6]. This high prevalence and mortality, allied to the elevated costs of treating this growing epidemic represents a big burden on healthcare systems worldwide, especially in low and middle income countries, where long term dialysis is financially unaffordable [7–9]. This dramatic scenario motivates the medical community to intensify the efforts in preventing kidney injury and to improve the early detection of this condition. Moreover, scientific investigation to elucidate the pathophysiological mechanisms involved in the evolution of chronic nephropathies is of paramount importance to the development of more effective therapeutic strategies to slow or even stop the progres-

Gradual renal function deterioration is generally caused by an initial kidney injury, which acutely or chronically affects both the glomerular filtration rate (GFR) and/or the tubular reabsorption/excretion [2, 10]. The decrease of renal blood flow and the blockage of the urinary tract are the main causes of acute kidney injury (AKI). Kidneys' hypoperfusion can be caused by hypovolemia, septic shock, bleeding, hypotension, or due to renal ischemia, caused by abnormal vasoconstriction, or by the presence of blood clots, arteriosclerosis or other renal

process.

last year [5].

sion of CKD.

Regardless of the nature of the initial renal insult, CKD is characterized by proteinuria, serum urea and creatinine retention, blood pressure rising, and imbalance in renal perfusion, which lead to the development of glomerular hypertension and hypertrophy, mesangial cells proliferation, and extracellular matrix (EM) overproduction, culminating in irreversible changes in glomerular and tubular architecture that impairs the function of the nephron [2, 9]. Notably, the involvement of the tubulointerstitial compartment has been correlated more closely with the evolution to kidney failure than the extent of glomerular injury per se [2, 9, 14]. The more filtering units are injured, the more overburdened the remaining nephrons become, which in turn end up succumbing due to overload in a vicious cycle of positive feedback. This process leads to global glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis, peritubular capillary rarefaction, and progressive renal function loss [2, 9, 14, 15], as illustrated in **Figure 1**.

mineralocorticoid steroid promotes renal and systemic vasoconstriction and tubular sodium conservation, leading to the elevation of blood pressure [9, 16]. In spite of its first description, RAAS became much more complex in the recent years, after the identification of many novel components, such as the enzyme chymase, which exerts the same function of ACE, the biologically active peptides angiotensin III, IV, 1–9 and 1–7, and a number of different Ang II receptors (AT2, AT4, among others) [16]. Moreover, depending on which intracellular downstream system is activated by Ang II, different physiological responses

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

157

Ang II has been related to inflammation followed to chronic nephropathy developed by the enhancing of the immune response and favoring renal infiltration by leukocyte [18, 19]. Additionally, there are growing *in vitro* and *in vivo* evidence that Ang II promotes cell proliferation and fibroblast activation, worsening the accumulation of EM and contributing to the development of renal fibrosis [18, 20, 21]. Furthermore, a variety of studies showed the presence of both Ang II and the receptor AT1 in the renal parenchyma of animals submitted to experimental models of CKD, leading to the discovery of a complex intrarenal pro-inflammatory RAAS that seems to become overactivated under kidney injury [18–22]. Accordingly, suppression of RAAS with both ACE inhibitors (ACEi) and/or AT1 receptor blockers (ARB) become a mainstay of treatment of progressive nephropathies and, although several innovative therapeutic measures have been recently proposed for the treatment of CKD, RAAS blockage, associated to diuretics or not, remains the best available resource in

In 1984, Schwartz and collaborators demonstrated for the first time an increase in fibroblast and the appearance of macrophages and lymphocytes in the renal parenchyma of rabbits submitted to a sterile model of renal ischemia/reperfusion [25]. This was one of the first studies suggesting that the inflammatory process, including mononuclear cell infiltration and fibroblast proliferation was a final pathway common to different forms of renal injury, independent of its etiology. We currently know that inflammation exerts a key role in the pathogenesis of CKD, although the mechanisms by which this process is activated and perpetuated,

There is growing evidence that the activation of both cellular and humoral immunity is related to the progression of renal insufficiency and a worse prognosis in nonimmunemediated CKD. Renal infiltration by macrophages has been demonstrated in a variety of human nonimmune-mediated renal diseases, such as diabetic nephropathy (DN) [26] and hypertensive nephrosclerosis (HN) [27]. Moreover, this phenomenon was also observed in different experimental models of CKD over the last years. Accordingly, the number of inflammatory cells in the renal *interstitium* closely correlates with the severity of nephropathy and with glomerular and tubulointerstitial lesions in these experimental models [28–30]. The increase of dendritic cells (DCs) in the renal parenchyma, in turns, is believed to indicate the spreading of inflammation from glomerular to the tubulointerstitial compartment, playing a pivotal role in the progression of both AKI and CKD [31, 32]. Finally, cortical

even when the initial insult is not immune-mediated, remain unclear.

can be triggered [16, 17].

this regard [9, 16, 23, 24].

The inordinate activation of the renin-angiotensin-aldosterone system (RAAS) is one of the major factors that can stimulate CKD progression [9]. Traditionally, RAAS used to be considered only as an endocrine system, whose major function was to maintain the blood pressure, even in situations of hypovolemia [16]. In the traditional description of RAAS, Renin, a hormone synthesized by the renal juxtaglomerular cells, promotes the conversion of angiotensinogen, produced in the liver, into angiotensin I (Ang I). This peptide is further cleaved by angiotensin-converting enzyme (ACE) into its active form, the Angiotensin II (Ang II), which, in turn, binds to its specific receptors (AT1) in the adrenal cortex, resulting in the release of aldosterone. Once released in the blood stream this

**Figure 1.** CKD pathophysiology. Different immune and nonimmune conditions may cause the initial renal insult that is been influenced by both modifiable and non-modifiable risk factors. This original damage causes several changes on renal function reducing the glomerular filtration rate, impairing the renal tubular hydroelectrolytic balance and damaging the glomerular filtration barrier. In a forward positive feedback, these events are able to lead to glomerulosclerosis, renal fibrosis and progressive loss of function.

mineralocorticoid steroid promotes renal and systemic vasoconstriction and tubular sodium conservation, leading to the elevation of blood pressure [9, 16]. In spite of its first description, RAAS became much more complex in the recent years, after the identification of many novel components, such as the enzyme chymase, which exerts the same function of ACE, the biologically active peptides angiotensin III, IV, 1–9 and 1–7, and a number of different Ang II receptors (AT2, AT4, among others) [16]. Moreover, depending on which intracellular downstream system is activated by Ang II, different physiological responses can be triggered [16, 17].

mesangial cells proliferation, and extracellular matrix (EM) overproduction, culminating in irreversible changes in glomerular and tubular architecture that impairs the function of the nephron [2, 9]. Notably, the involvement of the tubulointerstitial compartment has been correlated more closely with the evolution to kidney failure than the extent of glomerular injury per se [2, 9, 14]. The more filtering units are injured, the more overburdened the remaining nephrons become, which in turn end up succumbing due to overload in a vicious cycle of positive feedback. This process leads to global glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis, peritubular capillary rarefaction, and progressive renal

The inordinate activation of the renin-angiotensin-aldosterone system (RAAS) is one of the major factors that can stimulate CKD progression [9]. Traditionally, RAAS used to be considered only as an endocrine system, whose major function was to maintain the blood pressure, even in situations of hypovolemia [16]. In the traditional description of RAAS, Renin, a hormone synthesized by the renal juxtaglomerular cells, promotes the conversion of angiotensinogen, produced in the liver, into angiotensin I (Ang I). This peptide is further cleaved by angiotensin-converting enzyme (ACE) into its active form, the Angiotensin II (Ang II), which, in turn, binds to its specific receptors (AT1) in the adrenal cortex, resulting in the release of aldosterone. Once released in the blood stream this

**Figure 1.** CKD pathophysiology. Different immune and nonimmune conditions may cause the initial renal insult that is been influenced by both modifiable and non-modifiable risk factors. This original damage causes several changes on renal function reducing the glomerular filtration rate, impairing the renal tubular hydroelectrolytic balance and damaging the glomerular filtration barrier. In a forward positive feedback, these events are able to lead to glomerulosclerosis, renal

function loss [2, 9, 14, 15], as illustrated in **Figure 1**.

156 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

fibrosis and progressive loss of function.

Ang II has been related to inflammation followed to chronic nephropathy developed by the enhancing of the immune response and favoring renal infiltration by leukocyte [18, 19]. Additionally, there are growing *in vitro* and *in vivo* evidence that Ang II promotes cell proliferation and fibroblast activation, worsening the accumulation of EM and contributing to the development of renal fibrosis [18, 20, 21]. Furthermore, a variety of studies showed the presence of both Ang II and the receptor AT1 in the renal parenchyma of animals submitted to experimental models of CKD, leading to the discovery of a complex intrarenal pro-inflammatory RAAS that seems to become overactivated under kidney injury [18–22]. Accordingly, suppression of RAAS with both ACE inhibitors (ACEi) and/or AT1 receptor blockers (ARB) become a mainstay of treatment of progressive nephropathies and, although several innovative therapeutic measures have been recently proposed for the treatment of CKD, RAAS blockage, associated to diuretics or not, remains the best available resource in this regard [9, 16, 23, 24].

In 1984, Schwartz and collaborators demonstrated for the first time an increase in fibroblast and the appearance of macrophages and lymphocytes in the renal parenchyma of rabbits submitted to a sterile model of renal ischemia/reperfusion [25]. This was one of the first studies suggesting that the inflammatory process, including mononuclear cell infiltration and fibroblast proliferation was a final pathway common to different forms of renal injury, independent of its etiology. We currently know that inflammation exerts a key role in the pathogenesis of CKD, although the mechanisms by which this process is activated and perpetuated, even when the initial insult is not immune-mediated, remain unclear.

There is growing evidence that the activation of both cellular and humoral immunity is related to the progression of renal insufficiency and a worse prognosis in nonimmunemediated CKD. Renal infiltration by macrophages has been demonstrated in a variety of human nonimmune-mediated renal diseases, such as diabetic nephropathy (DN) [26] and hypertensive nephrosclerosis (HN) [27]. Moreover, this phenomenon was also observed in different experimental models of CKD over the last years. Accordingly, the number of inflammatory cells in the renal *interstitium* closely correlates with the severity of nephropathy and with glomerular and tubulointerstitial lesions in these experimental models [28–30]. The increase of dendritic cells (DCs) in the renal parenchyma, in turns, is believed to indicate the spreading of inflammation from glomerular to the tubulointerstitial compartment, playing a pivotal role in the progression of both AKI and CKD [31, 32]. Finally, cortical T-lymphocyte infiltration is a common finding in both genetic [33] and pharmacologically induced [34] DN in rodents. Moreover, it has also been described in the 5/6 renal ablation model (NX) [35] and in the chronic inhibition of nitric oxide synthase model (L-NAME) [29], among others [19]. In most of these studies, the amount of T-cells in the renal *interstitium* correlates positively with the progression of albuminuria, creatinine retention, and renal structural damage, as shown in **Table 1** [36–43]. Corroborating these findings, a number of experimental studies showing significant evidence that anti-inflammatory treatment, as well as the knockout (KO) of specific pro-inflammatory genes can be effective to detain the evolution of nephropathy in different animal models of CKD, have been recently published, as shown in **Table 2** [44–52].

**Authors (first, last) and year**

[44] Mouse Adenine/

[45] Rat Adenine-

[46] Mouse db/db

[47] Rat 5/6

[48] Rat Aldosterone/

[49] Rat Unilateral

[50] Rat 5/6

oxalateinduced nephritis

induced nephritis

geneticallyinduced DN

nephrectomy (NX) and ST-induced DN

salt-induced renal injury

ureteral obstruction (UUO)

nephrectomy (NX)

Ludwig-Portugall I, Kurts C. 2016

Okabe C, Fujihara CK. 2013

Kim JE, Cha DR. 2013

Gilbert RE, Kelly DJ. 2012

Ding W, Gu Y. 2012

Kaneyama T, Ehara T. 2010

Fujihara CK, Zatz R. 2007

**Ref. Species CKD studied Target cell/molecule Drug/compound Related improvements**

NLRP3 CP-456,773 CP-456,773 prevented

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

NFKB system PDTC PDTC prevented p65

NFKB system Celastrol Celastrol not

TGFβ FT011 FT011 attenuated

NFKB system PDTC PDTC significantly

TGFβ Tranilast Fibrosis and tubular

NFKB system PDTC PDTC attenuated

kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate

159

nuclear translocation, limited formation of renal interstitial foreign body granulomas, reduced the expression of Ifng, Il6, Fsp1, Mcp1 genes, and strongly attenuated interstitial fibrosis/inflammation

only improved insulin resistance, glycemic, control, and oxidative stress, but also improved renal functional and structural changes through both metabolic and anti-inflammatory effects in the kidney

hypertension, GS, and renal macrophage infiltration in Nx, as well as reduced albuminuria, GS, renal interstitial fibrosis, and inflammation in ST-DN

decreased the percentage of CTGF+ cells, the mRNA for TGF-β, CTGF, TGF-β, ICAM-1 and collagen IV, and protein levels of CTGF and ICAM-1

injuries were attenuated in UUO rats treated with tranilast compared with untreated UUO animals

renal injury and inflammation, as well as the density of cells staining positively for the phospho p65 subunit

or adenine.

http://dx.doi.org/10.5772/intechopen.70611

Although the exact sequence of the inflammatory events in progressive CKD has not been completely elucidated yet, we are currently aware that, the activation of tubular epithelial cells, inordinate production of cytokines, activation of resident phagocytes and fibroblasts, as well as the transdifferentiation of these last into pro-fibrotic myofibroblasts, parallels renal leukocyte infiltration, from the early beginning of renal disease. Furthermore, these processes follow the evolution of CKD, becoming autonomic and leading to excessive production of EM and fibrosis [9, 14, 32, 53].


**Table 1.** Evidences of innate and adaptive immunity activation in nonimmune-mediated CKD.


T-lymphocyte infiltration is a common finding in both genetic [33] and pharmacologically induced [34] DN in rodents. Moreover, it has also been described in the 5/6 renal ablation model (NX) [35] and in the chronic inhibition of nitric oxide synthase model (L-NAME) [29], among others [19]. In most of these studies, the amount of T-cells in the renal *interstitium* correlates positively with the progression of albuminuria, creatinine retention, and renal structural damage, as shown in **Table 1** [36–43]. Corroborating these findings, a number of experimental studies showing significant evidence that anti-inflammatory treatment, as well as the knockout (KO) of specific pro-inflammatory genes can be effective to detain the evolution of nephropathy in different animal models of CKD, have been recently published,

Although the exact sequence of the inflammatory events in progressive CKD has not been completely elucidated yet, we are currently aware that, the activation of tubular epithelial cells, inordinate production of cytokines, activation of resident phagocytes and fibroblasts, as well as the transdifferentiation of these last into pro-fibrotic myofibroblasts, parallels renal leukocyte infiltration, from the early beginning of renal disease. Furthermore, these processes follow the evolution of CKD, becoming autonomic and leading to excessive production of EM

**Authors (first, last) and year Ref. Species CKD studied Molecules/cells studied**

[40] Mouse Adenine-induced tubule interstitial nephritis

nephrogenesis

Utimura R, Zatz R. 2003 [28] Rat ST-induced DN T-lymphocytes

Donadelli R, Zoja C. 2000 [43] Rat 5/6 nephrectomy (NX) NFKB system

inhibition

[41] Mouse Unilateral ureteral obstruction (UUO) NLRP3

[42] Rat Spontaneously hypertensive rats (SHR) NFKB system, T-cells

[35] Rat 5/6 nephrectomy (NX) T-lymphocytes

(MPO)

TLR2, TLR4, MYD88, ASC, CASP1

T-lymphocytes

T-lymphocytes

D'Apolito M, Giardino I. 2015 [38] Mouse 5/6 nephrectomy (NX) Urea as a DAMP Lehners A, Wenzel UO. 2014 [39] Mouse 5/6 nephrectomy (NX) Myeloperoxidase

Gong W, Zhang A. 2016 [36] Mouse 5/6 nephrectomy (NX) NLRP3 Souza AC, Star RA. 2015 [37] Mouse 5/6 nephrectomy (NX) TLR4

Fanelli C, Zatz R. 2011 [19] Rat CKD caused by AT1 blockade during

Fujihara CK, Zatz R. 2001 [29] Rat L-NAME-induced nitric oxide synthase

**Table 1.** Evidences of innate and adaptive immunity activation in nonimmune-mediated CKD.

as shown in **Table 2** [44–52].

158 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

and fibrosis [9, 14, 32, 53].

Correa-Costa, Camara NOS.

Vilaysane A, Muruve DA.

Rodriguez-Iturbe, Vaziri ND.

Fujihara CK, Noronha IL.

2011

2010

2004

1998


other constitutive elements, producing a response of tolerance and preventing autoimmune reactions. This particular state of IS unresponsiveness is also essential to ensure the regular fetal development during pregnancy and to allow the colonization of human skin, digestive

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

161

The second and most well-known function of IS is the immunity itself. It is the ability to recognize foreign proteins and molecules, which may indicate the presence of invading microorganisms, such as bacteria or other parasites, and respond to these foreign elements with both cellular and humoral defenses, protecting the organism against infection [54]. Additionally, through its third property, immune surveillance, the IS patrols the body to recognize and destroy self-cells infected by virus or even constitutive cells that become cancerous or suffer phenotype alterations due to genetic mutations [54, 55]. For immune surveillance to work, cancer and/or mutated cells must express specific antigens that are not frequently found on normal cells, otherwise the IS would recognize them as "self" and be

Finally, the last property of IS is the ability of self-controlling the immune response. Through a complex mechanism of feedback and cell-to-cell communication, involving a number of cytokines and cell-cytokine receptors, IS modulates its response, which can be either tolerance or immunity, according to the specific stimulus to which the organism is subjected to [54]. This property is known as immunoregulation and is of paramount importance, not only for the kidneys but also for the whole organism. Failures on the immunoregulation may lead either to the development of autoimmune diseases that can impair renal function, such as systemic lupus erythematosus (SLE), whose renal involvement is a severe type of GN called lupus nephritis or to the vulnerability to opportunistic infections, leading to repeated episodes of pyelonephritis and/or immune-mediated GN due to the accumulation of antigen-antibody complexes in the glomerular filtration barrier

The integrity of the epithelial tissue can be listed as one of the most important nonimmunological physical barriers against infection. The skin represents the largest organ of the human body and its main function is to delimit the organism, separating it and protecting it from the environment that surrounds it. Of course, it is not an insurmountable insulation, since this would be incompatible with the maintenance of life: water, atmospheric gases, and ions are able to cross the epithelial barrier simply due to passive processes such as osmosis and diffu-

However, macromolecules, such as high-weight proteins or even whole cells are not able to transpose the barrier formed by epithelial tissue in a normal physiological situation, making the area covered by the intact epithelium protected from invasive pathogens. Accordingly, epithelial injury and/or scarification provide the invasive parasites a chance to enter into their future host [54, 55]. Some virulent microorganisms can produce elements capable of puncturing or injuring the epithelial tissue, opening a gateway to the host organism. Certain strains of uropathogenic *Escherichia coli* (UPEC), for instance, produce proteolytic enzymes, cytotoxic necrotizing factors, and numerous adhesive molecules (adhesins) as part of their

tract, and vagina by beneficial microorganisms referred as microbiota [56, 57].

tolerant of them [58, 59].

(GFB) [12].

invasion arsenal [60].

sion or through active transmembrane transport.

**Table 2.** Studies using experimental CKD development and its renoprotective effects.

## **4. The immune system and kidney disease**

The immune system (IS) is composed by a set of structures, cells, and processes that together enable an organism to recognize their self-elements from the foreign and potentially pathogenic ones, producing then, a physiological response consistent with the nature of the recognized element, which can be either a self-harmless protein or a dangerous bacterium [54]. As part of these systems, there are the so-called nonimmunological physical, chemical, and biological barriers and the immunological components itself, represented by innate and adaptive mechanisms of cellular and humoral immune response [54, 55].

In a simplistic way, the IS is responsible for four different body functions. The first one is the immune tolerance, the property that allows the body to recognize self-cells, proteins, and other constitutive elements, producing a response of tolerance and preventing autoimmune reactions. This particular state of IS unresponsiveness is also essential to ensure the regular fetal development during pregnancy and to allow the colonization of human skin, digestive tract, and vagina by beneficial microorganisms referred as microbiota [56, 57].

The second and most well-known function of IS is the immunity itself. It is the ability to recognize foreign proteins and molecules, which may indicate the presence of invading microorganisms, such as bacteria or other parasites, and respond to these foreign elements with both cellular and humoral defenses, protecting the organism against infection [54]. Additionally, through its third property, immune surveillance, the IS patrols the body to recognize and destroy self-cells infected by virus or even constitutive cells that become cancerous or suffer phenotype alterations due to genetic mutations [54, 55]. For immune surveillance to work, cancer and/or mutated cells must express specific antigens that are not frequently found on normal cells, otherwise the IS would recognize them as "self" and be tolerant of them [58, 59].

Finally, the last property of IS is the ability of self-controlling the immune response. Through a complex mechanism of feedback and cell-to-cell communication, involving a number of cytokines and cell-cytokine receptors, IS modulates its response, which can be either tolerance or immunity, according to the specific stimulus to which the organism is subjected to [54]. This property is known as immunoregulation and is of paramount importance, not only for the kidneys but also for the whole organism. Failures on the immunoregulation may lead either to the development of autoimmune diseases that can impair renal function, such as systemic lupus erythematosus (SLE), whose renal involvement is a severe type of GN called lupus nephritis or to the vulnerability to opportunistic infections, leading to repeated episodes of pyelonephritis and/or immune-mediated GN due to the accumulation of antigen-antibody complexes in the glomerular filtration barrier (GFB) [12].

The integrity of the epithelial tissue can be listed as one of the most important nonimmunological physical barriers against infection. The skin represents the largest organ of the human body and its main function is to delimit the organism, separating it and protecting it from the environment that surrounds it. Of course, it is not an insurmountable insulation, since this would be incompatible with the maintenance of life: water, atmospheric gases, and ions are able to cross the epithelial barrier simply due to passive processes such as osmosis and diffusion or through active transmembrane transport.

**4. The immune system and kidney disease**

**Authors (first, last) and year**

Utimura R, Zatz R. 2003

Shihab FS, Andoh Tf. 2002

Fujihara CK, Zatz R. 2001

Romero F, Tapia E. 1999

Fujihara CK, Noronha IL. 1998

[28] Rat ST-induced DN

160 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

[29] Rat L-NAME-

[52] Rat 5/6

[35] Rat 5/6

induced NO inhibition

nephrectomy (NX)

nephrectomy (NX)

**Table 2.** Studies using experimental CKD development and its renoprotective effects.

tive mechanisms of cellular and humoral immune response [54, 55].

The immune system (IS) is composed by a set of structures, cells, and processes that together enable an organism to recognize their self-elements from the foreign and potentially pathogenic ones, producing then, a physiological response consistent with the nature of the recognized element, which can be either a self-harmless protein or a dangerous bacterium [54]. As part of these systems, there are the so-called nonimmunological physical, chemical, and biological barriers and the immunological components itself, represented by innate and adap-

**Ref. Species CKD studied Target cell/molecule Drug/compound Related improvements**

[51] Human Human DN TGFβ, TNFa Pirfenidone Treatment with

T-lymphocytes MMF MMF prevented

T-lymphocytes MMF MMF significantly

T-lymphocytes MMF Segmental sclerosis,

T-lymphocytes MMF MMF significantly

albuminuria, GS, and renal cortical macrophage infiltration in DN

pirfenidone, which has been shown to inhibit renal fibrosis in experimental models, prolonged the period of conservative treatment of CKD in patients with ND, delaying the need

for dialysis

reduced

by CD43+

NX rats

glomerulosclerosis, renal interstitial expansion, macrophage and lymphocyte infiltration

interstitial fibrosis, and renal infiltration

prevented GS and interstitial expansion in

 and ED1+ cells were significantly reduced with MMF

In a simplistic way, the IS is responsible for four different body functions. The first one is the immune tolerance, the property that allows the body to recognize self-cells, proteins, and However, macromolecules, such as high-weight proteins or even whole cells are not able to transpose the barrier formed by epithelial tissue in a normal physiological situation, making the area covered by the intact epithelium protected from invasive pathogens. Accordingly, epithelial injury and/or scarification provide the invasive parasites a chance to enter into their future host [54, 55]. Some virulent microorganisms can produce elements capable of puncturing or injuring the epithelial tissue, opening a gateway to the host organism. Certain strains of uropathogenic *Escherichia coli* (UPEC), for instance, produce proteolytic enzymes, cytotoxic necrotizing factors, and numerous adhesive molecules (adhesins) as part of their invasion arsenal [60].

UTI is a worldwide health problem that affects over 13 million of people each year in the US. It is currently the most common infection in adult females and, in nearly all cases, it is caused by a few strains of UPEC. Although the symptoms of an uncomplicated UTI can be relatively mild, it can progress to pyelonephritis, leading to fever, nausea, vomiting, and, in about 30% of cases, bacteremia and risk of sepsis. Moreover, recurrent UTI may contribute to additional problems, including renal scarring, CKD, and an increased risk for developing bladder cancer [60]. Besides the presence of UPEC and the toxins produced by them in the urinary tract, there are evidence that proteinuria can itself cause injury to the renal and urinary epithelium. Since proteins are expected to be retained in the GFB, increased protein concentration in the urinary fluid is considered an irritating and pro-inflammatory factor for the tubular, ureteral, and bladder epithelium, leading to enhanced protein reabsorption by the tubular epithelial cells, overload of their catabolic capacity, leukocytes infiltration, and corruption of the integrity of the urinary epithelial barrier [54].

as an attempt to restore tissue integrity. In case of infection, for instance, the elimination of invading microorganisms becomes a necessary condition for tissue repair. Inflammatory reaction depends on the action of specific blood cells called leucocytes. Under normal physiological conditions, there are around 5000 and 10,000 leukocytes per blood microliter, but these numbers significantly rise in the presence of an infection. Mature leukocytes can be classified both according to their original lineage (myeloid or lymphoid cells) and/or to the number of cellular nuclei they appear to have under light microscopy (mononuclear or polymorpho-

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

163

Mononuclear cells represent 35% of the total peripheral blood leukocytes. This broadest category is composed by monocytes: phagocytic cells that give rise to both macrophages and dendritic cells; mast cells, which are mainly responsible for vasodilation on inflammatory processes; lymphocytes, the effectors of our specific immune response, and finally, the natural killer cells (NK). The remaining 65% of blood leukocytes are represented by the polymorphonuclear cells, which are didactically subdivided into three different groups, according to their affinity with acid (eosinophils), alkaline (basophils) or both (neutrophils) histological dyes; these last being the first cell type to reach an injured area of the organism and initiating the inflammatory response. Leukocytes whose cytoplasm is rich in granules of enzymes and cytotoxic substances, such as reactive oxygen species, are generally called granulocytes. Basophils, eosinophils, and neutrophils can be called granulocytes. Macrophages and dendritic cells also have a considerable amount of granules in their cytoplasm; however, they are described as phagocytes, due to their ability to phagocyte invading microorganisms. All leukocytes are capable of producing a broad range of chemical mediators involved in the immune response (generally called cytokines) in response to lesions or to the presence of microorganisms. In addition to being responsible for the synthesis of these cytokines, leukocytes are also responsive to the action of these mediators, which promote, among other biological effects, leukocyte chemotaxis toward the inflammatory focus as well as its activation [32, 54, 55]. Cytokines are soluble glycoproteins, which may have autocrine, paracrine, or endocrine action. A fraction of these mediators have been at least partially described, however, there is still an almost infinite range of little known pro-inflammatory cellular signaling molecules, whose activity

As far as we currently know, once the nonimmune body barriers are overcome by a pathogen or a dangerous substance, a microscopic battle begins in the injured tissue. The first line of defense of our immune system is the innate immunity, which comprises a group of cells, intracellular mechanisms, and chemical mediators, extremely conserved evolutionarily. Long before vertebrates first appeared on Earth, their primitive ancestors already had effective systems of immune cells recruitment, production of cytokines, activation of the complement cascade, identification of foreign elements through transmembrane and intracellular molecular pattern recognition receptors (MPRR), inactivation of pathogens through the production of reactive oxygen species (ROS), antimicrobial peptides and lytic enzymes, and, finally, removal of invader microorganisms through phagocytosis. Although innate immune system is a nonspecific evolutionarily older defense strategy, it is a fast mechanism that comes into play immediately or within hours of the appearance of a foreign element in

nuclear cells), as illustrated in **Figure 2** [32, 54].

has not yet been fully established.

the body, initiating the inflammatory process [32, 37–42, 54].

The intestinal and ureteral peristaltic movement and the flow of fluids like vomiting, diarrheal, or the urinary stream itself are also important physical barriers against infection, preventing the onset and permanence of microorganisms in the digestive system and in the lower urinary tract. In addition to these physical barriers, the maintenance of low pH in some body fluids is one of the chemical physiological strategies of greater prominence to avoid infections. Accordingly, low stomach and urinary pH can destroy most of the parasitic organisms which, by chance, succeed in penetrating these systems [55]. The last, but not least, of the "nonimmunological" barriers that protect our body from infection is the biological barrier, represented by the normal microbiota, a complete ecosystem composed by harmless microorganisms that live in balance with our body. The benefits of having the intestines, skin, and vagina occupied by specific strains of innocuous bacteria were once thought to be limited to the reduction of pathological colonization, due to the competition among the invaders and the resident flora. Nowadays, we know that the microbiota lives in fact in a mutualistic symbiosis with our body, benefiting themselves and the host [54, 55, 61].

The integrity of our intestinal microbiota, for instance, is essential to the digestion of a number of food components, making the absorption of important nutrients easier. Moreover, the anaerobic bacilli that inhabit the vaginal cavity are responsible for the maintenance of acid pH in that region, since they produce lactic acid as an anaerobic respiration metabolite, keeping the vagina free of fungal colonization. It is of note that the resident microbiota lives in a delicate balance with our IS. Its growth is controlled and limited by phagocytic cells and other elements of the IS, and the occurrence of imbalances in the property of immunoregulation, such as immunity reduction due to illness, immunosuppression, stress, or malnutrition, may lead to an exacerbated growth of microbiota population, which is potentially harmful for the human organism and should be controlled [54, 61].

## **5. Inflammation and innate immune response**

When the above mentioned nonimmunological natural barriers are overcome by pathogens or other irritative elements, the immune response is initiated through the inflammatory reaction, as an attempt to restore tissue integrity. In case of infection, for instance, the elimination of invading microorganisms becomes a necessary condition for tissue repair. Inflammatory reaction depends on the action of specific blood cells called leucocytes. Under normal physiological conditions, there are around 5000 and 10,000 leukocytes per blood microliter, but these numbers significantly rise in the presence of an infection. Mature leukocytes can be classified both according to their original lineage (myeloid or lymphoid cells) and/or to the number of cellular nuclei they appear to have under light microscopy (mononuclear or polymorphonuclear cells), as illustrated in **Figure 2** [32, 54].

UTI is a worldwide health problem that affects over 13 million of people each year in the US. It is currently the most common infection in adult females and, in nearly all cases, it is caused by a few strains of UPEC. Although the symptoms of an uncomplicated UTI can be relatively mild, it can progress to pyelonephritis, leading to fever, nausea, vomiting, and, in about 30% of cases, bacteremia and risk of sepsis. Moreover, recurrent UTI may contribute to additional problems, including renal scarring, CKD, and an increased risk for developing bladder cancer [60]. Besides the presence of UPEC and the toxins produced by them in the urinary tract, there are evidence that proteinuria can itself cause injury to the renal and urinary epithelium. Since proteins are expected to be retained in the GFB, increased protein concentration in the urinary fluid is considered an irritating and pro-inflammatory factor for the tubular, ureteral, and bladder epithelium, leading to enhanced protein reabsorption by the tubular epithelial cells, overload of their catabolic capacity, leukocytes infiltration, and corruption of the integrity of

The intestinal and ureteral peristaltic movement and the flow of fluids like vomiting, diarrheal, or the urinary stream itself are also important physical barriers against infection, preventing the onset and permanence of microorganisms in the digestive system and in the lower urinary tract. In addition to these physical barriers, the maintenance of low pH in some body fluids is one of the chemical physiological strategies of greater prominence to avoid infections. Accordingly, low stomach and urinary pH can destroy most of the parasitic organisms which, by chance, succeed in penetrating these systems [55]. The last, but not least, of the "nonimmunological" barriers that protect our body from infection is the biological barrier, represented by the normal microbiota, a complete ecosystem composed by harmless microorganisms that live in balance with our body. The benefits of having the intestines, skin, and vagina occupied by specific strains of innocuous bacteria were once thought to be limited to the reduction of pathological colonization, due to the competition among the invaders and the resident flora. Nowadays, we know that the microbiota lives in fact in a mutualistic symbiosis with our body, benefiting themselves and the host [54, 55, 61]. The integrity of our intestinal microbiota, for instance, is essential to the digestion of a number of food components, making the absorption of important nutrients easier. Moreover, the anaerobic bacilli that inhabit the vaginal cavity are responsible for the maintenance of acid pH in that region, since they produce lactic acid as an anaerobic respiration metabolite, keeping the vagina free of fungal colonization. It is of note that the resident microbiota lives in a delicate balance with our IS. Its growth is controlled and limited by phagocytic cells and other elements of the IS, and the occurrence of imbalances in the property of immunoregulation, such as immunity reduction due to illness, immunosuppression, stress, or malnutrition, may lead to an exacerbated growth of microbiota population, which is potentially harmful for the

When the above mentioned nonimmunological natural barriers are overcome by pathogens or other irritative elements, the immune response is initiated through the inflammatory reaction,

the urinary epithelial barrier [54].

162 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

human organism and should be controlled [54, 61].

**5. Inflammation and innate immune response**

Mononuclear cells represent 35% of the total peripheral blood leukocytes. This broadest category is composed by monocytes: phagocytic cells that give rise to both macrophages and dendritic cells; mast cells, which are mainly responsible for vasodilation on inflammatory processes; lymphocytes, the effectors of our specific immune response, and finally, the natural killer cells (NK). The remaining 65% of blood leukocytes are represented by the polymorphonuclear cells, which are didactically subdivided into three different groups, according to their affinity with acid (eosinophils), alkaline (basophils) or both (neutrophils) histological dyes; these last being the first cell type to reach an injured area of the organism and initiating the inflammatory response. Leukocytes whose cytoplasm is rich in granules of enzymes and cytotoxic substances, such as reactive oxygen species, are generally called granulocytes. Basophils, eosinophils, and neutrophils can be called granulocytes. Macrophages and dendritic cells also have a considerable amount of granules in their cytoplasm; however, they are described as phagocytes, due to their ability to phagocyte invading microorganisms. All leukocytes are capable of producing a broad range of chemical mediators involved in the immune response (generally called cytokines) in response to lesions or to the presence of microorganisms. In addition to being responsible for the synthesis of these cytokines, leukocytes are also responsive to the action of these mediators, which promote, among other biological effects, leukocyte chemotaxis toward the inflammatory focus as well as its activation [32, 54, 55]. Cytokines are soluble glycoproteins, which may have autocrine, paracrine, or endocrine action. A fraction of these mediators have been at least partially described, however, there is still an almost infinite range of little known pro-inflammatory cellular signaling molecules, whose activity has not yet been fully established.

As far as we currently know, once the nonimmune body barriers are overcome by a pathogen or a dangerous substance, a microscopic battle begins in the injured tissue. The first line of defense of our immune system is the innate immunity, which comprises a group of cells, intracellular mechanisms, and chemical mediators, extremely conserved evolutionarily. Long before vertebrates first appeared on Earth, their primitive ancestors already had effective systems of immune cells recruitment, production of cytokines, activation of the complement cascade, identification of foreign elements through transmembrane and intracellular molecular pattern recognition receptors (MPRR), inactivation of pathogens through the production of reactive oxygen species (ROS), antimicrobial peptides and lytic enzymes, and, finally, removal of invader microorganisms through phagocytosis. Although innate immune system is a nonspecific evolutionarily older defense strategy, it is a fast mechanism that comes into play immediately or within hours of the appearance of a foreign element in the body, initiating the inflammatory process [32, 37–42, 54].

suffering. Bacterial lipopolysaccharide (LPS), flagellin, peptidoglycans, glycolipids, zymosan, and profilin, as well as single-stranded DNA (ssDNA) and double-stranded RNA are examples of PAMPs. In turn, Interleukines IL-1β and IL-18, extracellular HMGB1, ATP, and DNA,

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

165

After this first identification, local cells synthesize and release vasoactive mediators that promote vasodilatation and increase the local blood supply, causing heat and flushing; common features of inflammation. The concomitant activation of resident innate immune cells also takes part in the process. Under physiological conditions, the most common kidney resident immune cells are tissue macrophages and dendritic cells. It is of note that these last acts as sentinels in homeostasis, local injury, and infection, rapidly producing neutrophil-recruiting chemokines. In a less extent, mast cells are also seen in renal tissue and have been pointed out as local renal producers of RAAS components [14, 18]. Once activated, in addition to increasing the renal production of Ang II, mast cells release the content of their cytoplasmic granules of histamine; a biogenic amine that promotes increased vascular permeability by distancing endothelial cells (enlargement of endothelial fenestrae) near the injured region. As a result, there is a blood plasma extravasation from local blood vessels to the injured region, diluting eventual toxins produced by invading microorganisms, and bringing the proteins of complement system to the inflammation site [54, 55]. This interstitial accumulation of plasma promotes both edema and local pain, due to the compression of nerve endings. The next step is the diapedesis, or transendothelial migration, which is the leukocyte outflow from the bloodstream toward the focus of inflammation. This process is only possible due to a complex chemical communication system between the injured local tissue, the endothelial cells and the leukocytes itself, as

The first cell types to reach the inflammatory focus are neutrophils, followed by circulating monocytes, which upon reaching the tissues become macrophages. Phagocytes also are able to reach the inflammatory spot and recognize PAMPs and DAMPs through two potential strategies: (1) phagocytosis followed by digestion of the microorganism and (2) production and excretion of anti-microbial compounds, as nitric oxide (NO), and ROS

) and hydrogen peroxide (H2

mation can promote systemic effects. Activated macrophages, for example, release IL-1β and tumor necrosis factor (TNFα), cytokines that bind to our thermoregulatory receptors causing body temperature rising (fever), and stimulate the hypothalamic-pituitaryadrenal axis, leading to increased production of corticoid hormones, including renin, by the adrenal gland [54, 55]. Moreover, TNFα acts on the bone marrow, accelerating leukocyte proliferation. At this initial nonspecific phase of inflammatory response, the phagocytic capacity of neutrophils, monocytes, and macrophages does not depend on specific antigenic recognition, on neither the immune memory nor the presence of antibodies. Resistant microorganisms, as well as remaining phagocytes, are then drained through the lymphatic vessels to the nearest lymph node, where the antigens will be presented to the lymphocytes, initiating a more complex and long-lasting reaction, the adaptive immune

O2

). The acute phase of inflam-

as well as uric acid crystals can be considered DAMPs [37–42].

illustrated in **Figure 3**.

such as superoxide anion (O2

response [32, 54, 55].

−

**Figure 2.** Leukocyte classification. Leukocytes can be classified as myeloid or lymphoid cells, according to their hematopoietic origin, or as mononuclear or polymorphonuclear cells, according to the number of cellular nuclei and cytoplasmic granules they appear to have, in their mature circulating form, under light microscopy.

Right after tissue aggression, the MPRRs of injured cells, which may be epithelial, endothelial, or mesangial cells, as well as resident phagocytes and fibroblasts, recognize pathogen-associated molecular patterns (PAMPs) that may indicate the presence of invading microorganisms and damage-associated molecular patterns (DAMPs), released by self-cells under cellular suffering. Bacterial lipopolysaccharide (LPS), flagellin, peptidoglycans, glycolipids, zymosan, and profilin, as well as single-stranded DNA (ssDNA) and double-stranded RNA are examples of PAMPs. In turn, Interleukines IL-1β and IL-18, extracellular HMGB1, ATP, and DNA, as well as uric acid crystals can be considered DAMPs [37–42].

After this first identification, local cells synthesize and release vasoactive mediators that promote vasodilatation and increase the local blood supply, causing heat and flushing; common features of inflammation. The concomitant activation of resident innate immune cells also takes part in the process. Under physiological conditions, the most common kidney resident immune cells are tissue macrophages and dendritic cells. It is of note that these last acts as sentinels in homeostasis, local injury, and infection, rapidly producing neutrophil-recruiting chemokines. In a less extent, mast cells are also seen in renal tissue and have been pointed out as local renal producers of RAAS components [14, 18]. Once activated, in addition to increasing the renal production of Ang II, mast cells release the content of their cytoplasmic granules of histamine; a biogenic amine that promotes increased vascular permeability by distancing endothelial cells (enlargement of endothelial fenestrae) near the injured region. As a result, there is a blood plasma extravasation from local blood vessels to the injured region, diluting eventual toxins produced by invading microorganisms, and bringing the proteins of complement system to the inflammation site [54, 55]. This interstitial accumulation of plasma promotes both edema and local pain, due to the compression of nerve endings. The next step is the diapedesis, or transendothelial migration, which is the leukocyte outflow from the bloodstream toward the focus of inflammation. This process is only possible due to a complex chemical communication system between the injured local tissue, the endothelial cells and the leukocytes itself, as illustrated in **Figure 3**.

The first cell types to reach the inflammatory focus are neutrophils, followed by circulating monocytes, which upon reaching the tissues become macrophages. Phagocytes also are able to reach the inflammatory spot and recognize PAMPs and DAMPs through two potential strategies: (1) phagocytosis followed by digestion of the microorganism and (2) production and excretion of anti-microbial compounds, as nitric oxide (NO), and ROS such as superoxide anion (O2 − ) and hydrogen peroxide (H2 O2 ). The acute phase of inflammation can promote systemic effects. Activated macrophages, for example, release IL-1β and tumor necrosis factor (TNFα), cytokines that bind to our thermoregulatory receptors causing body temperature rising (fever), and stimulate the hypothalamic-pituitaryadrenal axis, leading to increased production of corticoid hormones, including renin, by the adrenal gland [54, 55]. Moreover, TNFα acts on the bone marrow, accelerating leukocyte proliferation. At this initial nonspecific phase of inflammatory response, the phagocytic capacity of neutrophils, monocytes, and macrophages does not depend on specific antigenic recognition, on neither the immune memory nor the presence of antibodies. Resistant microorganisms, as well as remaining phagocytes, are then drained through the lymphatic vessels to the nearest lymph node, where the antigens will be presented to the lymphocytes, initiating a more complex and long-lasting reaction, the adaptive immune response [32, 54, 55].

Right after tissue aggression, the MPRRs of injured cells, which may be epithelial, endothelial, or mesangial cells, as well as resident phagocytes and fibroblasts, recognize pathogen-associated molecular patterns (PAMPs) that may indicate the presence of invading microorganisms and damage-associated molecular patterns (DAMPs), released by self-cells under cellular

**Figure 2.** Leukocyte classification. Leukocytes can be classified as myeloid or lymphoid cells, according to their hematopoietic origin, or as mononuclear or polymorphonuclear cells, according to the number of cellular nuclei and

cytoplasmic granules they appear to have, in their mature circulating form, under light microscopy.

164 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

**Figure 3.** Diapedesis. Inflammatory response initiates right after the recognition of a foreign element by the MPRRs of host cells, particularly the toll-like (TLRs) and NOD-like receptors (NLRs). Damaged cells release specific chemokines (CCL-2, -3, -4, -5, -11, -20 and CXCL10), which attract the circulating leukocytes, guiding their migration through a gradient of concentration in the bloodstream toward the inflamed area. When these cells reach the blood vessels with the highest concentration of chemokines, they firmly adhere to the endothelium and initiate a rolling process, getting closer to the inflamed region. Once near from the inflammation site, leukocytes stop rolling, change their shape by spreading on the endothelium, and finally pass through the enlarged endothelial fenestrae, reaching the potentially infected tissue. This process is called diapedesis and it is only possible due to the chemical affinity between the constitutive integrins, present on the surface of leukocyte cellular membrane, and some specific endothelial adhesion molecules, such as selectins E and P, which stimulate leukocyte rolling, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ECAM-1) and platelet and endothelial cell adhesion molecule 1 (PECAM-1), which contribute to the attachment of leukocytes to the endothelial membrane and to their transmigration through the endothelial barrier.

## **6. Innate immune response and nonimmune-mediated CKD**

In the past years, renal activation of innate immune mechanisms by sterile elements has been demonstrated in nonimmune-mediated human nephropathies. Moreover, such activation of innate immunity seems to be positively correlated with the progression of renal injury in a variety of experimental models of CKD (**Table 1**). Our understanding of the mechanisms underlying the triggering of sterile inflammation was largely enhanced after the discovery of specific MPRRs: the toll-like receptors' (TLRs) and the NOD-like receptors' (NLRs) families; primarily found in leukocytes, but also present in epithelial and endothelial cells. Once activated, transmembrane and cytoplasmic TLRs trigger multiple intracellular events, involving adaptor proteins, such as MyD88, Mal/TIRAP, and TRAM, leading to nuclear translocation of transcription factors such as IRF3, IRF7, and NFΚB, known to induce a variety of pro-inflammatory genes [32, 40]. On the other hand, NLRs are another class of intracellular MPRRs, very responsive to the presence of DAMPs. Their activation promotes the assembly of molecular complexes known as inflammasomes, such as the NOD2, NLRP1, NLRP3, NLRC4, etc. Inflammasomes assembly also promotes NFKB and MAPK activation, as well as the conversion of the inactive Pro-caspase 1 into the pro-inflammatory enzyme Caspase 1 (CASP1), which in turn, promotes the maturation of interleukins IL1β and IL18, thus amplifying the inflammatory response [36–41]. As mentioned above, the activation of these two main families of MPRRs, as well as, the components related to their intracellular signaling pathway were already described to be present in both human and experimental CKD. A proposed mechanism for sterile activation of immune response in nonimmunemediated CKD is illustrated in **Figure 4**.

Accordingly, experimental studies have been shown that chemical blockage of inflammasome NLRP3, NFKB system, and IL1β, limits blood pressure rising, albuminuria, creatinine retention, and renal histological alterations in different murine CKD models. Moreover, *Tlr2*, *Tlr4*, and *Nod2* knockout (KO) mice develop less tubulointerstitial nephritis and renal fibrosis when submitted to kidney injury [40]. The activation of innate immunity pathways in nonimmune-mediated CKD may represent an important link between nonspecific insults; such as glomerular wall stretching, due to glomerular hypertension and hypertrophy, tubular exposure to high protein, glucose or uremic toxins concentration, tissue damage by the presence of crystals; and late events, such as GS and interstitial fibrosis. Innate immune intracellular mechanisms are represented in detail in **Figure 5** [2, 18, 21, 54]. Since cell damage may further stimulate innate immunity, a positive feedback may establish, leading to the engagement of adaptive immunity, perpetuating inflammation, and culminating in the establishment of end-

**Figure 4.** Renal sterile inflammation. Beyond to be activated by pathogens, MPRRs are also sensible to molecules currently related to cell damage (DAMPs). These sterile stimuli may represent the link between the initial features of nonimmune renal aggression and the establishment of chronic kidney inflammation. It is currently known that different renal cells present the intracellular machinery necessary to activate innate immune response, from endothelial to resident dendritic cells. TLRs and NLRs are stimulated in tubular epithelial cell exposed to DAMPs starting an intracellular intricate response that leads to the release of pro-inflammatory interleukins and chemokines (A). These intercellular signaling compounds are capable of recruiting circulating leukocytes to the renal parenchyma, as well as to activate resident interstitial macrophages, dendritic and mast cells, similarly to what occurs in an infection episode (B). Moreover pro-inflammatory interleukins released by both epithelial cells and renal immune sentinels can activate resident fibroblasts leading to their transdifferentiation into profibrotic myofibroblasts; cells specialized in producing large amounts of EM proteins and further pro-inflammatory signaling molecules. Additionally, glomerular sterile damage can also trigger leukocyte recruitment through the activation of innate immunity pathways. Endothelial cells of glomerular capillaries potentially react to mechanical stress caused by tissue stretching due to glomerular hypertension and hypertrophy by releasing DAMPs. This possible event promotes mesangial cells proliferation and EM overproduction, which may lead to glomerulosclerosis and the activation of further pro-inflammatory

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

167

stage renal disease (ESRD).

mechanisms (C).

**Figure 4.** Renal sterile inflammation. Beyond to be activated by pathogens, MPRRs are also sensible to molecules currently related to cell damage (DAMPs). These sterile stimuli may represent the link between the initial features of nonimmune renal aggression and the establishment of chronic kidney inflammation. It is currently known that different renal cells present the intracellular machinery necessary to activate innate immune response, from endothelial to resident dendritic cells. TLRs and NLRs are stimulated in tubular epithelial cell exposed to DAMPs starting an intracellular intricate response that leads to the release of pro-inflammatory interleukins and chemokines (A). These intercellular signaling compounds are capable of recruiting circulating leukocytes to the renal parenchyma, as well as to activate resident interstitial macrophages, dendritic and mast cells, similarly to what occurs in an infection episode (B). Moreover pro-inflammatory interleukins released by both epithelial cells and renal immune sentinels can activate resident fibroblasts leading to their transdifferentiation into profibrotic myofibroblasts; cells specialized in producing large amounts of EM proteins and further pro-inflammatory signaling molecules. Additionally, glomerular sterile damage can also trigger leukocyte recruitment through the activation of innate immunity pathways. Endothelial cells of glomerular capillaries potentially react to mechanical stress caused by tissue stretching due to glomerular hypertension and hypertrophy by releasing DAMPs. This possible event promotes mesangial cells proliferation and EM overproduction, which may lead to glomerulosclerosis and the activation of further pro-inflammatory mechanisms (C).

**6. Innate immune response and nonimmune-mediated CKD**

166 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

mediated CKD is illustrated in **Figure 4**.

In the past years, renal activation of innate immune mechanisms by sterile elements has been demonstrated in nonimmune-mediated human nephropathies. Moreover, such activation of innate immunity seems to be positively correlated with the progression of renal injury in a variety of experimental models of CKD (**Table 1**). Our understanding of the mechanisms underlying the triggering of sterile inflammation was largely enhanced after the discovery of specific MPRRs: the toll-like receptors' (TLRs) and the NOD-like receptors' (NLRs) families; primarily found in leukocytes, but also present in epithelial and endothelial cells. Once activated, transmembrane and cytoplasmic TLRs trigger multiple intracellular events, involving adaptor proteins, such as MyD88, Mal/TIRAP, and TRAM, leading to nuclear translocation of transcription factors such as IRF3, IRF7, and NFΚB, known to induce a variety of pro-inflammatory genes [32, 40]. On the other hand, NLRs are another class of intracellular MPRRs, very responsive to the presence of DAMPs. Their activation promotes the assembly of molecular complexes known as inflammasomes, such as the NOD2, NLRP1, NLRP3, NLRC4, etc. Inflammasomes assembly also promotes NFKB and MAPK activation, as well as the conversion of the inactive Pro-caspase 1 into the pro-inflammatory enzyme Caspase 1 (CASP1), which in turn, promotes the maturation of interleukins IL1β and IL18, thus amplifying the inflammatory response [36–41]. As mentioned above, the activation of these two main families of MPRRs, as well as, the components related to their intracellular signaling pathway were already described to be present in both human and experimental CKD. A proposed mechanism for sterile activation of immune response in nonimmune-

**Figure 3.** Diapedesis. Inflammatory response initiates right after the recognition of a foreign element by the MPRRs of host cells, particularly the toll-like (TLRs) and NOD-like receptors (NLRs). Damaged cells release specific chemokines (CCL-2, -3, -4, -5, -11, -20 and CXCL10), which attract the circulating leukocytes, guiding their migration through a gradient of concentration in the bloodstream toward the inflamed area. When these cells reach the blood vessels with the highest concentration of chemokines, they firmly adhere to the endothelium and initiate a rolling process, getting closer to the inflamed region. Once near from the inflammation site, leukocytes stop rolling, change their shape by spreading on the endothelium, and finally pass through the enlarged endothelial fenestrae, reaching the potentially infected tissue. This process is called diapedesis and it is only possible due to the chemical affinity between the constitutive integrins, present on the surface of leukocyte cellular membrane, and some specific endothelial adhesion molecules, such as selectins E and P, which stimulate leukocyte rolling, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ECAM-1) and platelet and endothelial cell adhesion molecule 1 (PECAM-1), which contribute to the attachment of leukocytes to the endothelial membrane and to their transmigration through the endothelial barrier.

> Accordingly, experimental studies have been shown that chemical blockage of inflammasome NLRP3, NFKB system, and IL1β, limits blood pressure rising, albuminuria, creatinine retention, and renal histological alterations in different murine CKD models. Moreover, *Tlr2*, *Tlr4*, and *Nod2* knockout (KO) mice develop less tubulointerstitial nephritis and renal fibrosis when submitted to kidney injury [40]. The activation of innate immunity pathways in nonimmune-mediated CKD may represent an important link between nonspecific insults; such as glomerular wall stretching, due to glomerular hypertension and hypertrophy, tubular exposure to high protein, glucose or uremic toxins concentration, tissue damage by the presence of crystals; and late events, such as GS and interstitial fibrosis. Innate immune intracellular mechanisms are represented in detail in **Figure 5** [2, 18, 21, 54]. Since cell damage may further stimulate innate immunity, a positive feedback may establish, leading to the engagement of adaptive immunity, perpetuating inflammation, and culminating in the establishment of endstage renal disease (ESRD).

through the lymphatic vessels to the nearest lymph node, where a most specific and long lasting reaction begins: the adaptive immune response. It is important to emphasize that macrophages, dendritic cells, and other innate phagocytes represent the link between the nonspecific and the specific immune response. These leukocytes are designated as antigen presenting cells (APCs), since they have the ability of presenting foreign molecules to the lymphocytes in the lymph nodes, thereby activating and stimulating these specific cells. Lymphocytes are mononuclear leukocytes involved with the specific immune response. They originate from a lymphoid progenitor cell in the bone marrow, and may undergo differentiation in the bone marrow itself, been called B-lymphocytes or simply B-cells, or in the thymus, called T-lymphocytes or T-cells [54, 55]. Once the APCs phagocyte an invading microorganisms, they digest their proteins (antigen processing) and migrate to the lymph nodes, where they expose small peptide portions of the invader in the surface of their cellular membrane, associated with their molecules of the major histocompatibility complex of class II (MHC II). Both types of lymphocytes are able to recognize processed antigens associated with molecules of the MHC II of APCs through their membrane receptors (TCR of T-lymphocytes or BCR of B-lymphocytes). Unstimulated B or T lymphocytes, also called "naive" cells are generally small and present scarce cytoplasm. However, once stimulated, they became "effector lymphocytes," increase in size, have the cytoplasm hypertrophied and suffer mitosis, promoting clonal amplification, thus increasing the number of cells that

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

169

In an extremely simplified view, when an antigen is recognized by the TCR of a naive T-cell, this leukocyte is activated, initiating the cellular adaptive response. First of all, the effector t-cell give rise to two different cell types through cell division: the T-Helper lymphocyte,

tion of the T-Helper cells migrate to the inflamed area and, according to the type of stimulus they receive, these cells differentiate into one of the five known phenotypes: Th1, Th2, Th17, Tfh, and Treg [55]. Most of these subtypes of T-cells produce pro-inflammatory cytokines that acts especially upon macrophages, attracting them close to the target antigen, giving them increased membrane mobility and increasing their phagocytic and microbicidal potential. Only the Treg phenotype is described to release anti-inflammatory mediators, thus contribut-

Cytotoxic T lymphocytes, in turn, can directly lysate bacteria, virus-infected cells, as well as self-cells that have suffered genetic mutation. Once the cytotoxic T-lymphocyte gets in touch with the target microorganism or antigen, a series of granzymes, perforins, and other cytotoxic molecules are released from within their cytoplasmic granules directly into the extracellular medium. Perforins are molecules that promote the formation of pores in the plasma membrane of target cells, causing abrupt entry of liquid, due to osmotic pressure, into the cytoplasm of these cells, leading to its apoptosis. Furthermore, both T-Helper and Cytotoxic lymphocytes give

the other populations of T-lymphocytes, memory T-cells may be inactive for years in the bloodstream, generating copies of themselves; thus, maintaining the memory of the recognition of the antigen that caused the activation of its precursor. Such cells are readily activated in the presence of a reinfection, being extremely important to defend our body from recurrent infections.

T-cell will be sensitive to the same antigen that promoted the activa-

cells, respectively. This process is illustrated in **Figure 6**. Unlike

T-cell), and the

T-cell).

that have the CD4 glycoprotein on the surface of their cell membrane (CD4+

Cytotoxic T lymphocyte, characterized by the presence of CD8 in its membrane (CD8+

would be sensitive to that specific activating antigen [32, 54].

Both CD4+

and CD8+

ing to immunotolerance.

rise to memory CD4+

and CD8+

**Figure 5.** Some intracellular mechanisms of sterile innate immune reaction. Many different sterile stimuli can be identified as DAMPs by epithelial, endothelial, mesangial cells and also by renal resident leukocytes. Once a DAMP is recognized by a TLR, for instance, it leads to the activation of NFΚB system, one of the most important intracellular pro-inflammatory pathways. The NFΚB system is composed by the subunits p50 and p65, which in physiological conditions are maintained in their inactive form in the cytoplasm due to binding to the inhibitory protein IKB. Under stimulation, IKB is degraded, releasing the p50/p65 heterodimer, which penetrates into the cell nucleus to bind to DNA and act as a transcription factor, promoting the synthesis of a bunch of pro-inflammatory proteins, including the immature interleukins pro-IL1β and pro-IL18 and the active IL-6, VCAM, PAI-1, MCP-1 and IFNγ. It is of note that the NFΚB system is not exclusively activated by TLRs signaling, but also by oxidative stress, Ang II and other proinflammatory mediators. On the other hand, the identification of intracellular DAMPs by a NLR, such as the NLRP3 for instance, promote the assembly of a molecular complex known as NLRP3 inflammasome, that also promotes NFΚB system activation, as well as the conversion of the inactive pro-caspase 1 into the pro-inflammatory Caspase 1 (CASP1), promoting IL1β and IL18 maturation, thus amplifying the inflammatory response.

## **7. Adaptive immune response**

As previously mentioned, in the presence of an infection the microorganisms, which were not eliminated by the innate immune response, are drained together with remaining phagocytes through the lymphatic vessels to the nearest lymph node, where a most specific and long lasting reaction begins: the adaptive immune response. It is important to emphasize that macrophages, dendritic cells, and other innate phagocytes represent the link between the nonspecific and the specific immune response. These leukocytes are designated as antigen presenting cells (APCs), since they have the ability of presenting foreign molecules to the lymphocytes in the lymph nodes, thereby activating and stimulating these specific cells. Lymphocytes are mononuclear leukocytes involved with the specific immune response. They originate from a lymphoid progenitor cell in the bone marrow, and may undergo differentiation in the bone marrow itself, been called B-lymphocytes or simply B-cells, or in the thymus, called T-lymphocytes or T-cells [54, 55]. Once the APCs phagocyte an invading microorganisms, they digest their proteins (antigen processing) and migrate to the lymph nodes, where they expose small peptide portions of the invader in the surface of their cellular membrane, associated with their molecules of the major histocompatibility complex of class II (MHC II). Both types of lymphocytes are able to recognize processed antigens associated with molecules of the MHC II of APCs through their membrane receptors (TCR of T-lymphocytes or BCR of B-lymphocytes). Unstimulated B or T lymphocytes, also called "naive" cells are generally small and present scarce cytoplasm. However, once stimulated, they became "effector lymphocytes," increase in size, have the cytoplasm hypertrophied and suffer mitosis, promoting clonal amplification, thus increasing the number of cells that would be sensitive to that specific activating antigen [32, 54].

In an extremely simplified view, when an antigen is recognized by the TCR of a naive T-cell, this leukocyte is activated, initiating the cellular adaptive response. First of all, the effector t-cell give rise to two different cell types through cell division: the T-Helper lymphocyte, that have the CD4 glycoprotein on the surface of their cell membrane (CD4+ T-cell), and the Cytotoxic T lymphocyte, characterized by the presence of CD8 in its membrane (CD8+ T-cell). Both CD4+ and CD8+ T-cell will be sensitive to the same antigen that promoted the activation of the T-Helper cells migrate to the inflamed area and, according to the type of stimulus they receive, these cells differentiate into one of the five known phenotypes: Th1, Th2, Th17, Tfh, and Treg [55]. Most of these subtypes of T-cells produce pro-inflammatory cytokines that acts especially upon macrophages, attracting them close to the target antigen, giving them increased membrane mobility and increasing their phagocytic and microbicidal potential. Only the Treg phenotype is described to release anti-inflammatory mediators, thus contributing to immunotolerance.

Cytotoxic T lymphocytes, in turn, can directly lysate bacteria, virus-infected cells, as well as self-cells that have suffered genetic mutation. Once the cytotoxic T-lymphocyte gets in touch with the target microorganism or antigen, a series of granzymes, perforins, and other cytotoxic molecules are released from within their cytoplasmic granules directly into the extracellular medium. Perforins are molecules that promote the formation of pores in the plasma membrane of target cells, causing abrupt entry of liquid, due to osmotic pressure, into the cytoplasm of these cells, leading to its apoptosis. Furthermore, both T-Helper and Cytotoxic lymphocytes give rise to memory CD4+ and CD8+ cells, respectively. This process is illustrated in **Figure 6**. Unlike the other populations of T-lymphocytes, memory T-cells may be inactive for years in the bloodstream, generating copies of themselves; thus, maintaining the memory of the recognition of the antigen that caused the activation of its precursor. Such cells are readily activated in the presence of a reinfection, being extremely important to defend our body from recurrent infections.

**7. Adaptive immune response**

promoting IL1β and IL18 maturation, thus amplifying the inflammatory response.

168 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

As previously mentioned, in the presence of an infection the microorganisms, which were not eliminated by the innate immune response, are drained together with remaining phagocytes

**Figure 5.** Some intracellular mechanisms of sterile innate immune reaction. Many different sterile stimuli can be identified as DAMPs by epithelial, endothelial, mesangial cells and also by renal resident leukocytes. Once a DAMP is recognized by a TLR, for instance, it leads to the activation of NFΚB system, one of the most important intracellular pro-inflammatory pathways. The NFΚB system is composed by the subunits p50 and p65, which in physiological conditions are maintained in their inactive form in the cytoplasm due to binding to the inhibitory protein IKB. Under stimulation, IKB is degraded, releasing the p50/p65 heterodimer, which penetrates into the cell nucleus to bind to DNA and act as a transcription factor, promoting the synthesis of a bunch of pro-inflammatory proteins, including the immature interleukins pro-IL1β and pro-IL18 and the active IL-6, VCAM, PAI-1, MCP-1 and IFNγ. It is of note that the NFΚB system is not exclusively activated by TLRs signaling, but also by oxidative stress, Ang II and other proinflammatory mediators. On the other hand, the identification of intracellular DAMPs by a NLR, such as the NLRP3 for instance, promote the assembly of a molecular complex known as NLRP3 inflammasome, that also promotes NFΚB system activation, as well as the conversion of the inactive pro-caspase 1 into the pro-inflammatory Caspase 1 (CASP1),

#### 170 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

often correlates positively with worsening of renal function loss. T-lymphocytes are commonly seen in the kidneys of rats submitted to NX, streptozotocin-induced (ST) DN, chronic nitric oxide inhibition, among others. Accordingly, the treatment of these animals with mycophenolate mofetil (MMF), a lymphocytic inhibitor, was shown to reduce albuminuria, hypertension, glomerular, and interstitial damage. Although the exact mechanisms by which adaptive response is triggered in such "sterile" conditions are presently unclear, some hypotheses have gained strength with the

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

171

One of these hypotheses points to Ang II as a pivotal element to stimulate the activation of specific cellular immunity in nonimmune-mediated nephropathies. The role of Ang II in the activation of adaptive immunocompetent cells *in vivo* is increasingly recognized by the beneficial effects of ARBs and ACE is in several models of immune-mediated diseases and even as an adjuvant in avoiding allograft rejection after kidney transplantation. It was widely demonstrated that experimental venal infusion of Ang II in rodents induces T lymphocyte migration to specific target organs, such as the kidneys and the spleen. Moreover, these infiltrating lymphocytes assume mainly Th1 and Th17 pro-inflammatory phenotypes, increasing the release of IFN-γ and decreasing IL4 concentration in these organs, thus participating in the mechanism that drives to inflammation and hypertension. Accordingly, *in vitro* studies showed Ang II to act as an "antigen" upon cultured mouse spleen lymphocytes, promoting their activation and further clonal proliferation. T-cells have been shown to be also activated in the murine model of DOCA-salt hypertension, supposedly a nonimmune-mediated condition, in which Ang II plays an important role. In this model, pharmacological inhibition of the T-lymphocyte CD28 receptor and of its co-stimulatory protein CD80 prevented the development of hypertension and consequent renal injury. Corroborating these findings, further studies showed that *Cd80* KO mice are renoprotected when submitted to the Ang II-induced hypertension model [35, 52]. Curiously, Ang II was shown to be released by activated T cells during the blood-stage of plasmodium infection in an experimental model of malaria. Once T-cells are described to have the complete intracellular machinery to synthesize all RAAS components, including transmembrane AT1 receptors, Ang II produced by the infected cells may promote the recruitment and activation of further naive lymphocytes. According to this study, Ang II binding to the AT1 receptors of cultured T-cells leads to: upregulation of CD69 and CD25, increased cellular adhesion, and migration due to overexpression of CCR2 and CCR5 chemokine receptors and LFA-1 adhesion molecule, as well as T-cell differentiation, observed by the increased production of IL17 and IFN-γ and by the presence of cell perforins. However, the reasons why intracellular RAAS seems to be overactivated in T-cells exposed to inflammation, remains unknown.

Besides Ang II, advanced glycation end products (AGEs), represent another possible sterile "antigen" which may activate adaptive immunity in nonimmune-mediated CKD. AGEs are proteins or lipids that become glycated as a result of exposure to high glucose levels. Under some pathologic conditions, such as DM, sustained hyperglycemia and ROS production lead to increased AGE formation. Excessive AGE production is involved with the development and worsening of many degenerative diseases; including DN. Human AGE receptor (RAGE) is a multiligand cell surface MPRR that also binds Hmgb1, S100, and other DAMPs. Highly expressed in macrophages, T-, and B lymphocytes, RAGE contributes to inflammatory mechanisms, including the differentiation of Th0 in Th1 cells. RAGE-mediated leukocyte

development of experimental studies over the last decades [28, 29, 35, 52].

**Figure 6.** Presentation of antigens to lymphocytes and the onset of adaptive immune response. Mechanisms that link innate and adaptive immunity and the onset of the activation of lymphocytes.

On the other hand, when a foreign antigen is recognized by the BCR of a naive B cell, the humoral branch of adaptive immune response sets in motion. Activated B lymphocytes, or plasmocytes, synthesize specific antibodies against the invading microorganism. The antibodies produced by plasma cells may remain adhered to the cellular membrane of B-cells, promoting the binding of the cell as a whole to the parasite antigen, or be released to the bloodstream. In both cases, binding of the specific antibody to the antigen of invading microorganism promotes opsonization of its phagocytosis by neutrophils, macrophages, monocytes, and dendritic cells, besides promoting the neutralization of microbial toxins. Activated B-cells also produce memory B-cells, important to generate an accelerated and more robust antibody-mediated immune response in the case of re-infection by the same antigen [54].

## **8. Adaptive immune response in nonimmune-mediated CKD**

Similar to the innate arm of immune response, adaptive immunity seems to be activated in both human and experimental CKD, even when the initial renal injury is not caused by infection or by any autoimmune condition. Moreover, the recruitment of lymphocytes to the renal parenchyma often correlates positively with worsening of renal function loss. T-lymphocytes are commonly seen in the kidneys of rats submitted to NX, streptozotocin-induced (ST) DN, chronic nitric oxide inhibition, among others. Accordingly, the treatment of these animals with mycophenolate mofetil (MMF), a lymphocytic inhibitor, was shown to reduce albuminuria, hypertension, glomerular, and interstitial damage. Although the exact mechanisms by which adaptive response is triggered in such "sterile" conditions are presently unclear, some hypotheses have gained strength with the development of experimental studies over the last decades [28, 29, 35, 52].

One of these hypotheses points to Ang II as a pivotal element to stimulate the activation of specific cellular immunity in nonimmune-mediated nephropathies. The role of Ang II in the activation of adaptive immunocompetent cells *in vivo* is increasingly recognized by the beneficial effects of ARBs and ACE is in several models of immune-mediated diseases and even as an adjuvant in avoiding allograft rejection after kidney transplantation. It was widely demonstrated that experimental venal infusion of Ang II in rodents induces T lymphocyte migration to specific target organs, such as the kidneys and the spleen. Moreover, these infiltrating lymphocytes assume mainly Th1 and Th17 pro-inflammatory phenotypes, increasing the release of IFN-γ and decreasing IL4 concentration in these organs, thus participating in the mechanism that drives to inflammation and hypertension. Accordingly, *in vitro* studies showed Ang II to act as an "antigen" upon cultured mouse spleen lymphocytes, promoting their activation and further clonal proliferation. T-cells have been shown to be also activated in the murine model of DOCA-salt hypertension, supposedly a nonimmune-mediated condition, in which Ang II plays an important role. In this model, pharmacological inhibition of the T-lymphocyte CD28 receptor and of its co-stimulatory protein CD80 prevented the development of hypertension and consequent renal injury. Corroborating these findings, further studies showed that *Cd80* KO mice are renoprotected when submitted to the Ang II-induced hypertension model [35, 52].

Curiously, Ang II was shown to be released by activated T cells during the blood-stage of plasmodium infection in an experimental model of malaria. Once T-cells are described to have the complete intracellular machinery to synthesize all RAAS components, including transmembrane AT1 receptors, Ang II produced by the infected cells may promote the recruitment and activation of further naive lymphocytes. According to this study, Ang II binding to the AT1 receptors of cultured T-cells leads to: upregulation of CD69 and CD25, increased cellular adhesion, and migration due to overexpression of CCR2 and CCR5 chemokine receptors and LFA-1 adhesion molecule, as well as T-cell differentiation, observed by the increased production of IL17 and IFN-γ and by the presence of cell perforins. However, the reasons why intracellular RAAS seems to be overactivated in T-cells exposed to inflammation, remains unknown.

On the other hand, when a foreign antigen is recognized by the BCR of a naive B cell, the humoral branch of adaptive immune response sets in motion. Activated B lymphocytes, or plasmocytes, synthesize specific antibodies against the invading microorganism. The antibodies produced by plasma cells may remain adhered to the cellular membrane of B-cells, promoting the binding of the cell as a whole to the parasite antigen, or be released to the bloodstream. In both cases, binding of the specific antibody to the antigen of invading microorganism promotes opsonization of its phagocytosis by neutrophils, macrophages, monocytes, and dendritic cells, besides promoting the neutralization of microbial toxins. Activated B-cells also produce memory B-cells, important to generate an accelerated and more robust antibody-mediated immune response in the case of re-infection by the same antigen [54].

**Figure 6.** Presentation of antigens to lymphocytes and the onset of adaptive immune response. Mechanisms that link

innate and adaptive immunity and the onset of the activation of lymphocytes.

170 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

Similar to the innate arm of immune response, adaptive immunity seems to be activated in both human and experimental CKD, even when the initial renal injury is not caused by infection or by any autoimmune condition. Moreover, the recruitment of lymphocytes to the renal parenchyma

**8. Adaptive immune response in nonimmune-mediated CKD**

Besides Ang II, advanced glycation end products (AGEs), represent another possible sterile "antigen" which may activate adaptive immunity in nonimmune-mediated CKD. AGEs are proteins or lipids that become glycated as a result of exposure to high glucose levels. Under some pathologic conditions, such as DM, sustained hyperglycemia and ROS production lead to increased AGE formation. Excessive AGE production is involved with the development and worsening of many degenerative diseases; including DN. Human AGE receptor (RAGE) is a multiligand cell surface MPRR that also binds Hmgb1, S100, and other DAMPs. Highly expressed in macrophages, T-, and B lymphocytes, RAGE contributes to inflammatory mechanisms, including the differentiation of Th0 in Th1 cells. RAGE-mediated leukocyte recruitment is particularly important in conditions associated with higher RAGE expression, such as DM. In these cases, when overexpressed in the surface of endothelial cells, RAGE directly mediate leukocyte recruitment, acting as a cell adhesive receptor. Moreover, AGE binding to RAGE result in overexpression of cytokines and pro-inflammatory molecules.

are able to trigger adaptive immune response in the same way PAMPs would be. However, further studies are required for the complete elucidation of the mechanisms involved in this

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

173

Sterile inflammation exerts a key pathogenic role to the development and evolution of CKD. Although all the mechanisms involved in the activation of immune response in nonimmune-mediated kidney conditions are not yet fully elucidated, some of the main assumptions for this phenomenon were discussed here. Based on our review of the literature and on the proposed integrative schemes, we can conclude that both innate and adaptive arms of immunity can be activated in CKD, with no pathological stimulus needed. Moreover, chronic inflammation contributes to CKD worsening and progression, leading to GS and renal fibrosis. The use of anti-inflammatory drugs, chemical blockers of innate immunity and antilymphocyte drugs have been shown to be partially effective to decelerate the chronic inflammatory process that accompanies nephropathy in experimental models of CKD (**Table 2**). However, to date, blockade of systemic and intrarenal RAAS by ACEis and/or ARBs remains

and Ane Nunes3

2 College of Pharmacy, University of Sharjah (UOS), Sharjah, United Arab Emirates

[1] El Nahas M. The global challenge of chronic kidney disease. Kidney International.

[2] Anderson S, et al. Mechanisms of injury in progressive renal disease. Experimental

[3] National Kidney Foundation. A to Z Health Guide About Chronic Kidney Disease [Internet]. 2017. Available from: https://www.kidney.org/atoz/content/about-chronic-

3 School of Medicine, University of California Irvine (UCI), Irvine, United States

\*

the most effective treatment for delaying renal function loss.

, Ayman Noreddin2

\*Address all correspondence to: nunes.acf@gmail.com

1 Faculty of Medicine, University of São Paulo (USP), São Paulo, Brazil

process.

**9. Conclusion**

**Author details**

Camilla Fanelli1

**References**

2005;**68**(6):2918-2929

Nephrology Supplement. 1996;**1**:34-40

kidney-disease#ckd [Accessed: 15 February 2017]

As illustrated in **Figure 7**, it is finally possible that the sterile DAMPs, which were, recognized by the innate MPRR of APCs, processed as antigens and presented to naive t-cells

**Figure 7.** Some mechanisms of adaptive T-cell sterile activation. Through the binding of processed antigens to the T-lymphocyte receptors TCR, CD4, CD8 and CD28, an intracellular mechanism is set in motion, leading to the activation of NFKB system, with further production of immature interleukins pro-IL1β and pro-IL18 among other mediators. Such sterile antigens particles are believed to be originated from phagocyted DAMPs, recognized by the innate immune APCs, as previously described. Ang II also exerts a pivotal role in the activation of T cells. Although the mechanism that leads activated T cells to overproduce intracellular RAAS components remains unclear, it is well known that, in addition to enhance Ang II production, when subjected to inflammatory stimuli, T cells also expose more AT1 receptors, making themselves more responsive to Ang II produced by other leukocytes or by the cells of injured tissue. Through the binding of Ang II to its AT1 receptor, T-cells become more active, thus expressing a greater number of CCR2 and CCR5 chemokine receptors. Finally, T-lymphocytes have constitutively high expression of the advanced glycation end products receptor (RAGE). Once it binds to its specific ligand (AGE), or to other DAMPs, such as Hmgb1 or S100 proteins, it starts the conversion of Th0 lymphocyte toward the pro-inflammatory Th1 phenotype, which in turn, produces some of the most potent pro-inflammatory mediators that will further increase M1 macrophage population.

are able to trigger adaptive immune response in the same way PAMPs would be. However, further studies are required for the complete elucidation of the mechanisms involved in this process.

## **9. Conclusion**

Sterile inflammation exerts a key pathogenic role to the development and evolution of CKD. Although all the mechanisms involved in the activation of immune response in nonimmune-mediated kidney conditions are not yet fully elucidated, some of the main assumptions for this phenomenon were discussed here. Based on our review of the literature and on the proposed integrative schemes, we can conclude that both innate and adaptive arms of immunity can be activated in CKD, with no pathological stimulus needed. Moreover, chronic inflammation contributes to CKD worsening and progression, leading to GS and renal fibrosis. The use of anti-inflammatory drugs, chemical blockers of innate immunity and antilymphocyte drugs have been shown to be partially effective to decelerate the chronic inflammatory process that accompanies nephropathy in experimental models of CKD (**Table 2**). However, to date, blockade of systemic and intrarenal RAAS by ACEis and/or ARBs remains the most effective treatment for delaying renal function loss.

## **Author details**

Camilla Fanelli1 , Ayman Noreddin2 and Ane Nunes3 \*

\*Address all correspondence to: nunes.acf@gmail.com


## **References**

**Figure 7.** Some mechanisms of adaptive T-cell sterile activation. Through the binding of processed antigens to the T-lymphocyte receptors TCR, CD4, CD8 and CD28, an intracellular mechanism is set in motion, leading to the activation of NFKB system, with further production of immature interleukins pro-IL1β and pro-IL18 among other mediators. Such sterile antigens particles are believed to be originated from phagocyted DAMPs, recognized by the innate immune APCs, as previously described. Ang II also exerts a pivotal role in the activation of T cells. Although the mechanism that leads activated T cells to overproduce intracellular RAAS components remains unclear, it is well known that, in addition to enhance Ang II production, when subjected to inflammatory stimuli, T cells also expose more AT1 receptors, making themselves more responsive to Ang II produced by other leukocytes or by the cells of injured tissue. Through the binding of Ang II to its AT1 receptor, T-cells become more active, thus expressing a greater number of CCR2 and CCR5 chemokine receptors. Finally, T-lymphocytes have constitutively high expression of the advanced glycation end products receptor (RAGE). Once it binds to its specific ligand (AGE), or to other DAMPs, such as Hmgb1 or S100 proteins, it starts the conversion of Th0 lymphocyte toward the pro-inflammatory Th1 phenotype, which in turn, produces some of the most

recruitment is particularly important in conditions associated with higher RAGE expression, such as DM. In these cases, when overexpressed in the surface of endothelial cells, RAGE directly mediate leukocyte recruitment, acting as a cell adhesive receptor. Moreover, AGE binding to RAGE result in overexpression of cytokines and pro-inflammatory molecules.

172 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

As illustrated in **Figure 7**, it is finally possible that the sterile DAMPs, which were, recognized by the innate MPRR of APCs, processed as antigens and presented to naive t-cells

potent pro-inflammatory mediators that will further increase M1 macrophage population.


[4] Saran R, et al. US renal data system 2016 annual data report: Epidemiology of kidney disease in the United States. American Journal of Kidney Diseases. 2017;**69**(3S1):A7-A8

[20] Wolf G, et al. Angiotensin II and cell cycle regulation. Hypertension. 2004;**43**:693-698

angiotensin II. Kidney International. Supplement. 1997;**63**:S221-S225

kidney disease. American Journal of Nephrology. 2010;**31**:541-550

humans. Nephron. Experimental Nephrology. 2014;**126**:91-96

diabetic nephropathy. PloS One. 2016;**11**(10):e0164135

American Society of Nephrology. 2000;**11**(2):283-290

nephropathy. PloS One. 2013;**8**(2):e56215

Research. 2007;**30**(7):635-642

2003;**63**(1):209-216

2001;**37**(1):170-175

[21] LL W, et al. Macrophage and myofibroblast proliferation in remnant kidney: Role of

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

175

[22] Siragy HM, et al. Role of the intrarenal renin-angiotensin-aldosterone system in chronic

[23] Gagliardini E, et al. Drugs to Foster kidney regeneration in experimental animals and

[24] Arias SC, et al. Regression of albuminuria and hypertension and arrest of severe renal injury by a losartan-hydrochlorothiazide association in a model of very advanced

[25] Schwartz D, DeSchryver-Kecskemeti K, Needleman P. Renal arachidonic acid metabolism and cellular changes in the rabbit renal vein constricted kidney: Inflammation as a

[26] Yuan F, Kolb R, Pandey G, Li W, et al. Involvement of the NLRC4-inflammasome in

[27] Imakiire T, Kikuchi Y, Yamada M, et al. Effects of renin-angiotensin system blockade on macrophage infiltration in patients with hypertensive nephrosclerosis. Hypertension

[28] Utimura R, Fujihara CK, Mattar AL, et al. Mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes. Kidney International.

[29] Fujihara CK, Malheiros DMAC, Noronha IL, et al. Mycophenolate mofetil reduces renal injury in the chronic nitric oxide synthase inhibition model. Hypertension.

[30] Fujihara CK, Noronha IL, Malheiros DMAC, et al. Combined mycophenolate mofetil and losartan therapy arrests established injury in the remnant kidney. Journal of the

[31] Hochheiser K, Tittel A, Kurts C. Kidney dendritic cells in acute and chronic renal dis-

[32] Kurts C, Panzer U, Anders HJ, et al. The immune system and kidney disease: Basic concepts and clinical implications. Nature Reviews Immunology. 2013;**13**:738-753

[33] Seo JW, Kim YG, Lee SH, et al. Mycophenolate mofetil ameliorates diabetic nephropathy

[34] Mensah-Brown EPK, Obineche EN, Galadari S, et al. Streptozotocin-induced diabetic nephropathy in rats: The role of inflammatory cytokines. Cytokine. 2005;**31**:180-190 [35] Fujihara CK, Malheiros DMAC, Zatz R, et al. Mycophenolate mofetil attenuates renal

injury in the rat remnant kidney. Kidney International. 1998;**54**:1510-1519

ease. International Journal of Experimental Pathology. 2011;**92**:193-201

in db/db mice. BioMed Research International 2015;**2015**:301627.

common process in renal injury models. Prostaglandins. 1984;**27**(4):605-613


[20] Wolf G, et al. Angiotensin II and cell cycle regulation. Hypertension. 2004;**43**:693-698

[4] Saran R, et al. US renal data system 2016 annual data report: Epidemiology of kidney disease in the United States. American Journal of Kidney Diseases. 2017;**69**(3S1):A7-A8

[5] United States Renal Data System, USRDS. 2016 Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health,

[6] Mayo Foundation for Medical Education and Research (MFMER). Chronic Kidney Disease [Internet]. 2017. Available from: http://www.mayoclinic.org/diseases-condi-

[7] Couser WG, et al. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney International. 2011;**80**(12):1258-1270

[8] Schieppati A, et al. Chronic renal disease as a public health problem: Epidemiology,

[9] White SL, et al. How can we achieve global equity in provision of renal replacement

[11] Thakar CV, et al. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clinical Journal of the American Society of Nephrology. 2011;**6**:2567-2572

[12] Floege J. Primary glomerulonephritis: A review of important recent discoveries. Kidney

[13] Chapman AB, et al. Autosomal-dominant polycystic kidney disease (ADPKD): Executive summary from a kidney disease: Improving global outcomes (KDIGO) controversies

[14] Noronha IL, et al. The inflammatory component in progressive renal disease—Are interventions possible? Nephrology, Dialysis, Transplantation. 2002;**17**(3):363-368

[15] Zeisberg M, et al. Mechanisms of tubulointerstitial fibrosis. Journal of the American

[16] Rüster C, et al. Renin-angiotensin-aldosterone system and progression of renal disease.

[17] Machado FG, et al. AT1 blockade during lactation as a model of chronic nephropathy: Mechanisms of renal injury. American Journal of Physiology. Renal Physiology.

[18] Graciano ML, et al. Intrarenal renin-angiotensin system is upregulated in experimental model of progressive renal disease induced by chronic inhibition of nitric oxide synthe-

[19] Fanelli C, et al. Effects of losartan, in monotherapy or in association with hydrochlorothiazide, in chronic nephropathy resulting from losartan treatment during lactation.

Journal of the American Society of Nephrology. 2006;**17**:2985-2991

sis. Journal of the American Society of Nephrology. 2004;**15**:1805-1815

American Journal of Physiology. Renal Physiology. 2011;**301**:F580-F587

tions/chronic-kidney-disease/home/ovc-20207456 [Accessed: 10 February 2017]

social, and economic implications. Kidney International. 2005;**68**(Suppl):7-10

therapy? Bulletin of the World Health Organization. 2008;**86**(3):229-237

[10] Zatz R. Bases Fisiológicas da Nefrologia. Atheneu; 2012. 394 p

Research and Clinical Practice. 2013;**32**:103-110

174 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

conference. Kidney International. 2015;**88**(1):17-27

Society of Nephrology. 2010;**21**:1819-1834

2008;**294**:F1345-F1353

National Institute of Diabetes and Digestive and Kidney Diseases; 2016


[36] Gong W, et al. NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy. American Journal of Physiology. Renal Physiology. 2016;**310**:F1081-F1088

[51] Shihab FS, et al. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity.

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

http://dx.doi.org/10.5772/intechopen.70611

177

[52] Romero F, et al. Mycophenolate mofetil prevents the progressive renal failure induced

[53] Imig JD, Ryan MJ. Immune and inflammatory role in renal disease. Comprehensive

[54] Abbas AK, Lichtman AHH, Pillai S. Cellular and Molecular Immunology. 7th ed.

[55] Murphy KM. Janeway's Immunobiology. Revised ed. Taylor & Francis Group; 2011. 888p [56] Christiansen OB. Reproductive immunology. Molecular Immunology. 2013;**55**(1):8-16

[57] Round JL, O'Connell RM, Mazmanian SK. Coordination of tolerogenic immune responses by the commensal microbiota. Journal of Autoimmunity. 2010;**34**(3):J220-J225

[58] Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: From immuno-surveillance

[59] Swann JB, Smyth MK. Immune surveillance of tumors. The Journal of Clinical Inves-

[60] Bower JM, Eto DS, Mulvey MA. Covert operations of uropathogenic *Escherichia coli*

[61] Reid G, Younes JA, Van der Meiet HC, et al. Microbiota restoration: Natural and supplemented recovery of human microbial communities. Nature Reviews. Microbiology.

by 5/6 renal ablation in rats. Kidney International. 1999;**55**(3):945-955

American Journal of Transplantation. 2002;**2**(2):111-119

to tumor escape. Nature Immunology. 2002;**3**(11):991-998

within the urinary tract. Traffic. 2005;**6**(1):18-31

Physiology. 2013;**3**(2):957-976

tigation. 2007;**117**(5):1137-1146

2011;**9**:27-38

Elsevier Health Sciences; 2012. 560p


[51] Shihab FS, et al. Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity. American Journal of Transplantation. 2002;**2**(2):111-119

[36] Gong W, et al. NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy. American Journal of Physiology.

[37] Souza ACP, et al. TLR4 mutant mice are protected from renal fibrosis and chronic kid-

[38] D'Apolito M, et al. Urea-induced ROS cause endothelial dysfunction in chronic renal

[39] Lehners A, et al. Myeloperoxidase deficiency ameliorates progression of chronic kidney disease in mice. American Journal of Physiology. Renal Physiology. 2014;**307**(4):F407-F417

[40] Correa-Costa M, et al. Pivotal role of toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis. PloS

[41] Vilaysane A, et al. The NLRP3 inflammasome promotes renal inflammation and contributes to CKD. Journal of the American Society of Nephrology. 2010;**21**:1732-1744

[42] Rodríguez-Iturbe B, et al. Evolution of renal interstitial inflammation and NF-kappaB activation in spontaneously hypertensive rats. American Journal of Nephrology. 2004;

[43] Donadelli R, et al. Protein traffic activates NF-kB gene signaling and promotes MCP-1 dependent interstitial inflammation. American Journal of Kidney Diseases. 2000;**36**(6):

[44] Ludwig Portugall I, et al. An NLRP3-specific inflammasome inhibitor attenuates crystal-

[45] Okabe C, et al. NF-kB activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy. American Journal of Physiology. Renal

[46] Kim JE, et al. Celastrol, an NF-kB inhibitor, improves insulin resistance and attenuates

[47] Gilbert RE, et al. A purpose-synthesised anti-fibrotic agent attenuates experimental kid-

[48] Ding W, et al. Chronic inhibition of nuclear factor kappa B attenuates aldosterone/salt-

[49] Kaneyama T, et al. Tranilast modulates fibrosis, epithelial-mesenchymal transition and peritubular capillary injury in unilateral ureteral obstruction rats. Pathology. 2010;**42**(6):

[50] Fujihara CK, et al. Chronic inhibition of nuclear factor-kappaB attenuates renal injury in the 5/6 renal ablation model. American Journal of Physiology. Renal Physiology.

induced kidney fibrosis in mice. Kidney International. 2016;**90**:525-539

Renal Physiology. 2016;**310**:F1081-F1088

176 Chronic Kidney Disease - from Pathophysiology to Clinical Improvements

failure. Atherosclerosis. 2015;**239**(2):393-400

One. 2011;**6**(12):e29004

Physiology. 2012;**305**(2):F155-F163

renal injury in db/db mice. PloS One. 2013;**8**(4):e62068

ney diseases in the rat. PloS One. 2012;**7**(10):e47160

induced renal injury. Life Sciences. 2012;**90**(15-16):600-606

**24**(6):587-594

1226-1241

564-573

2007;**292**(1):F92-F99

ney disease progression. Physiological Reports. 2015;**3**(9)


**Section 3**

**Nutrition in CKD**

**Section 3**
