2. Risk factors for cardiovascular disease after kidney transplantation

Risk factors for the development cardiovascular diseases in patients with a transplanted kidney are more common than the risk factors in the general population.

They include traditional risk factors, such as arterial hypertension, diabetes mellitus, hyperlipidemia, and nontraditional risk factors associated with reduced glomerular filtration, such as anemia, hyperhomocysteinemia, or factors typical for transplantation, including direct effects of immunosuppression or rejection [5].

Patients with a transplanted kidney are exposed to atherogenic risk which is associated with previous dialysis treatment and the use of immunosuppressive drugs. An excessive risk of developing cardiovascular disease in patients with a transplanted kidney is due to the high frequency and accumulation of atherogenic risk factors before and after transplantation. Pretransplant cardiovascular disease is a major risk factor for the development of post-transplant cardiovascular disease [6].

Cardiovascular diseases represent the most frequent cause of morbidity and mortality in patients at the end stage of renal diseases. Left ventricle hypertrophy occurs in 75% of patients treated by chronic dialysis. The prevalence of coronary heart disease in patients who are treated by chronic hemodialysis is 40%. The frequency of congestive heart failure in patients undergoing hemodialysis is 46%. Cardiac diseases represent the leading cause of death of dialyzed patients of which sudden cardiac death is the most frequent that is responsible for around 25% of all deadly outcomes. The rate of cardiovascular mortality in patients undergoing chronic dialysis is nearly 9% per annum. In patients treated by chronic dialysis, the risk of development of CVD is 10–20 times higher than in general population. Uremic milieu contributes to occurrence of atherosclerosis and atherosclerotic cardiovascular complications and often the development of accelerated, galloping atherosclerosis is present. The patients undergoing chronic dialysis are exposed to traditional and nontraditional risk factors for the development of cardiovascular complications. Nontraditional risk factors are the consequences of the uremic milieu and are related with the dialysis technique itself, and they are divided into hemodynamic and metabolic risk factors. Hemodynamic risk factors are anemia, retention of sodium and water, arteriovenous (AV) fistula, while the metabolic risk factors are hyperhomocysteinemia, hypoalbuminemia, oxidative stress, microinflammation and secondary hyperparathyroidism.

Risk factors for cardiovascular diseases in patients with a transplanted kidney are divided into traditional and nontraditional [5]: traditional risk factors are: immutable (age, gender, and inheritance), variable (smoking, hyperlipidemia, hypertension, obesity, diabetes mellitus, physical activity, and stress); and nontraditional risk factors are: risk factors related to the status of transplantation and its treatment (immunosuppressive agents, graft rejection, and viral infection —cytomegalovirus) and risk factors associated with chronic regression in allograft function (anemia, volume load, hyperhomocysteinemia, oxidative stress, secondary hyperparathyroidism, and microinflammation).

#### 2.1. Traditional risk factors

side effects of immunosuppressants are the increased risk of infection and the atherogenic

The early period after kidney transplantation relates to the first 2 months after the surgery [3]. Acute surgical complications (bleeding, thrombosis of the transplanted kidney) are common in first few days after surgery, other clinical and immunological complications occur later.

Reactions of graft rejections are classified into four types based on the clinical picture, but differ in pathogenesis, histomorphological picture, and reactions own flow [4]. Those are hyperactivity, acceleration, acute and chronic rejection. Hyperacute rejection occurs in the first minutes or hours after kidney transplantation. Accelerating rejection begins 5–7 days after kidney transplantation and is demonstrated by rapid deterioration of the graft function. Acute rejection usually occurs from the fifth day to the end of the third month after kidney transplantation, but it can occur later on. Chronic graft rejection signifies the process in which transplanted kidney progressively deteriorates for several months and years, although the transplantation was successful in the first place. Other complications after kidney transplant are: urological complications, cardiovascular diseases, infections, gastrointestinal tract and

liver diseases, malignant tumors, skin, bone and muscle diseases [4].

kidney are more common than the risk factors in the general population.

2. Risk factors for cardiovascular disease after kidney transplantation

Risk factors for the development cardiovascular diseases in patients with a transplanted

They include traditional risk factors, such as arterial hypertension, diabetes mellitus, hyperlipidemia, and nontraditional risk factors associated with reduced glomerular filtration, such as anemia, hyperhomocysteinemia, or factors typical for transplantation, including direct effects

Patients with a transplanted kidney are exposed to atherogenic risk which is associated with previous dialysis treatment and the use of immunosuppressive drugs. An excessive risk of developing cardiovascular disease in patients with a transplanted kidney is due to the high frequency and accumulation of atherogenic risk factors before and after transplantation. Pretransplant cardiovascular disease is a major risk factor for the development of post-transplant

Cardiovascular diseases represent the most frequent cause of morbidity and mortality in patients at the end stage of renal diseases. Left ventricle hypertrophy occurs in 75% of patients treated by chronic dialysis. The prevalence of coronary heart disease in patients who are treated by chronic hemodialysis is 40%. The frequency of congestive heart failure in patients undergoing hemodialysis is 46%. Cardiac diseases represent the leading cause of death of dialyzed patients of which sudden cardiac death is the most frequent that is responsible for

effect of immunosuppressive therapy.

316 Organ Donation and Transplantation - Current Status and Future Challenges

1.7. Transplantation complications

of immunosuppression or rejection [5].

cardiovascular disease [6].

Smoking is not only a risk factor for the development of cardiovascular diseases, but is also associated with the risk of developing chronic kidney disease defined as a reduction in glomerular filtration to <45 ml/min/1.73 m2 . Long-term smoking of more than 20 cigarettes per day is associated with 1.52 times higher relative risk of chronic kidney disease [7]. For comparison, smoking and obesity are associated with a 1.77 times higher relative risk of chronic kidney disease. These risks are more conspicuous in men than in women. Smoking begins and improves the process of atherosclerosis in the blood vessels. In various studies, it has been shown that smoking leads to cardiovascular complications, reduces survival of the patient and graft, and its effect on patient survival is similar to the same one on patients with diabetes mellitus [8]. Smoking cigarette is an independent risk factor for the development of cardiovascular events in patients with a transplanted kidney. In the population of patients with transplanted kidney, the prevalence of smoking is 25%, and the smoking cessation includes pharmacological therapy—NRT (nicotine replacement therapy).

Risks of cardiovascular diseases increase with increasing body weight because it increases the blood pressure, serum lipids, and glucose intolerance. A particularly harmful factor is the central obesity characterized by an increase in intra-abdominal fat tissue. Central obesity (waistline >88 cm for women and >102 cm for men) is a risk factor for declining allograft function in patients with a transplanted kidney. Obesity fosters the development of the insulin resistance, diabetes mellitus, ischemic heart disease, and reduces survival of allograft [9].

A cohort study by Adabag of 14,941 men and women, aged 45–64 years, showed that obesity was associated with an increased risk of sudden cardiac death [10]. According to research by Chan, obesity is a risk factor for the development of cardiovascular disease following kidney transplantation [11]. Although the role of obesity in the pre-transplant period is uncertain, after kidney transplantation, obesity increases the risk of graft failure and mortality.

transplanted kidney. It is believed that corticosteroids aggravate hypertension through hemodynamic and hormonal disorders as well as retention of salt and water. The role of cyclosporin in the development of hypertension in the transplantation of the heart, liver and bone marrow, as well as in patients with uveitis and diabetes mellitus, has been demonstrated, while its role in kidney transplantation is controversial. On the one hand, cyclosporin can cause hypertension with its nephrotoxic effect, and on the other hand, if cyclosporin prevents chronic rejection, it may delay the occurrence of hypertension. In two large retrospective studies with a follow-up period of 2 and 3 years, the prevalence of hypertension remained stable over time, but in the group of patients treated with ciclosporin, the prevalence of hypertension increased by 25% compared to patients treated with azathioprine [15]. Tacrolimus therapy causes hypertension, whose mechanism is probably similar to cyclosporin-induced hypertension. It is a general opinion that the main cause of hypertension after renal transplantation is chronic graft dysfunction or chronic graft nephropathy. Hypertension is often the first clinical sign of chronic rejection. It is known that arterial hypertension is a risk factor for cardiovascular disease in the general population. In a retrospective analysis, Ponticelli and associates have found a higher number of cardiac infarcts after kidney transplantation in patients with hypertension than in normotensive patients [16]. Arterial hypertension correlates with cardiovascular disease after transplantation [17]. In most cases for treatment post-transplant hypertension, routine antihypertensive treatment is effective. We can use ACE inhibitors, beta blockers and

Cardiovascular Diseases in Patients with Renal Transplantation

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Hyperlipidemia is known as the traditional risk factor for the development of cardiovascular diseases, both in the general population and in the population of patients with terminal stage of renal failure. Several observational studies have shown that total cholesterol and low-density lipoproteins (LDL) are one of the most important independent factors of cardiovascular morbidity and mortality [18]. Patients with renal function impairment have significant changes in the metabolism of lipoproteins, whose exact role in the pathogenesis of atherosclerosis in these patients is still controversial [19]. Hyperlipidemia can occur already after 3 months of transplantation and does not resolve spontaneously, and in most patients, it can persist for a very long, even 10 or more years after kidney transplantation [20]. Patients with a transplanted kidney usually have an increased total cholesterol, LDL cholesterol and triglycerides, while HDL cholesterol is usually normal or even high, although its composition may be pathological [21]. Immunosuppressive drugs such as corticosteroids, cyclosporin, tacrolimus and, in particular, sirolimus contribute to the development of post-transplant hyperlipidemia, usually depending on the dose of medicine [22]. Many epidemiological studies of patients with a transplanted kidney showed a correlation between elevated total cholesterol, triglyceride, LDL and incidence of cardiovascular diseases, the same as a low level of HDL is associated with an increase in cardiovascular risk [23]. Hyperlipidemia in patients with a transplanted kidney may affect the progression of chronic graft nephropathy. Based on data about the prevention of cardiovascular disease, it is known that the reduction of LDL-cholesterol by 1 mmol/l over 4–5 years reduces the risk of coronary and cerebrovascular incidents by 25%. Extrapolation from general population studies and some data in kidney transplant patients support the view that the assessment and treatment of dyslipidemias should be part of routine post-renal trans-

plant care. For treating hyperlipidemia in kidney transplant patient, we use statins.

calcium channel blockers.

Weight loss reduces and changes other risk factors for the development of cardiovascular disease [12]. Metabolic syndrome is a risk factor for the development of cardiovascular disease in patients with a transplanted kidney. It is characterized by obesity (central type of obesity), physical inactivity, hypertension (arterial blood pressure greater than 130/80 mmHg), hyperlipidaemia (triglycerides greater than 1.7 mmol/l, HDL cholesterol less than 1.0 mmol/l in men and less than 1.3 mmol/l in women) and systemic insulin resistance (fasting blood sugar greater than 6.5 mmol/l). Six years after kidney transplantation, 63% of patients have criteria for metabolic syndrome, reduced survival of allograft and an increased number of cardiovascular incidents [9].

Diabetes mellitus is one of the most common causes of renal disease, this disease independent and in itself increases the risk of cardiovascular disease. The results of two large clinical studies, Framingham Study and Multiple Risk Factor Intervention Trial (MRFIT) show that diabetes mellitus doubles the possibility of coronary artery disease in men and triples the risk of coronary artery disease in women [13]. Diabetes mellitus is a relatively common complication after kidney transplantation and is defined as a fasting glucose greater than 7 mmol/l. The incidence of diabetes mellitus is between 3.6 and 18% and depends mainly on immunosuppressive therapy. Kidney transplantation can lead to the deterioration of existing diabetes mellitus or to the development of "de novo" diabetes mellitus. The most common cause of posttransplantation diabetes mellitus is corticosteroid therapy, and it depends on immunosuppressive therapy. The two main mechanisms by which corticosteroids cause diabetes mellitus are inducing insulin resistance and increasing body weight [14]. Immunosuppressive drugs can lead to the development of diabetes. The prevalence of post-transplant diabetes in patients treated with cyclosporin ranges from 2.5 to 20%. The treatment of diabetes in hospitalized transplant recipients requires attention to a multitude of factors that can impact glycemic control and influence the risk for adverse effects. Methods to manage hyperglycemia vary among transplant centers and also vary according to whether the patient is immediately posttransplant or is being admitted in the post-transplant setting for another issue. Immediately after transplantation in post-transplant we use frequently require IV insulin infusion protocol. Once iv requirements are established and stable, switch to insulin every 8 h plus fast-acting correction insulin every 4–6 h.

The prevalence of post-transplant hypertension is between 60 and 85%. Causes of hypertension in patients with a transplanted kidney are as follows: stenosis of graft renal artery, presence of native kidneys, immunosuppressive therapy, graft dysfunction, genetic predisposition of donors and recipients. Native kidneys and pre-transplant hypertension have been described as independent factors associated with post-transplant hypertension. Native kidney of recipient can cause systemic hypertension through the renin-angiotensin system. Immuno suppressive drugs are also responsible for the appearance of hypertension in patients with a transplanted kidney. It is believed that corticosteroids aggravate hypertension through hemodynamic and hormonal disorders as well as retention of salt and water. The role of cyclosporin in the development of hypertension in the transplantation of the heart, liver and bone marrow, as well as in patients with uveitis and diabetes mellitus, has been demonstrated, while its role in kidney transplantation is controversial. On the one hand, cyclosporin can cause hypertension with its nephrotoxic effect, and on the other hand, if cyclosporin prevents chronic rejection, it may delay the occurrence of hypertension. In two large retrospective studies with a follow-up period of 2 and 3 years, the prevalence of hypertension remained stable over time, but in the group of patients treated with ciclosporin, the prevalence of hypertension increased by 25% compared to patients treated with azathioprine [15]. Tacrolimus therapy causes hypertension, whose mechanism is probably similar to cyclosporin-induced hypertension. It is a general opinion that the main cause of hypertension after renal transplantation is chronic graft dysfunction or chronic graft nephropathy. Hypertension is often the first clinical sign of chronic rejection. It is known that arterial hypertension is a risk factor for cardiovascular disease in the general population. In a retrospective analysis, Ponticelli and associates have found a higher number of cardiac infarcts after kidney transplantation in patients with hypertension than in normotensive patients [16]. Arterial hypertension correlates with cardiovascular disease after transplantation [17]. In most cases for treatment post-transplant hypertension, routine antihypertensive treatment is effective. We can use ACE inhibitors, beta blockers and calcium channel blockers.

A cohort study by Adabag of 14,941 men and women, aged 45–64 years, showed that obesity was associated with an increased risk of sudden cardiac death [10]. According to research by Chan, obesity is a risk factor for the development of cardiovascular disease following kidney transplantation [11]. Although the role of obesity in the pre-transplant period is uncertain,

Weight loss reduces and changes other risk factors for the development of cardiovascular disease [12]. Metabolic syndrome is a risk factor for the development of cardiovascular disease in patients with a transplanted kidney. It is characterized by obesity (central type of obesity), physical inactivity, hypertension (arterial blood pressure greater than 130/80 mmHg), hyperlipidaemia (triglycerides greater than 1.7 mmol/l, HDL cholesterol less than 1.0 mmol/l in men and less than 1.3 mmol/l in women) and systemic insulin resistance (fasting blood sugar greater than 6.5 mmol/l). Six years after kidney transplantation, 63% of patients have criteria for metabolic syndrome, reduced survival of allograft and an increased number of cardiovascular

Diabetes mellitus is one of the most common causes of renal disease, this disease independent and in itself increases the risk of cardiovascular disease. The results of two large clinical studies, Framingham Study and Multiple Risk Factor Intervention Trial (MRFIT) show that diabetes mellitus doubles the possibility of coronary artery disease in men and triples the risk of coronary artery disease in women [13]. Diabetes mellitus is a relatively common complication after kidney transplantation and is defined as a fasting glucose greater than 7 mmol/l. The incidence of diabetes mellitus is between 3.6 and 18% and depends mainly on immunosuppressive therapy. Kidney transplantation can lead to the deterioration of existing diabetes mellitus or to the development of "de novo" diabetes mellitus. The most common cause of posttransplantation diabetes mellitus is corticosteroid therapy, and it depends on immunosuppressive therapy. The two main mechanisms by which corticosteroids cause diabetes mellitus are inducing insulin resistance and increasing body weight [14]. Immunosuppressive drugs can lead to the development of diabetes. The prevalence of post-transplant diabetes in patients treated with cyclosporin ranges from 2.5 to 20%. The treatment of diabetes in hospitalized transplant recipients requires attention to a multitude of factors that can impact glycemic control and influence the risk for adverse effects. Methods to manage hyperglycemia vary among transplant centers and also vary according to whether the patient is immediately posttransplant or is being admitted in the post-transplant setting for another issue. Immediately after transplantation in post-transplant we use frequently require IV insulin infusion protocol. Once iv requirements are established and stable, switch to insulin every 8 h plus fast-acting

The prevalence of post-transplant hypertension is between 60 and 85%. Causes of hypertension in patients with a transplanted kidney are as follows: stenosis of graft renal artery, presence of native kidneys, immunosuppressive therapy, graft dysfunction, genetic predisposition of donors and recipients. Native kidneys and pre-transplant hypertension have been described as independent factors associated with post-transplant hypertension. Native kidney of recipient can cause systemic hypertension through the renin-angiotensin system. Immuno suppressive drugs are also responsible for the appearance of hypertension in patients with a

after kidney transplantation, obesity increases the risk of graft failure and mortality.

318 Organ Donation and Transplantation - Current Status and Future Challenges

incidents [9].

correction insulin every 4–6 h.

Hyperlipidemia is known as the traditional risk factor for the development of cardiovascular diseases, both in the general population and in the population of patients with terminal stage of renal failure. Several observational studies have shown that total cholesterol and low-density lipoproteins (LDL) are one of the most important independent factors of cardiovascular morbidity and mortality [18]. Patients with renal function impairment have significant changes in the metabolism of lipoproteins, whose exact role in the pathogenesis of atherosclerosis in these patients is still controversial [19]. Hyperlipidemia can occur already after 3 months of transplantation and does not resolve spontaneously, and in most patients, it can persist for a very long, even 10 or more years after kidney transplantation [20]. Patients with a transplanted kidney usually have an increased total cholesterol, LDL cholesterol and triglycerides, while HDL cholesterol is usually normal or even high, although its composition may be pathological [21]. Immunosuppressive drugs such as corticosteroids, cyclosporin, tacrolimus and, in particular, sirolimus contribute to the development of post-transplant hyperlipidemia, usually depending on the dose of medicine [22]. Many epidemiological studies of patients with a transplanted kidney showed a correlation between elevated total cholesterol, triglyceride, LDL and incidence of cardiovascular diseases, the same as a low level of HDL is associated with an increase in cardiovascular risk [23]. Hyperlipidemia in patients with a transplanted kidney may affect the progression of chronic graft nephropathy. Based on data about the prevention of cardiovascular disease, it is known that the reduction of LDL-cholesterol by 1 mmol/l over 4–5 years reduces the risk of coronary and cerebrovascular incidents by 25%. Extrapolation from general population studies and some data in kidney transplant patients support the view that the assessment and treatment of dyslipidemias should be part of routine post-renal transplant care. For treating hyperlipidemia in kidney transplant patient, we use statins.
