Cardiovascular risk in the peritoneal dialysis patient

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1 Cardiovascular risk in the peritoneal dialysis patient Raymond T. Krediet and Olga Balafa Abstract Cardiovascular death is the most frequent cause of death in patients on peritoneal dialysis. Risk factors for cardiovascular death in these patients include those that affect the general population as well as those related to end-stage renal disease (ESRD) and those that are specific to peritoneal dialysis. The development of overhydration after loss of residual renal function is probably the most important cardiovascular risk factor specific to peritoneal dialysis. The high glucose load associated with peritoneal dialysis may lead to insulin resistance and to the development of an atherogenic lipid profile. The presence of glucose degradation products in conventional dialysis solutions, which leads to the local formation of advanced glycation end products, is also specific to peritoneal dialysis. Other risk factors that are not specific to peritoneal dialysis but are related to ESRD include calcifications and protein-energy wasting. When present together with inflammation and atherosclerosis, protein-energy wasting is associated with a marked increase in the risk of cardiovascular death. Obesity is not associated with increased cardiovascular risk in patients on any form of dialysis. Left ventricular hypertrophy and increased arterial stiffness are the most important risk factors for cardiovascular events in the general population. Krediet, R. T. & Balafa, O. Nat. Rev. Nephrol. 6, (2010); published online 22 June 2010; doi: /nrneph REviEWS Introduction Cardiovascular disease is the most important cause of death in patients with end-stage renal disease (esrd) on chronic dialysis in the us and europe, accounting for 40% of all deaths in patients on dialysis in the us and 36% of such deaths in europe. 1,2 of interest, a 2009 study in european patients with esrd demonstrated that the risks of cardiovascular and non cardiovascular mortality were increased equally during the first 3 years of dialysis, compared with the risks of cardiovascular and noncardiovascular mortality in the general popula tion, indicating that physicians should not under estimate the risk of noncardiovascular mortality in dialysis patients. 3 nonetheless, the risk of cardio vascular mortality in patients on dialysis is huge, almost ninefold higher than in the general population. Cardiovascular disease is often present in patients initiating renal replacement therapy, but may also develop during chronic dialysis treatment. 4 Consequently, a distinction must be made between the contributions of general risk factors to the development of cardiovascular disease, risk factors related to esrd, and risk factors specifically related to chronic peritoneal dialysis. this review focuses on the above three groups of risk factors and how they may be modified by kidney failure and/or peritoneal dialysis. a summary of the risk factors discussed is provided in table 1. Competing interests The authors declare no competing interests. General risk factors Hypertension, smoking, hyperlipidemia, obesity, and diabetes mellitus are all associated with cardiovascular disease in the general population. hypertension Hypertension is highly prevalent in patients with chronic kidney disease (CKD) 5,6 and is associated with an increased risk of cardiovascular death. 7 Hypertension is also often present in patients on peritoneal dialysis. a multicenter study from italy showed that 88% of 504 patients on peritoneal dialysis were hypertensive. of these, 362 were receiving antihypertensive treatment. 8 Hypertension in patients on peritoneal dialysis is usually associated with fluid overload. 9,10 in the 2008 report of the uk renal registry, a greater number of hemo dialysis patients achieved their blood pressure target than did peritoneal dialysis patients (45% and 33%, respectively). 11 in contrast to the general population, however, the associa tion between high blood pressure and mortality is not very strong in patients on dialysis. the necosad study found an association between a high systolic blood pressure and increased risk of death in patients on peritoneal dialysis, 12 but this association was not confirmed in an analysis of a larger cohort. 13 in a uk study, a higher systolic and diastolic blood pressure was associated with mortality after 1 year on peritoneal dialysis. 14 a relatively small study from turkey in patients on peritoneal dialysis reported that hypertension, low removal of sodium, and low total fluid removal were all significantly associated with mortality. 15 moreover, a 2009 meta-analysis of randomized trials showed that treatment of patients on Division of Nephrology, Department of Medicine, Academic Medical Centre University of Amsterdam, P. O. Box 22700, 1100 DE Amsterdam, The Netherlands (r. T. Krediet, o. Balafa). Correspondence to: R. T. Krediet c.n.deboer@amc.uva.nl nature reviews nephrology volume 6 august

2 Key points Overhydration, which develops easily in the absence of residual renal function, is probably the most important cardiovascular risk factor in patients on long-term peritoneal dialysis vascular and valvular calcifications are important cardiovascular risk factors in patients with end-stage renal disease and in those on peritoneal dialysis The presence of malnutrition, inflammation, and atherosclerosis contributes to cardiovascular mortality; the presence of all three factors in patients with end-stage renal disease is associated with an increased risk of cardiovascular mortality Obesity is not associated with an increased risk of cardiovascular death in patients on peritoneal dialysis maintenance dialysis with antihypertensives reduced their risk of cardio vascular morbidity and mortality. 16 Hypertension correlates strongly with left ventricular hypertrophy (lvh) an entity that is also very frequent among patients with CKD. almost 70% of patients starting dialysis have lvh detectable by echocardiography and changes in cardiac structure tend to progress during dialysis treatment. 17,18 one study reported that lvh was more severe in patients on long-term continuous ambulatory peritoneal dialysis than in patients on hemodialysis, 19 probably owing to an inadequate control of fluid volume. the adverse impact of lvh on short-term (that is, 2-year) survival of incident patients on dialysis has been confirmed by population-based studies. 20 in a large cohort study of patients on peritoneal dialysis, inflammation (as determined by level of C-reactive protein [CrP]) and lvh synergistically increased the risk of all-cause mortality and cardiovascular death. 21 arterial stiffness, which is typically measured by aortic pulse wave velocity, has proven useful in the prediction of cardiovascular morbidity and mortality in the general population and in patients with CKD. 22 in a large cohort of patients with CKD, aortic stiffness was independently associated with age, blood pressure and other risk factors for cardiovascular disease. 23 vascular calcification is the factor most strongly associated with arterial stiffness. 24 relevant studies in patients on peritoneal dialysis are, however, rather small and have numerous limitations. 25,26 Table 1 Cardiovascular risk factors and their importance in patients on peritoneal dialysis risk factor risk factor for CV death references General risk factors Hypertension Unknown (contradictory findings) Jager et al. (1999); 12 Termorshuizen et al. (2003); 13 Udayaraj et al. (2009); 14 Ates et al. (2001) 15 Smoking Unknown Kemperman et al. (1991); 29 Braatvedt et al. (2006) 30 Lipids Unknown Wanner et al. (2005); 32 Fellstrom et al. (2009) 33 Obesity Probably not Johnson et al. (2000); 36 Snyder et al. (2003); 37 Abbott et al. (2004); 38 McDonald et al. (2003); 39 Stack et al. (2004); 40 Aslam et al. (2002); 41 de Mutsert et al. (2009) 42 Factors related to ESRD inflammation Yes Wang et al. (2003); 48 Ducloux et al. (2002); 49 Herzig et al. (2001); 50 Pecoits-Filho et al. (2002) 53 Malnutrition PEW syndrome Yes de Mutsert et al. (2008); 66 Chung et al. (2003); 67 Fouque et al. (2008); 68 Cheng et al. (2009); 73 Ho et al. (2010) 74 Endothelial dysfunction Probably van Guldener et al. (1998); 55 Wang et al. (2005) 62 Oxidative stress Unknown Kocak et al. (2009); 79 Tarng et al. (2002); 80 ignace et al. (2009); 81 Furuya et al. (2009) 82 Calcification Yes Wang et al. (2003); 94 Ketteler et al. (2003); 96 Wang et al. (2005); 97 Hermans et al. (2007) 98 vitamin D Yes Wang et al. (2008) 106 Hyperhomocysteinemia No Suliman et al. (2007); 108 Righetti et al. (2004); 109 Baragetti et al. (2007); 110 Heinz et al. (2009); 111 Heinz et al. (2010) 112 insulin resistance Probably Fortes et al. (2009); 113 Shinohara et al. (2002) 114 Anemia Factors related to peritoneal dialysis No (if hemoglobin levels are normalized) Gunnell et al. (1999); 116 Singh et al. (2010) 117 AGEs No Ateshkadi et al. (1995); 127 Miyata et al. (2000); 130 Zeier et al. (2003); 131 Schalkwijk et al. (2000); 132 Williams et al. (2004) 133 Dialysis solutions Probably not Williams et al. (2004); 133 Fan et al. (2008); 134 Lee et al. (2005) 135 Residual renal function Yes Shemin et al. (2010); 140 Bargman et al. (2001); 141 Paniagua et al. (2002); 142 Termorshuizen et al. (2003); 143 Liao et al. (2009) 144 Ultrafiltration failure and overhydration Yes Mallamaci et al. (2005); 147 Rutten et al. (2006); 148 Wang et al. (2007); 149 Krediet et al. (2006); 150 Brown et al. (2003); 151 Jansen et al. (2005) 152 Abbreviations: AGEs, advanced glycation end products; Cv, cardiovascular; ESRD, end-stage renal disease; PEW, protein-energy wasting. 452 AUGUST 2010 volume 6

3 smoking smoking is not only a risk factor for cardiovascular disease, but is also associated with the risk of CKD (as defined by an estimated glomerular filtration rate [GFr] <45 ml/min/1.73 m 2 ). in a large, cross- sectional study from norway, smoking >25 pack years was associ ated with a 1.52-fold increase in the relative risk of CKD. 27 By comparison, obesity was associated with a 1.77-fold increase in the relative risk of CKD. these associations were more evident in men than in women. smoking also increases the risk of progression of various nephropathies. 28 remarkably little is known, however, about whether smoking increases the risk of cardiovascular death in patients on peri toneal dialysis. one small study in patients on peritoneal dialysis with diabetes mellitus found no effect of smoking on cardiovascular death, 29 although another study showed that smoking or a history of smoking was a risk factor for all-cause death. 30 these apparent discrepancies may be caused by the presence of other risk factors in some populations, which may override the influence of smoking in multivariate analyses. lipids the lipid profile of patients on peritoneal dialysis is typically characterized by elevated levels of total cholesterol, B apolipoproteins and triglycerides. 31 low levels of HDl are often present in patients with CKD. However, no evidence exists to suggest that this highly atherogenic lipid profile is directly associated with cardiovascular risk. Data on the effects of statins on the risk of cardiovascular death in patients on peritoneal dialysis are not available, as trials that have investigated statins have been performed in patients on hemodialysis. 32,33 Both trials in patients on hemodialysis showed that statins had no effect on cardiovascular mortality. obesity obesity is a risk factor for cardiovascular disease in the general population and as mentioned above, its presence is associated with an increased risk of CKD. 27 in contrast to the situation in the general population where either a low Bmi or a high Bmi is associated with an increased risk of death, a study in obese patients on hemo dialysis demonstrated that these patients may in fact have a survival advantage. 34 this unexpected finding is frequently referred to as reverse epidemiology ; however, we believe that this apparent discrepancy may in part be explained by differences in the duration of follow-up. Participants in population-based studies are generally followed for >10 years but most studies of patients on dialysis only follow participants for a few years. in patients on hemodialysis, obesity might actually be a risk factor for long-term mortality. a 2007 comparison of patients on hemodialysis from the necosad study, who were followed for 7 years along with individuals from another population-based cohort with similar age and duration of follow-up, revealed that a high Bmi was not associated with the risk of all-cause mortality in either group. 35 in our opinion, this finding implies that the term reverse epidemiology should not be used to describe the apparent inverse association between Bmi and risk of death in patients on hemodialysis. results from studies in patients on peritoneal dialysis are, however, inconsistent. some studies have found that obesity confers a survival advantage, whereas others have reported an association of obesity with an increased risk of mortality, 39,40 or no association at all. 41 a prospective, time-dependent, longitudinal analysis in 688 incident patients on peritoneal dialysis showed that only those with a Bmi <18.5 kg/m² had an increased risk of death. 42 a high Bmi had no protective effect, but was also not associated with a reduced risk of survival. Risk factors related to ESRD the presence of a GFr <60 ml/min/1.73 m 2 is a risk factor for cardiovascular death, 43 and the risk of cardiovascular death increases further for GFr values <45 ml/ min/1.73 m a number of potential factors have been investigated to find an explanation for the association between CKD and cardiovascular mortal ity, including inflammation, malnutrition, endothelial dysfunction, oxidative stress, calcification, vitamin D deficiency, and hyperhomocysteinemia. all of these factors can be studied by investigating levels of serum markers. although cross-sectional studies have reported these factors to be present in patients with esrd, few largescale studies have demonstrated a link between these factors and cardiovascular mortality. Furthermore, studies investigating the use of therapies that target such risk factors have been unable to demonstrate a survival benefit. inflammation according to the inflammation hypothesis of atherosclerosis, local inflammatory stimuli such as products modified by oxidation, advanced glycation end products (ages), or persistent infectious processes, alter the environ ment of the vasculature. these changes promote the production of proatherogenic adhesion molecules (for example, icam-1 and vcam-1), growth factors, and chemokines (for example, il-6 and tnf). these inflammatory mediators induce the synthesis of acutephase proteins such as CrP, and inhibit the hepatic genera tion of albumin. 45 endothelial dysfunction which mainly presents as an impairment in vasodilation seems to be an early phenomenon of atherosclerosis. However, the question as to whether inflammation is a reflection of vascular injury or actually promotes vascular injury remains to be answered. the precise links between inflammation, endothelial dysfunction, oxidative stress, and cardiovascular mortality in patients on dialysis remain unknown. in europe, 70% of patients with esrd have a CrP level >32.4 nmol/l (>3.4 mg/l). 46 as in the general population, CrP predicts all-cause and cardiovascular mortality in patients on hemodialysis or peritoneal dialysis although CrP levels in patients on peritoneal dialysis decline over time and tend to be lower than levels in patients on hemodialysis, 51 a single random highsensitivity CrP value is a sufficient prognostic marker nature reviews nephrology volume 6 august

4 for cardiovascular mortality. 48 in a prospective study in patients on peritoneal dialysis, a high CrP level (that is, >57 nmol/l [>6 mg/l]) was an independent, predictive marker of future myocardial infarction. 50 moreover, the proinflammatory marker il-6 was not only found to be increased in patients with esrd, 52 but was also an independent predictor of mortality in patients starting dialysis. 53 stompor et al. demonstrated that levels of CrP, il-6 and tnf correlated with increasing thickness of the carotid artery in a cohort of patients on peritoneal dialysis over 1 year of follow-up. 54 endothelial dysfunction endothelial function is impaired in patients on either peritoneal dialysis or hemodialysis, 55,56 probably owing to a decreased bioavailability of nitric oxide. 57 in a 2009 study, flow-mediated vasodilation was markedly lower in 105 patients on peritoneal dialysis than in healthy controls and correlated negatively with markers of inflamma tion such as CrP and il Growing evidence also suggests that the endogenous inhibitor of nitric oxide, asymmetric dimethylarginine, has a role in cardio vascular mortality in patients on dialysis; the accumula tion of this factor promotes endothelial dysfunction, vasoconstriction and arteriothrombosis. 59,60 other markers of endo thelial dysfunction, such as soluble adhesion molecules, are predictors of all-cause and cardio vascular mortality in patients with esrd. 61 levels of vcam-1 were negatively correlated with cardiac hypertrophy and residual renal function in a group of prevalent peritoneal dialysis patients. 62 Contrary to other studies in CKD patients, 63,64 vcam-1 was found to be only weakly correlated with CrP levels. Malnutrition and protein-energy wasting a strong relationship between malnutrition, elevated CrP level and atherosclerosis is well established, despite the precise mechanisms for this relationship remaining unknown. this relationship was first described by stenvinkel et al. in a study of patients with CKD. 65 Patients with a CrP level >95 nmol/l (>10 mg/l) had signifi cantly lower levels of serum albumin and a higher prevalence of atherosclerosis than patients with lower CrP levels. the combined presence of malnutrition, inflammation, and atherosclerosis has been termed the mia syndrome. a 2008 study demonstrated that the mia syndrome was associated with an increased risk of mortality that was attributed to interaction between the three factors. 66 in a Korean study, comorbid diseases were present in 78% of incident peritoneal dialysis patients with malnutrition. these patients had a 3.3-fold greater risk of mortality than malnourished patients without other comorbidities. 67 the use of nonuniform and confusing definitions with regard to wasting, malnutrition, and inflammation led to the recommendation that the term proteinenergy wasting syndrome (Pew) be used to describe this entity in patients with CKD. 68 Pew is characterized by decreased body stores of protein and energy fuels. several studies have clearly demonstrated that two types of malnutrition exist; 69 the first is associated with poor nutritional intake and the second is associated with inflammation and marked comorbidity. 69 low levels of serum albumin are only found in the latter, 70 but the exact contributions of malnutrition or inflammation to risk of mortality in patients on dialysis remain unclear. 71 Despite the fact that serum albumin is robustly and inversely related to risk of mortality in patients on dialysis, it is a better marker of illness than of nutritional status. 72 several scoring systems that assess multiple markers of Pew (for example, the subjective Global assessment of nutrition and the malnutrition inflammation score), have therefore been developed and have revealed an associa tion between Pew and risk of mortality in patients on peritoneal dialysis. 73,74 oxidative stress oxidative stress is defined as the tissue damage that results from an imbalance between the excessive generation of oxidant compounds and insufficient antioxidant defense mechanisms. Patients with CKD have deficiencies in antioxidant defense mechanisms (caused, for example, by reduced levels of dietary vitamins or hypo albuminemia), and increased pro-oxidant activity (caused, for example, by the accumulation of solutes such as ages and β2-microglobulin with kidney failure). oxidative stress leads to the formation of free radicals highly reactive compounds that can oxidize proteins, lipids and nucleic acids. High concentrations of such molecules have been reported in patients with CKD 75,76 and in patients on hemodialysis. 77,78 advanced oxidation protein products and oxidized Dna have been reported in the peripheral blood leukocytes of patients on peritoneal dialysis. 79,80 moreover, malondialdehyde, lipid hydro peroxides, advanced oxidation protein products, and pentosidine have been negatively correlated with residual renal function in these patients. 81,82 Few observational studies have correlated oxidative markers with impaired endothelial function or carotid thickness. 79,83 nevertheless, the exact pathways that increase oxidative stress in patients with CKD are still unknown and the causal relationship between increased levels of oxidative stress and cardio vascular mortality has not been established in these patients. 84 a small, prospective study that investigated the association between cardio vascular mortal ity and oxidative stress in patients with CKD concluded that oxidative stress may be a risk factor for cardiovascular mortality in patients with esrd. 85 a few small studies have assessed the efficacy of anti oxidant treatment (such as vitamin e and acetylcysteine) in patients on hemodialysis; 86,87 however, these studies did not assess the effects of these interventions on markers of oxidative stress. 88 Calcification arterial calcification is a significant risk factor for cardio vascular mortality in the general population. the vasculature of patients with esrd is often extensively calcified. 89 this calcification mainly occurs in the intimal and medial layers, but calcification of the valves is also 454 AUGUST 2010 volume 6

5 common. Calcification of the intimal layer is associated with atherosclerotic changes in the vessel wall and with the development of plaques and occlusive lesions. 90 Calcification of the medial layer is responsible for arterial stiffness, which leads to hypertension and lvh. 90 Hyperphosphatemia is probably the main risk factor for calcification because it stimulates the deposition of hydroxyapatite crystals. Hypercalcemia (caused by high doses of vitamin D) and hyperparathyroidism 91 have also been implicated in the process of calcification. the process of calcification is therefore influenced by many factors some that favor the deposition of calcium and others, such matrix Gla protein and fetuin-a, 92 that antagonize it. arterial calcification, particularly that of the arterial medial layer, is a strong and independent predictor of mortality in patients on hemodialysis. 93 wang and colleagues were the first to demonstrate that valvular calcification correlates positively with all-cause and cardio vascular mortality in patients on long-term peritoneal dialysis. 94 in that study, 89% of patients with both valvular calcification and atherosclerotic vascular disease died within 1 year of follow-up. a number of observational studies have demonstrated a correlation between calcification and markers of inflammation such as adhesion molecules and CrP. 95 a 2005 study demonstrated an inverse association between levels of fetuin-a and cardiovascular mortality in patients with esrd, 96 especially in those with Pew and inflammation. 97 interestingly, in the necosad cohort, patients on peritoneal dialysis had higher levels of fetuin-a than did patients on hemodialysis, even after adjustment for potential confounders. 98 the combined use of markers of inflammation (for example, CrP and il-6) and calcifica tion (for example, low levels of fetuin-a) may therefore not only accurately predict cardiovascular mortality but may also provide a valuable clinical tool for stratifica tion of the cardio vascular risk of patients on chronic peritoneal dialysis. 99 Vitamin D an increasing body of evidence suggests that low levels of vitamin D are associated with cardiovascular disease in the general population 100 and that vitamin D supplementa tion may have a favorable impact on survival. 101 a number of studies in predialysis CKD patients in whom calcitriol deficiency is evident from early stages have yielded similar conclusions. 102,103 moreover, cross-sectional studies in patients on hemodialysis have reported that treatment with vitamin D analogues is associ ated with improved survival. 104,105 in patients on peritoneal dialysis, wang et al. 106 confirmed that a low serum concentration of 25-hydroxyvitamin D was a s s o c i a t e d with an increased risk of fatal or nonfatal cardiovascular events. However, in that study the influence of vitamin D on cardiovascular outcomes seemed to closely relate to residual renal function, severity of cardiac hypertrophy, and cardiac dysfunction. we believe that this finding implies that vitamin D deficiency probably has an important role in the early stages of lvh; however, no prospective, randomized, controlled studies have investigated whether correction of vitamin D deficiency could improve cardiovascular outcomes in patients on dialysis. hyperhomocysteinemia High levels of homocysteine (a sulfur-containing amino acid) are present in 90% of patients with CKD. 107 Clinical studies that have investigated the relationship of hyperhomocysteinemia with cardiovascular mortality have reported conflicting results and a reverse epidemiology hypothesis even exists in which low levels of homocysteine are associated with poor survival. 108 High intakes of folic acid or vitamin B in patients on peritoneal dialysis normalize homocysteine levels. 109,110 a 2009 meta-analysis of heterogenic studies in patients with esrd concluded that homocysteine level may be a risk factor for cardiovascular mortality in patients who do not receive folic acid. 111 However, a 2010 randomized, controlled trial showed that vitamin B supplementation did not lower the risk of cardiovascular disease in patients on hemodialysis. 112 insulin resistance Glucose metabolism is altered in patients with CKD, even in the earliest stages of disease. although insulin secretion is normal in early stages of CKD, tissue sensitivity to insulin is decreased, glucose uptake is abnormal, and liver gluconeogenesis is elevated. 113 several different approaches may be used to quantify insulin resistance. the homeostatic model assessment (Homa) technique derives a measurement of insulin resistance from fasting plasma glucose and insulin concentrations and has been shown to predict cardiovascular mortality in patients on hemodialysis. 114 we are not aware of similar studies in patients on peritoneal dialysis; however, the authors of a 2009 review suggested that cardiovascular outcomes for nondiabetic patients with insulin resistance, defined by a mild increase in fasting glycemia and an altered glycated hemoglobulin level, may be worse for patients on peri toneal dialysis than for those on hemodialysis. 113 Anemia inflammation has also been linked with erythropoietin resistance in patients with esrd. increased inflammatory factors associated with the acute-phase response interact with the hematopoietic system at several levels, which leads to a decreased number of erythrocytes. 115 Gunnell et al. reported that low levels of serum albumin and high levels of CrP also predict erythropoietin resistance in patients on either hemodialysis or peritoneal dialysis. 116 However, large interventional studies in patients with CKD (that is, the treat, CHoir and Create trials), 117 demonstrated that correction of hemoglobin to normal levels did not confer a survival benefit. similarly, in a study of 1,265 patients on hemodialysis with heart failure or ischemic heart disease, patients who were randomly allocated to receive a higher hematocrit target had a trend toward higher rates of mortality and nonfatal myo cardial infarction than patients who had a lower hematocrit target. 118 moreover, the administration of iron has been nature reviews nephrology volume 6 august

6 suggested to increase oxidative stress and may therefore also contribute to the increased risk of cardiovascular mortality in patients with esrd. 119 Risk factors related to peritoneal dialysis two main differences exist between patients on peritoneal dialysis and those with esrd who are not on dialy sis patients on peritoneal dialysis have more severe kidney failure and their peritoneal cavities are exposed to a dialysis solution. as such, all risk factors present in patients with esrd will also apply to patients on peritoneal dialysis. the instillation of a dialysis solution into the peri toneal cavity not only causes an increase in intraperitoneal pressure, but also results in an elevation of systemic blood pressure owing to a rise in total peripheral resistance. 120 Dialysate infusion also leads to a rise in plasma levels of atrial natriuretic peptide (anp). 121 whether these acute changes can be considered to be cardiovascular risk factors is unknown. Conventional dialysis solutions contain extremely high concentrations of glucose (>200 mmol/l) and glucose degradation products that are formed during heat steriliza tion of the solution. Glucose degradation products mainly consist of aldehydes and di carbonyl compounds but lactate is used as a buffer in conventional solutions. on average, 65% of the amount of intra peritoneally instilled glucose is absorbed during a 4 h dwell, irrespective of the initial dialysate glucose concentra tion. 122 in extreme situations, this process can lead to an additional carbohydrate load of >500 g per day. this excess of carbohydrates may promote obesity, insulin resistance, and an atherogenic lipid profile. 123 Dialysis solutions and Ages the continuous exposure to extremely high dialysate glucose concentrations leads to the formation of ages in peritoneal tissues. 124,125 the formation of ages is not induced in nonperitoneal tissues such as the skin; 126 however, the contribution of ages to arterial stiffness cannot be excluded, especially when glucose absorption in the peritoneum would lead to hyperglycemia. Concentrations of plasma ages are elevated in patients on peritoneal dialysis or hemodialysis compared with levels in healthy individuals, but concentrations do not differ between patients on the two dialysis techniques. 127,128 Pulse wave velocity a marker of arterial stiffness was slower in patients on peritoneal dialysis than in patients on hemodialysis after 1 year of therapy, 128 suggesting that the dialysate glucose concentration does not have a pathogenetic role in the development of arterial stiffness. we therefore conclude that ages generated in peritoneal tissue are unlikely to lead to systemic vascular effects. the presence of glucose degradation products is cytotoxic in vitro, 129 and enhances the formation of ages. 130 the low molecular weights of these compounds means that they are almost completely absorbed during a dialysis dwell. 131 all so-called biocompatible dialysis solutions have a reduced amount of glucose degradation products, 132 and two studies have shown that the use of these solutions is associated with a decrease in concentrations of plasma ages. 131,133 the clinical relevance of these solutions to cardiovascular or all-cause mortality is unknown. the euro-balance trial suggested that preserva tion of residual renal function is better when biocompatible solutions are used rather than conventional solutions. 133 However, this finding was not confirmed in a randomized, controlled trial in incident patients on peritoneal dialysis. 134 a retrospective observational study reported improved survival rates in patients treated with biocompatible dialysis solutions compared with rates in those treated with conventional solutions. 135 However, that study had many methodological flaws; for example, flaws existed in the allocation of treatment owing to the fact that not all dialysis departments offered both treatments, making interpretation of the results impossible. a large observational cohort study also reported improved survival rates in patients treated with bio compatible dialysis solutions than rates in patients treated with conventional solutions. 136 we believe that the use of biocompatible dialysis fluids is unlikely to lead to a direct reduction in cardiovascular risk factors. Yet, these solutions may reduce peritoneal neoangiogenesis, 137,138 and thereby reduce the risk of ultrafiltration failure and, potentially, of encapsulating peritoneal sclerosis. residual renal function residual renal function is related to all-cause mortality and risk of cardiovascular death in patients on hemodialysis or peritoneal dialysis. 139,140 the cardinal role of residual renal function in the survival of patients on peritoneal dialysis has been demonstrated in large, prospective studies such as the Canusa and ademex studies. the reanalysis of the Canusa study, 141 a prospective cohort of 601 incident patients on peritoneal dialysis, clearly established that patient survival was linked with the magnitude of residual renal function and urine volume. each 5 l per week per 1.73 m 2 increment in GFr corresponded to a 12% decrease in the relative risk of death. in the ademex study, 142 a prospective, randomized trial in 965 prevalent peritoneal dialysis patients, a 11% decrease in the relative risk of death was present for each 10 l per week per 1.73 m 2 increment in residual renal function. these results were confirmed by the necosad study. 143 in a cohort of patients from north taiwan, the rate of decline of residual renal function was more powerful than baseline residual renal function in predicting all-cause mortality and technique failure in patients on long-term peritoneal dialysis. 144 wang et al. demonstrated an associa tion between residual renal function and lvh in nondiabetic patients with esrd on peritoneal dialysis. 145 Ultrafiltration failure and overhydration ultrafiltration failure occurs in about one-third of patients on peritoneal dialysis 146 and may easily lead to hypertension and overhydration. overhydration promotes the development of lvh and elevated serum concentrations of natriuretic peptides owing to their increased production 456 AUGUST 2010 volume 6

7 by the myocardium. these peptides have been used as prognostic markers for overall mortality in patients with esrd. 147 High plasma concentrations of anp and B-type natriuretic peptide (BnP) in patients on peritoneal dialysis were each associated with an approximately eightfold increase in the risk of mortality compared with low concentra tions of these peptides. 148 BnP is secreted as a prohormone that is cleaved into an active form and to the inactive N-terminal propeptide BnP (n-bnp). n-bnp has a lower half-life than active BnP and the plasma concentrations are therefore more stable. a 2007 study showed that serum n-bnp levels were >10-fold higher in patients on peritoneal dialysis than in the general population. 149 associations between level of n-bnp and residual glomerular filtration rate, cardiovascular congestion, and cardiovascular death were reported. 149 the development of overhydration may be exacerbated by the limited capacity for sodium removal during peritoneal dialysis. 150 associations between peritoneal ultrafiltration and mortality have been reported in anuric patients. 151,152 when fluid intake is not adapted to peritoneal ultrafiltration, patients will develop over hydration, increasing the risk of cardiovascular events. Conclusions we believe that overhydration may be the most important of the cardiovascular risk factors specific to peritoneal dialysis. the risk of overhydration increases with deteriorating residual renal function and is obviously highest in anuric patients. ages may be important for the development of peritoneal alterations such as peritoneal fibrosis, but we believe they are unlikely to be a major risk factor for cardiovascular events. in addition, risk factors that are related to the presence of esrd are also applicable to patients on peritoneal dialysis, including Pew and calcification. Pew is particularly important when it is present as part of the mia syndrome. with regard to general risk factors, lvh and increased arterial stiffness are probably the most important risk factors that also affect the general population. other Framinghambased risk factors such as hypertension may also contribute to the increased risk of cardiovascular death in patients on peritoneal dialysis, but the contribution of these factors to overall risk of death are probably minor compared with the more prominent effects of the factors mentioned above. Review criteria PubMed was searched using the search terms cardiovascular disease, cardiovascular risk factors, cardiovascular mortality, chronic kidney disease, dialysis, and peritoneal dialysis. We mainly selected publications from the past 10 years but older manuscripts were also selected if they were deemed to be important. We also searched the reference lists of the selected articles for relevant articles. We searched only for articles written in English. 1. Levey, A. S. Controlling the epidemic of cardiovascular disease in chronic renal disease. What we know? What do we need to learn? Where do we go from here? Am. J. Kidney Dis. 32, (1998). 2. van Dijk, P. C. et al. Renal replacement therapy in Europe: the results of a collaborative effort by the ERA-EDTA registry and six national regional registries. Nephrol. Dial. Transplant. 16, (2001). 3. de Jager, D. et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 302, (2009). 4. Locatelli, F., Pozzoni, P., Tentori, F. & del vecchio, L. Epidemiology of cardiovascular risk in patients with chronic kidney disease. Nephrol. Dial. Transplant. 18 (Suppl. 7), vii2 vii9 (2003). 5. Rao, M. v., Qiu, Y., Wang, C. & Bakris, G. Hypertension and CKD: Kidney early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) Am. J. Kidney Dis. 51, S30 S37 (2008). 6. National High Blood Pressure Education Program Working Group Update of the working group reports on chronic renal failure and renovascular hypertension. Arch. Intern. Med. 156, (1995). 7. Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 32, S112 S119 (1998). 8. Cocchi, R. et al. Prevalence of hypertension in patients on peritoneal dialysis: results of an italian multicentre study. Nephrol. Dial. Transplant. 14, (1999). 9. Günal, A. i. et al. Blood pressure control and left ventricular hypertrophy in long-term CAPD and hemodialysis patients: a cross-sectional study. Perit. Dial. Int. 23, (2003). 10. Konings, C. J. et al. Fluid status, blood pressure, and cardiovascular abnormalities in patients on peritoneal dialysis. Perit. Dial. Int. 22, (2002). 11. Harper, J., Nicholas, J., Ford, D., Casula, A. & Williams, A. J. UK Renal Registry 11 th Annual Report (December 2008): Chapter 11 Blood pressure profile of prevalent patients receiving dialysis in the UK in 2007: national and centrespecific analyses. Nephron Clin. Pract. 111 (Suppl. 1), c227 c245 (2009). 12. Jager, K. J. et al. Mortality and technique failure in patients starting chronic peritoneal dialysis: results of The Netherlands Cooperative Study on the Adequacy of Dialysis. NECOSAD Study Group. Kidney Int. 55, (1999). 13. Termorshuizen, F. et al. The relative importance of residual renal function compared with peritoneal clearance for patient survival and quality of life: an analysis of the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD)-2. Am. J. Kidney Dis. 41, (2003). 14. Udayaraj, U. P. et al. Blood pressure and mortality risk on peritoneal dialysis. Am. J. Kidney Dis. 53, (2009). 15. Ates, K. et al. Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int. 60, (2001). 16. Heerspink, H. J. et al. Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials. Lancet 373, (2009). 17. Foley, R. N. et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int. 47, (1995). 18. Foley, R. N. et al. Long-term evolution of cardiomyopathy in dialysis patients. Kidney Int. 54, (1998). 19. Enia, G. et al. Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients. Nephrol. Dial. Transplant. 16, (2001). 20. Stack, A. G. & Saran, R. Clinical correlates and mortality impact of left ventricular hypertrophy among new ESRD patients in the United States. Am. J. Kidney Dis. 40, (2002). 21. Wang, A. Y. et al. inflammation, residual kidney function, and cardiac hypertrophy are interrelated and combine adversely to enhance mortality and cardiovascular death risk of peritoneal dialysis patients. J. Am. Soc. Nephrol. 15, (2004). 22. London, G. M. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol. Dial. Transplant. 18, (2003). 23. Townsend, R. et al. M. Aortic PWv in chronic kidney disease: a CRiC ancillary study. Am. J. Hypertens. 23, (2009). 24. Guérin, A. P., London, G. M., Marchais, S. J. & Metivier, F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol. Dial. Transplant. 15, (2000). 25. Gao, N. et al. Arterial pulse wave velocity and peritoneal transport characteristics independently predict hospitalization in chinese nature reviews nephrology volume 6 august

8 peritoneal dialysis patients. Perit. Dial. Int. 30, (2010). 26. Cheng, L. T. et al. The study of aortic stiffness in different hypertension subtypes in dialysis patients. Hypertens. Res. 31, (2008). 27. Hallan, S. et al. Obesity, smoking, and physical inactivity as risk factors for CKD: are men more vulnerable? Am. J. Kidney Dis. 47, (2006). 28. Orth, S. R. & Hallan, S. i. Smoking: a risk factor for progression of chronic kidney disease and for cardiovascular morbidity and mortality in renal patients--absence of evidence or evidence of absence? Clin. J. Am. Soc. Nephrol. 3, (2008). 29. Kemperman, F. et al. Continuous ambulatory peritoneal dialysis (CAPD) in patients with diabetic nephropathy. Neth. J. Med. 38, (1991). 30. Braatvedt, G. D., Rosie, B., Bagg, W. & Collins, J. Current and former smoking increases mortality in patients on peritoneal dialysis. N. Z. Med. J. 119, U1977 (2006). 31. Sniderman, A. et al. Hyperapobetalipoproteinemia: the major dyslipoproteinemia in patients with chronic renal failure treated with chronic ambulatory peritoneal dialysis. Atherosclerosis 65, (1987). 32. Wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, (2005). 33. Fellstrom, B. C. et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N. Engl. J. Med. 360, (2009). 34. Kalantar-Zadeh, K. et al. Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction. Nephrol. Dial. Transplant. 20, (2005). 35. de Mutsert, R. et al. Association between body mass index and mortality is similar in the hemodialysis population and the general population at high age and equal duration of follow-up. J. Am. Soc. Nephrol. 18, (2007). 36. Johnson, D. W. et al. is obesity a favorable prognostic factor in peritoneal dialysis patients? Perit. Dial. Int. 20, (2000). 37. Snyder, J. J., Foley, R. N., Gilbertson, D. T., vonesh, E. F. & Collins, A. J. Body size and outcomes on peritoneal dialysis in the United States. Kidney Int. 64, (2003). 38. Abbott, K. C. et al. Body mass index, dialysis modality, and survival: analysis of the United States Renal Data System Dialysis Morbidity and Mortality Wave ii Study. Kidney Int. 65, (2004). 39. McDonald, S. P., Collins, J. F. & Johnson, D. W. Obesity is associated with worse peritoneal dialysis outcomes in the Australia and New Zealand patient populations. J. Am. Soc. Nephrol. 14, (2003). 40. Stack, A. G., Murthy, B. v. & Molony, D. A. Survival differences between peritoneal dialysis and hemodialysis among large ESRD patients in the United States. Kidney Int. 65, (2004). 41. Aslam, N., Bernardini, J., Fried, L. & Piraino, B. Large body mass index does not predict shortterm survival in peritoneal dialysis patients. Perit. Dial. Int. 22, (2002). 42. de Mutsert, R., Grootendorst, D. C., Boeschoten, E. W., Dekker, F. W. & Krediet, R. T. is obesity associated with a survival advantage in patients starting peritoneal dialysis? Contrib. Nephrol. 163, (2009). 43. Henry, R. M. et al. Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int. 62, (2002). 44. Anavekar, N. S. et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infaction. N. Engl. J. Med. 351, (2004). 45. Liao, W. S., Ma, K. T., Woodworth, C. D., Mengel, L. & isom, H. C. Stimulation of the acute-phase response in simian virus 40-hepatocyte cell lines. Mol. Cell. Biol. 9, (1989). 46. Stenvinkel, P. et al. inflammation and outcome in end-stage renal failure: Does female gender constitute a survival advantage? Kidney Int. 62, (2002). 47. Yeun, J. Y., Levine, R. A., Mantadilok, v. & Kaysen, G. A. C-Reactive protein predicts allcause and cardiovascular mortality in hemodialysis patients. Am. J. Kidney Dis. 35, (2000). 48. Wang, A. Y. et al. is a single time point C-reactive protein predictive of outcome in peritoneal dialysis patients? J. Am. Soc. Nephrol. 14, (2003). 49. Ducloux, D., Bresson-vautrin, C., Kribs, M., Abdelfatah, A. & Chalopin, J. M. C-reactive protein and cardiovascular disease in peritoneal dialysis patients. Kidney Int. 62, (2002). 50. Herzig, K. A. et al. is C-reactive protein a useful predictor of outcome in peritoneal dialysis patients? J. Am. Soc. Nephrol. 12, (2001). 51. Haubitz, M. et al. Chronic induction of C-reactive protein by hemodialysis, but not by peritoneal dialysis therapy. Perit. Dial. Int. 16, (1996). 52. Shlipak, M. G. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 107, (2003). 53. Pecoits-Filho, R., Bárány, P., Lindholm, B., Heimbürger, O. & Stenvinkel, P. interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol. Dial. Transplant. 17, (2002). 54. Stompor, T. et al. Changes in common carotid artery intima-media thickness over 1 year in patients on peritoneal dialysis. Nephrol. Dial. Transplant. 20, (2005). 55. van Guldener, C. et al. Endothelium-dependent vasodilatation is impaired in peritoneal dialysis patients. Nephrol. Dial. Transplant. 13, (1998). 56. van Guldener, C., Lambert, J., Janssen, M. J., Donker, A. J. & Stehouwer, C. D. Endotheliumdependent vasodilatation and distensibility of large arteries in chronic haemodialysis patients. Nephrol. Dial. Transplant. 12 (Suppl. 2), (1997). 57. Tatematsu, S. et al. Role of nitric oxideproducing and -degrading pathways in coronary endothelial dysfunction in chronic kidney disease. J. Am. Soc. Nephrol. 18, (2007). 58. Choi, H. Y. et al. Association of inflammation and protein-energy wasting with endothelial dysfunction in peritoneal dialysis patients. Nephrol. Dial. Transplant. 25, (2010). 59. Kielstein, J. T. & Zoccali, C. Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am. J. Kidney Dis. 46, (2005). 60. Zoccali, C. et al. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358, (2001). 61. Suliman, M. E., Qureshi, A. R., Heimbürger, O., Lindholm, B. & Stenvinkel, P. Soluble adhesion molecules in end-stage renal disease: a predictor of outcome. Nephrol. Dial. Transplant. 21, (2006). 62. Wang, A. Y. et al. Circulating soluble vascular cell adhesion molecule 1: relationships with residual renal function, cardiac hypertrophy, and outcome of peritoneal dialysis patients. Am. J. Kidney Dis. 45, (2005). 63. Papagianni, A. et al. Carotid atherosclerosis is associated with inflammation and endothelial cell adhesion molecules in chronic haemodialysis patients. Nephrol. Dial. Transplant. 18, (2003). 64. Stenvinkel, P., Lindholm, B., Heimbürger, M. & Heimbürger, O. Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease. Nephrol. Dial. Transplant. 15, (2000). 65. Stenvinkel, P. et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 55, (1999). 66. de Mutsert, R. et al. Excess mortality due to interaction between protein-energy wasting, inflammation and cardiovascular disease in chronic dialysis patients. Nephrol. Dial. Transplant. 23, (2008). 67. Chung, S. H., Lindholm, B. & Lee, H. B. is malnutrition an independent predictor of mortality in peritoneal dialysis patients? Nephrol. Dial. Transplant. 18, (2003). 68. Fouque, D. et al. C. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 73, (2008). 69. Stenvinkel, P., Heimbürger, O., Lindholm, B., Kaysen, G. A. & Bergström, J. Are there two types of malnutrition in chronic renal failure? Evidence for relationships between malnutrition, inflammation and atherosclerosis (MiA syndrome). Nephrol. Dial. Transplant. 15, (2000). 70. de Mutsert, R. et al. Association between serum albumin and mortality in dialysis patients is partly explained by inflammation, and not by malnutrition. J. Ren. Nutr. 19, (2009). 71. Kalantar-Zadeh, K., ikizler, T. A., Block, G., Avram, M. M. & Kopple, J. D. Malnutritioninflammation complex syndrome in dialysis patients: causes and consequences. Am. J. Kidney Dis. 42, (2003). 72. Friedman, A. N. & Fadem, S. Z. Reassessment of albumin as a nutritional marker in kidney disease. J. Am. Soc. Nephrol. 21, (2010). 73. Cheng, T. H. et al. Serial monitoring of nutritional status in Chinese peritoneal dialysis patients by Subjective Global Assessment and comprehensive Malnutrition inflammation Score. Nephrology (Carlton) 14, (2009). 74. Ho, L. C., Wang, H. H., Chiang, C. K., Hung, K. Y. & Wu, K. D. Malnutrition-inflammation score independently determined cardiovascular and infection risk in peritoneal dialysis patients. Blood Purif. 29, (2010). 75. Oberg, B. P. et al. increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 65, (2004). 458 AUGUST 2010 volume 6