Cardiovascular disease in haemodialysis and peritoneal dialysis: arguments pro peritoneal dialysis

Nephrol Dial Transplant (2007) 22: 53–58 doi:10.1093/ndt/gfl601 Advance Access publication 18 October 2006

Pro-Con Debate

Cardiovascular disease in haemodialysis and peritoneal dialysis: arguments pro peritoneal dialysis Wim Van Biesen, Francio Verbeke and Raymond Vanholder Renal Division, Department of Internal Medicine, University Hospital Ghent, Belgium

Introduction Cardiovascular disease is frequent in end-stage renal disease (ESRD) patients, and it is the major cause of morbidity [1,2] and mortality [3] in this population. It can manifest itself as ischaemic heart disease, congestive heart failure, atherosclerotic peripheral vascular disease [4] or cerebrovascular disease [5]. In the last decade, evidence has accrued that part of this cardiovascular damage might be due to renal replacement therapy (RRT) itself, and the question whether haemodialysis (HD) or peritoneal dialysis (PD) is more harmful than the other is, therefore, of high relevance. Some recent publications have suggested a worse outcome in PD as compared with HD patients [6,7] with congestive heart failure or coronary heart disease, pleading to avoid PD in cardiovascular-compromised patients. Are these results the confirmation that PD is a second-class treatment, or are we listening to the wrong heartbeat?

Clinical outcome studies Despite the relevance of the subject, only few studies compare the cardiovascular outcome of PD vs HD. The question whether dialysis modality impacts cardiovascular outcome should be addressed in different stages: (i) outcome compared between dialysis modalities in the general population after correction for presence of cardiovascular risk factors; (ii) impact of dialysis modality on emergence of ‘de novo’ cardiac disease; (iii) outcome in patients with existing Correspondence and offprint requests to: W. Van Biesen, Renal division, Department of Internal Medicine, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium. Email: [email protected]

cardiovascular disease; and (iv) traditional cardiovascular risk factors. General population studies. Studies based on populations from Europe, Asia or Canada do not show a survival difference between PD and HD, and even suggest that starting PD and transferring patients to HD when indicated, the integrated care concept, is related to an increased survival [8–11]. Studies based on US data mostly showed a survival disadvantage for PD patients [12,13]. It appears that the conflicting results are attributable to differences in methodology with regard to inclusion of incident vs prevalent patients [12,14] and the degree of case-mix adjustment. In addition, we believe that in view of the very large patient numbers, the difference between ‘statistically different’ and ‘clinically different’ can be wide [14]. Dialysis modality and de novo cardiac disease Limited data on this topic have been published. In the Lombardy registry, Locatelli et al. [15] found that dialysis modality had no impact on development of de novo cardiac disease or cardiovascular mortality [relative risk (RR) for PD vs HD 0.9, P ¼ 0.22] after correcting for age, gender and diabetes in incident patients without pre-existing cardiac disease (RR for PD vs HD 1.06, P ¼ 0.69, N for HD ¼ 2772, N for PD ¼ 1292). Foley et al. [16] compared 433 incident PD and HD patients regarding ‘de novo’ development of left ventricular hypertrophy and left ventricular dysfunction, and found no difference. Trespalacios et al. [17] found an increased risk for hospitalization because of de novo heart failure in HD (RR 1.08–2.53). In the same cohort, no difference between PD and HD patients was found in the incidence of de novo coronary heart disease [18]. Other reports [6,11,16] demonstrate that the initial survival of patients without coronary heart disease or myocardial infarction at start of dialysis was better in PD than in HD (P < 0.001), with after some years a survival advantage for HD. In another analysis of United States Renal Database System (USRDS) data [19], comparing only patients

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Keywords: cardiovascular; hemodialysis; outcome; peritoneal dialysis; survival; uraemic toxins

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Patients with existing cardiovascular disease. Cardiovascular disease is highly prevalent in patients starting RRT. The impact of the RRT modality on the further progression of cardiovascular disease is thus of importance. Unfortunately, there is evidence that cardiovascular risk factors are not managed very well in patients on RRT. From the DOPPS registry, it became apparent that aspirin, statins and beta blockade are underused in HD patients [22,23]. Vascular calcification and vascular stiffness are important markers of cardiovascular damage that can also be applied in ESRD patients. The relevance of vascular stiffness comes not only from the fact that it relates more to intima-media damage, but especially from the physiological consequences of increased vascular stiffness: increased afterload and decreased coronary perfusion. Sigrist et al. [24] demonstrated that PD patients had not only lower calcification scores as compared with HD patients, but also that

vascular stiffness tended to decline after 12 months of treatment on PD, whereas it increased on HD. Bloembergen et al. [12] described a higher mortality in PD as compared with HD patients, and attributed this excess mortality to differences in cardiovascular causes of mortality. However, this study was biased by the inclusion of prevalent patients, typically leading to a survival bias in favour of the modality with the highest initial mortality risk [14,25]. More recently, Ganesh et al. [6] and Stack et al. [7] found a worse outcome of patients with coronary artery disease or with congestive heart failure, respectively, on PD. Although these studies contain large patient numbers, leading to impressive statistical differences, there are some pitfalls that should lead us to caution before generalizing the statement that PD increases cardiovascular risks more than HD. Both these studies rely on the USRDS database, and large differences in practices might be present between the US and other regions, leading to differences in outcomes [26]. Also it is likely that there were differences in experience with PD and HD, and no correction for centre size was applied, although this is an important confounder, with a relative risk for centres with less than 20 patients of 1.13 (P ¼ 0.001) [27]. In addition, the data of the USRDS database cannot be transposed as such to other patient populations, as at the moment of the registry, the Food and Drug Administration (FDA) had not yet approved the use of low-GDP (glucose degradation products) solutions and of icodextrin. Especially the latter is an important tool in the maintenance of fluid balance, an important factor in the emergence of cardiovascular disease. In addition, there might be a selection bias induced by exclusion of patients who died during the first 90 days of treatment. By this approach, a bias comparable with that observed when ‘prevalent’ patients are included in an analysis is created [25], especially for patients with cardiovascular damage, as only the fittest patients might have survived the first 90 days. As the haemodynamic instability is a stronger selection drive during HD than PD, it is well conceivable that in HD only the better patients survived the first 90 days, leaving many potential casualties out of the analysis. In the observation period of the paper by Ganesh et al. [6] 167 000 patients started dialysis, but only 107 922 were included in the study. Neither the fate nor the dialysis modality of the 60 000 missing patients was described. At our centre, mortality during the first 3 months after start of dialysis is 7.9% as compared with 2.5% in the HD and PD patients, respectively (P ¼ 0.013). In the USRDS database, the mortality due to left ventricular hypertrophy was highest in HD patients during the first 6 months of treatment, declining afterwards, also pointing to a ‘selection effect’ [28]. The idea that survival of patients with congestive heart failure is comparable between PD and HD, except for the older female diabetics, where mortality is higher on PD, is further supported by the findings of Vonesh et al. [19].

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without comorbidity, survival was worse in HD as compared with PD patients without diabetes (RR varying between 1.13 and 1.24 depending on age category, P < 0.05). Even in the patients with diabetes, but no cardiovascular damage at start of renal replacement therapy, HD had a higher mortality risk than PD if they were below 45 years of age (RR 1.22, CI 1.05–1.42). In the age category between 45 and 64 years, there appears to be no difference in outcome in this subgroup of patients (RR 0.92, CI 0.85–1.00), whereas once above 65, the risk was higher in the PD patients (RR 0.86, CI 0.79–0.93). In addition, it appears that PD and HD patients have comparable odds to be referred for heart catheterization, pointing to a similar risk for development or worsening of coronary heart disease in the two groups [20]. Stroke is an important cause of disability and mortality in ESRD patients. Iseki et al. [21] found an increased risk (RR 5.2, P < 0.001) for stroke-related mortality in HD patients, the majority of events being haemorrhagic in nature (incidence per 1000 personyear of 2.2 in cerebral infarction, 8.7 in cerebral haemorrhage and 0.6 in subarachnoid haemorrhage). A comparable incidence of stroke-related death of 11.5 per 1000 person-year was observed both in PD as in HD in the USRDS database [5]. A subgroup analysis revealed a lower risk for stroke-related death for PD in non-diabetic patients, whereas in diabetic patients, the risk appeared to be higher in PD patients, especially in blacks and in older women. Unfortunately, in the separate analysis of risk factors for ischaemic and haemorrhagic stroke, dialysis modality was not reported as a variable. It is quite conceivable that, in HD patients, especially the risk for haemorrhagic stroke is increased, whereas in PD patients, in view of the reported hypercoagulability, there is a higher incidence of ischaemic stroke. Overall, in patients without cardiovascular disease at start of dialysis, the clinical evidence seems to indicate that neither PD or HD is superior in preventing the emergence of new cardiovascular disease.

W. Van Biesen et al.

Cardiovascular disease in haemodialysis and peritoneal dialysis

Causes of cardiovascular risk in ESRD patients, performance differences between different modes of PD and HD and their relation to impact on cardiovascular outcome Potential differences in how PD and HD alter cardiovascular risk factors might give insight on how the cardiovascular impact of both modalities will differ. The driving forces for cardiovascular disease in ESRD patients are (i) retention of uraemic toxin products; (ii) fluid overload and (iii) inflammation.

Volume status, modality and cardiovascular outcome. Fluid overload is an important risk factor for development of congestive heart failure, itself being a risk factor for cardiovascular mortality. There is a clear relationship between RRF and left ventricular hypertrophy (LVH) [39,40], once again pointing to the importance of maintenance of RRF, and explaining why PD patients have less LVH in the beginning of their treatment, with a progressive increase as their RRF declines with time [41,42]. However, in the measurement of LVH, formulas are applied that rely heavily on the cube root of end diastolic diameter [43], so that small differences in hydration status have substantial impacts on the obtained values. With regard to blood pressure control, 44 h blood pressure monitoring has shown that hypertension is less prevalent in HD than in PD patients on the day of dialysis but on the second day, is more prevalent and more expressed [44]. Once again, major differences in the way patients are treated by HD or PD can impact tremendously on the result. The use of low sodium diet [45,46], diuretics [47] and/or icodextrin [48,49] result in a substantial improvement of fluid status. The evaluation of volume status might be somewhat more complicated in a PD as compared with an HD patient, but tools like echocardiograpy, or the use of troponin T [50] might serve the clinician to decide on the volume status of the PD patient. Substantial differences in salt removal might arise between APD regimens and CAPD regimens due to sodium sieving [51]. Insufficient attention to this mechanism, whereby patients ultrafilter only free water, but not sodium, might give rise to a state of chronic hypervolaemia in PD patients. Once again, it appears that the way the methodology is applied is more important than the method itself. As an interim conclusion, it appears that maintenance of fluid balance might be problematic in PD once RRF has declined. However, effective strategies to optimize fluid balance in PD patients like sodium restriction, diuretics and icodextrin are efficient but underused. Inflammation, modality and cardiovascular risk. Inflammation is an important cardiovascular risk factor [52], with a malicious synergy with uraemia and malnutrition (MIA syndrome) [53]. In contrast with prevailing opinion, the risk of infection in PD patients is comparable with that of HD patients with a native arteriovenous (AV) fistula and even lower than in HD patients with a catheter or a graft [54]. In HD, microinflammation is related to the contact of blood with bio-incompatible membranes, the use of impurities in the dialysate, accumulation of advanced glycation end products (AGEs) and uraemic retention products [29]. Strategies that use low-complement activating membranes for high flux or HF, and ultra-pure dialysate should thus theoretically lead to an improved cardiovascular outcome, although firm clinical prove for this concept is still lacking. In PD, microinflammation can be induced by bio-incompatibility

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Uraemic retention products, modality and cardiovascular outcome. Uraemic retention products add to cardiovascular damage [29–31]. Most of these substances are either protein bound, of middle molecular weight or a combination of both, so that their removal with conventional HD is limited. Guanidines, for example, are related to chronic inflammation in ESRD patients [29]. The removal of guanidines by conventional haemodialysis is low because of their high distribution volume due to protein binding [32]. Other substances like dinucleoside polyphosphates, which induce vascular smooth muscle cell growth [33], and uridine adenosine polyphosphate, a potent vasconstrictor acting on the endothelium [34], behave like middle molecular structures, and potentially need convective and/or extended dialysis for their removal. The failure of the hemodialysis (HEMO) study [35] to find a difference in outcome between patients with higher or lower levels of Kt/Vurea might be attributed to the fact that we measure the wrong indicator for describing our dose of dialysis, and that the meaning of Kt/Vurea is different in low vs high flux vs haemofiltration, and is also related to the duration of the dialysis session. Also in the field of PD, the impact of the removal as expressed by Kt/V, is for larger or protein bound solutes completely different in patients on continuous ambulatory PD (CAPD) and those on automated PD (APD), and this difference is even dependent upon the transport characteristics of the peritoneal membrane. From the point of view of ‘removal of uremic toxins’, a general comparison between ‘cardiovascular outcome on PD or HD’ as such will only reveal a very blurred picture, because tremendous differences will arise already between patients on low flux HD compared with high flux HD or haemofiltration (HF) and also between patients on CAPD and APD. The way these treatments are performed will potentially more influence the outcome results than the treatments themselves. Residual renal function (RRF) is important for the removal of uremic toxins. Preservation of RRF is better in PD as compared with HD patients [36], with the exception of HF [37], giving these two modalities a theoretical advantage in cardioprotection. In addition, the intermittent nature of HD poses high demands to dietary compliance of the HD patient, potentially leading to lethal complications like hyperkalaemia or pulmonary oedema, if not mastered appropriately [38].

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of the dialysate, mainly due to the presence of GDPs [55]. It can be hoped that the implementation of low-GDP containing solutions should lead to a decreased prevalence of circulating GDP levels [56] and micro-inflammation. Also RRF is related to inflammation, and preservation of RRF postpones the occurrence of inflammation [57].

Conclusions There is no doubt that every effort to reduce cardiovascular mortality in ESRD patients should be encouraged. Early intervention by correction of risk factors, long before ESRD develops, is most beneficial. The definite answer as to whether dialysis modality is a risk factor for cardiovascular disease is thus still debatable if this question is reduced that of PD vs HD. There is enough evidence that the way each of the RRT modalities is performed is more important than which modality is performed, showing that the available evidence comparing PD and HD with regard to cardiovascular risk, is aiming at a fast moving target, because the introduction of icodextrin and low-GDP solutions for PD and the more widespread use of HDF and extended (nocturnal dialysis) for HD might change the picture completely. For PD patients, the optimization of fluid balance as an important parameter of adequacy has long been neglected. This has lead to a higher prevalence of congestive heart failure and hypertension in PD as compared with HD patients, especially after disappearance of RRF. Use of salt restriction [45],

diuretics [47], and/or icodextrin have all proven to be effective in lowering the extracellular body water, reduce blood pressure and LVH [48,49]. Their impact on cardiovascular outcome however, remains, to be determined. Today, there is insufficient evidence to let concerns on cardiovascular outcome prevail over the free choice of the patient to select either PD or HD as his or her preferred first-line RRT modality. In older diabetics, especially women, there might be an excess cardiovascular mortality in PD for reasons we still do not understand. Although some studies indicate a higher mortality in cardiovascular compromised patients, these studies have some particularities making it dangerous to base firm conclusions on them or to generalize their results. Conflict of interest statement. None declared.

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Received for publication: 26.7.06 Accepted in revised form: 1.9.06

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