1 Proceedings of the ISPD 2006 The 11th Congress of the ISPD /07 $ August 25 29, 2006, Hong Kong Copyright 2007 International Society for Peritoneal Dialysis Peritoneal Dialysis International, Vol. 27 (2007), Supplement 2 Printed in Canada. All rights reserved. CARDIOVASCULAR RISK FACTORS IN PERITONEAL DIALYSIS PATIENTS REVISITED Angela Yee-Moon Wang University Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong SAR, PR China End-stage renal disease patients are at a heightened risk of developing cardiovascular disease, with contributions from both traditional and nontraditional cardiovascular risk factors. Some of the nontraditional risk factors, such as extracellular volume overload, inflammation, and hyperphosphatemia, have also been shown to be important predictors of mortality in the dialysis population. This article provides an in-depth review of the evidence that supports the substantial contributions of nontraditional risk factors to adverse cardiovascular outcomes in chronic peritoneal dialysis patients. In addition, it provides evidence to demonstrate how loss of residual renal function may be central to the development of cardiovascular disease in the peritoneal dialysis population. Perit Dial Int 2007; 27(S2):S223 S227 KEY WORDS: Cardiovascular; residual renal function; inflammation; calcification; cardiac hypertrophy. According to the U.S. Renal Data System and the European Renal Association European Dialysis and Transplantation Association registry (1), mortality among end-stage renal disease (ESRD) patients is at least 10 to 20 times that of an age-, race-, and sex-matched general population. Moreover, at least half of all deaths in ESRD patients are attributable to cardiovascular causes. These facts are in keeping with data from the Hong Kong renal registry, which show that more than 50% of the mortality in chronic peritoneal dialysis (PD) patients is attributable to cardiovascular disease. Although a greater prevalence of traditional Framingham risk factors such as hypertension, high blood cholesterol, and diabetes have been observed in chronic kidney disease patients and in patients on dialysis as compared with patients having normal kidney function Correspondence to: A.Y.M. Wang, University Department of Medicine, Queen Mary Hospital, University of Hong Kong, 102 Pokfulam Road, Hong Kong SAR, PR China. (2), evidence is accumulating that a whole host of nontraditional risk factors or, more correctly, kidney disease-related risk factors, including chronic inflammation, deranged calcium phosphorus metabolism, extracellular volume overload, anemia, increased oxidative stress, hyperparathyroidism, hyperhomocysteinemia, insulin resistance, and sympathetic overactivity also predispose those patients to an increased risk of cardiovascular events and mortality. This article reviews some of these highly prevalent cardiovascular risk factors that have been shown to predict cardiovascular outcome in PD patients. EXTRACELLULAR VOLUME OVERLOAD Chronic PD patients frequently exhibit the complication of extracellular volume overload. According to a study by Tzamaloukas et al. (3), symptomatic volume overload may manifest in various ways, including peripheral edema (100% of patients), pulmonary congestion (80%), pleural effusion (76%), systolic hypertension (83%), and diastolic hypertension (66%). A recent study showed that close to 40% of chronic PD patients developed one or more episodes of circulatory congestion during a 3-year prospective follow-up (4). The causes of extracellular volume overload are usually multifactorial, including noncompliance with fluid intake restrictions, low effluent drain volumes, and high membrane transport status. Diabetes is also associated with increased risk of extracellular volume overload (3). As shown by Ates et al. (5), the degree of sodium and fluid removal significantly influences the survival of PD patients, in that patients with lower sodium and fluid removal have a higher mortality rate that may be attributable to extracellular volume overload with resulting greater left ventricular (LV) hypertrophy and dysfunction. That finding is in keeping with a study that showed more severe LV hypertrophy, dilatation, and ventricular dysfunction among patients with a previous history of S223
2 PROCEEDINGS OF THE 11TH CONGRESS OF THE ISPD JUNE 2007 VOL. 27, SUPPL 2 PDI volume overload than in those with no such previous history (6). The foregoing observations raise two possibilities. First, as compared with patients having with no previous history of volume overload, patients with such a history may remain persistently volume overloaded. Second, an episode of volume overload, though now in the past and presumably resolved, may continue to exert negative effects on the myocardium, resulting in more severe LV hypertrophy. In chronic PD patients, LV hypertrophy is an important predictor of mortality and cardiovascular death (7). A previous study showed that more than 90% of prevalent PD patients have LV hypertrophy (7). The presence of congestive heart failure also predicts mortality in patients on dialysis (8). Furthermore, progression of LV hypertrophy provides important prognostic information (9). Controlling for baseline LV mass index and other clinical and demographic factors, patients with a >75th percentile increase in LV mass over a mean interval of 18 ± 2 months (standard deviation) had a mortality and cardiovascular event risk that was 3 times that of patients having minimal increases in LV mass. Thus, achieving strict volume control appears to be an important therapeutic strategy for inducing regression of LV hypertrophy and lowering cardiovascular event risk in chronic PD patients. On the other hand, extracellular volume overload in PD patients may be partly attributable to decline of residual renal function (RRF), which itself is an important predictor of mortality (10). Long-term continuous ambulatory PD (CAPD) has been suggested to be disadvantageous in preserving cardiac performance (11). Evidence also suggests that long-term CAPD patients show greater volume expansion and LV hypertrophy than hemodialysis patients do (12). In the reanalysis of data from the CANUSA study (13), RRF was shown to be a more important contributor to the overall survival of PD patients than PD clearance was. The importance of RRF in PD patients appears to be mediated partly by its influence on fluid removal: entering urine volume into the Cox regression model for mortality completely displaces residual glomerular filtration rate (GFR) from the model. That finding accords well with a study showing that volume expansion in PD patients is related not only to peritoneal transport characteristics but also to residual GFR (14). Taken together with the previous demonstration of the novel association between residual GFR and LV hypertrophy (15), this suggests that RRF may play an important role in extracellular volume control and that extracellular volume overload may in part explain the link between loss of RRF and development of LV hypertrophy in PD patients. S224 INFLAMMATION Dialysis patients are at an increased risk of accelerated atherosclerosis partly because of the presence of inflammation. The prototypic markers of inflammation, C-reactive protein (CRP) and interleukin-6 (IL-6), have been shown to play a role in atherosclerosis (16,17). Previous studies have demonstrated the importance of inflammation, as denoted by CRP, in predicting mortality and cardiovascular death in PD and hemodialysis patients (18). More recently, CRP was shown to predict the time to occurrence of cardiac events in dialysis patients (19). The causes of inflammation in PD patients are usually multifactorial: infections, malnutrition, bioincompatible dialysis solution, and cardiovascular disease (20). Of note is the important inverse relationship observed between inflammation and RRF in PD patients (10). Anuric PD patients had higher serum levels of CRP than did patients with preserved RRF (21). In addition, CRP was positively linked with arterial stiffening, as denoted by arterial pulse pressure, LV hypertrophy, dilatation, and systolic dysfunction (7). Although the exact relationships between inflammation, RRF, and LV hypertrophy have yet to be determined, the previous study clearly demonstrated that inflammation, loss of RRF, and LV hypertrophy combined adversely to heighten risk of mortality and cardiovascular death in PD patients (7). Vascular cell adhesion molecule 1 (VCAM-1) is involved in leukocyte endothelial cell interactions and plays a pivotal role in inflammation. In PD patients, a strong inverse relationship was recently observed between RRF and circulating soluble VCAM-1 (22). In addition, there is evidence that the association between loss of RRF and increased mortality and cardiovascular events in PD patients may be partly mediated by an increased inflammatory profile as evidenced by elevated levels of the adhesion molecule in the circulation. Data also suggest that IL-6 may serve as a better inflammatory biomarker than CRP in predicting mortality and cardiovascular outcomes in ESRD patients (23 25). Tripepi et al. showed that, in ESRD patients, IL-6 adds significant predictive power to estimates of mortality and cardiovascular death risk (26). In another study, Honda et al. found that, in comparison with other inflammatory markers including serum albumin, high-sensitivity CRP, and fetuin-a, IL-6 had the highest predictive value for cardiovascular disease and clinical outcome in ESRD patients (27). The importance of IL-6 in mediating cardiovascular disease is further reinforced by a recent study showing that functional variants of the IL-6 gene ( 174C carriers in the absence of 162 Val allele) affect inflammation and risk of cardiovascular disease in dialysis patients (28).
3 PDI JUNE 2007 VOL. 27, SUPPL 2 PROCEEDINGS OF THE 11TH CONGRESS OF THE ISPD HYPERPHOSPHATEMIA Hyperphosphatemia and increased Ca P product are well-established risk factors for mortality and cardiovascular death in hemodialysis patients and PD patients alike (29,30). They also contribute to an increased risk of vascular, valvular, and other tissue calcification. Although hyperphosphatemia was once considered to be a relatively infrequent complication in PD patients, increasing evidence suggests that it is highly prevalent in the PD population. The Netherlands Cooperative Study on the Adequacy of Dialysis and a study by Wang et al. (30,31) both showed that about 40% of chronic PD patients have a serum phosphorus level above the target 1.78 mmol/l recommended by the Kidney Disease Outcomes Quality Initiative. Among patients with preserved RRF, residual GFR was second to dietary protein intake in the list of the most important factors associated with hyperphosphatemia. Residual GFR was even more important than PD clearance. However, among anuric patients, the adequacy of PD clearance appeared to be the most important determinant of serum phosphorus control (31). Based on the data, it appears that total weekly urea and creatinine clearances of at least 2.0 and 60 L/1.73 m 2 respectively may be optimal targets for maintaining serum phosphorus below 5 mg/dl in Chinese CAPD patients. However, the data also suggest the inadequacy of PD alone in achieving adequate phosphorus control in anuric PD patients. One major clinical consequence of hyperphosphatemia is the development of vascular, valvular, and other tissue calcification. The importance of vascular calcification in predicting mortality and cardiovascular death has been demonstrated in hemodialysis patients (32). Valvular calcification is also a powerful predictor of mortality and cardiovascular death in PD patients (33). Vascular calcification in ESRD patients commonly occurs in both the intimal and the medial layers. Vascular calcification secondary to hyperphosphatemia typically occurs in the media and is associated with generalized arterial stiffening that increases the afterload and results in LV hypertrophy (34,35), which may reduce coronary flow reserve and increase risk of myocardial ischemia. Further, data from animal studies show that hyperphosphatemia may increase cardiac fibrosis and hypertrophy, and aggravate microvascular disease (36). On the other hand, vascular calcification occurring in the intimal layer is typically atherosclerotic in nature and may lead to obstructive coronary lesions with resulting coronary ischemia. Interestingly, previous data suggest that valvular calcification also represents a marker of atherosclerosis in PD patients, as evidenced by its association with greater carotid intima media thickness and more plaque calcification (37). The prevalence of coronary artery calcification (CAC) was reported to range from 40% to 100% in the dialysis population (38 41). To date, most of those surveys were conducted in hemodialysis populations, and only a few surveys in PD populations are available. In one of the latter surveys, the prevalence of CAC was reported to be 60% (42). Using echocardiography, one third of the Chinese PD population were noted to have valvular calcification. In addition, a much higher CAC score was observed in dialysis patients than in age- and sex-matched non-dialysis control subjects with coronary artery disease (38). In dialysis patients, CAC is rapidly progressive (41). In a recent longitudinal study that included PD patients only, serum phosphorus and Ca P product were found to be the most important factors predicting progression of CAC (43). Other factors that may predispose to cardiac calcification include increasing age, increasing dialysis duration, and cumulative dose of calcium-based binders (41). The use of calcium-based binders was most likely to be associated with progressive CAC when mineral metabolism was not well controlled (44). That finding is in keeping with a study showing that sevelamer hydrochloride, a non-calcium-based binder, attenuates the progression of CAC in hemodialysis patients (45). Evidence that inflammation may be involved in the calcification process is also increasing, as shown by the important link between inflammation and valvular calcification (46). Reduced circulating levels of the calcification inhibitor fetuin-a, which is a negative acute-phase reactant, predicts mortality in dialysis patients (47) and is also associated with increased risk of valvular calcification (48). The recent finding that higher CRP is associated with more rapid annualized progression of CAC score in dialysis patients is further evidence to support the role of inflammation in mediating calcification (49). On the other hand, a recent unpublished observation by Wang and colleagues suggests that loss of RRF also predisposes PD patients to an increased risk of valvular calcification as a result of higher Ca P product and increased inflammation. Of additional importance is the observation that inflammation, high Ca P product, loss of RRF, and valvular calcification combine adversely to increase the severity of LV hypertrophy in PD patients. CONCLUSIONS Patients on PD are at a heightened risk of developing accelerated atherosclerosis, vascular and valvular calcification, and LV hypertrophy secondary to a S225
4 PROCEEDINGS OF THE 11TH CONGRESS OF THE ISPD JUNE 2007 VOL. 27, SUPPL 2 PDI multitude of traditional and kidney disease related risk factors. Previous studies suggest that the prevalence and severity of some of these risk factors may increase with decline in RRF. More attention should be paid to preserving RRF and improving cardiovascular outcomes in PD patients. ACKNOWLEDGMENT The work described here is supported by funds from the Hong Kong Health Service Research Grant, Hong Kong Society of Nephrology Research Grants, and the Baxter Extramural Grant Program. REFERENCES 1. Raine AE, Margreiter R, Brunner FP, Ehrich JH, Geerlings W, Landais P, et al. Report on management of renal failure in Europe, XXII, Nephrol Dial Transplant 1992; 7(Suppl 2): Longenecker JC, Coresh J, Powe NR, Levey AS, Fink NE, Martin A, et al. Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study. J Am Soc Nephrol 2002; 13: Tzamaloukas AH, Saddler MC, Murata GH, Malhotra D, Sena P, Simon D, et al. Symptomatic fluid retention in patients on continuous peritoneal dialysis. J Am Soc Nephrol 1995; 6: Wang AY, Lam CW, Yu CM, Wang M, Chan IH, Lui SF, et al. Troponin T, left ventricular mass, and function are excellent predictors of cardiovascular congestion in peritoneal dialysis. Kidney Int 2006; 70: Ates K, Nergizoglu G, Keven K, Sen A, Kutlay S, Erturk S, et al. Effect of fluid and sodium removal on mortality in peritoneal dialysis patients. Kidney Int 2001; 60: Wang AY, Sanderson J, Sea MM, Wang M, Lam CW, Li PK, et al. Important factors other than dialysis adequacy associated with inadequate dietary protein and energy intakes in patients receiving maintenance peritoneal dialysis. Am J Clin Nutr 2003; 77: Wang AY, Wang M, Woo J, Lam CW, Lui SF, Li PK, 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 2004; 15: Harnett JD, Foley RN, Kent GM, Barré PE, Murray D, Parfrey PS. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int 1995; 47: Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Giacone G, Stancanelli B, et al. Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression. Kidney Int 2004; 65: S Wang AY, Woo J, Lam CW, Wang M, Sea MM, Lui SF, et al. Is a single time point C-reactive protein predictive of outcome in peritoneal dialysis patients? J Am Soc Nephrol 2003; 14: Takeda K, Nakamoto M, Hirakata H, Baba M, Kubo M, Fujishima M. Disadvantage of long-term CAPD for preserving cardiac performance: an echocardiographic study. Am J Kidney Dis 1998; 32: Enia G, Mallamaci F, Benedetto FA, Panuccio V, Parlongo S, Cutrupi S, et al. Long-term CAPD patients are volume expanded and display more severe left ventricular hypertrophy than haemodialysis patients. Nephrol Dial Transplant 2001; 16: Bargman JM, Thorpe KE, Churchill DN. Relative contribution of residual renal function and peritoneal clearance to adequacy of dialysis: a reanalysis of the CANUSA study. J Am Soc Nephrol 2001; 12: Konings CJ, Kooman JP, Schonck M, Struijk DG, Gladziwa U, Hoorntje SJ, et al. Fluid status in CAPD patients is related to peritoneal transport and residual renal function: evidence from a longitudinal study. Nephrol Dial Transplant 2003; 18: Wang AY, Wang M, Woo J, Law MC, Chow KM, Li PK, et al. A novel association between residual renal function and left ventricular hypertrophy in peritoneal dialysis patients. Kidney Int 2002; 62: Libby P. Inflammation in atherosclerosis. Nature 2002; 420: Rattazzi M, Puato M, Faggin E, Bertipaglia B, Zambon A, Pauletto P. C-Reactive protein and interleukin-6 in vascular disease: culprits or passive bystanders? J Hypertens 2003; 21: Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int 1999; 55: Hase H, Joki N, Ishikawa H, Saijyo T, Tanaka Y, Takahashi Y, et al. Independent risk factors for progression of coronary atherosclerosis in hemodialysis patients. Ther Apher Dial 2006; 10: Wang AY. Prognostic value of C-reactive protein for heart disease in dialysis patients. Curr Opin Investig Drugs 2005; 6: Wang AY, Woo J, Wang M, Sea MM, Sanderson JE, Lui SF, et al. Important differentiation of factors that predict outcome in peritoneal dialysis patients with different degrees of residual renal function. Nephrol Dial Transplant 2005; 20: Wang AY, Lam CW, Wang M, Woo J, Chan IH, Lui SF, 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 2005; 45: Panichi V, Maggiore U, Taccola D, Migliori M, Rizza GM, Consani C, et al. Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein
5 PDI JUNE 2007 VOL. 27, SUPPL 2 PROCEEDINGS OF THE 11TH CONGRESS OF THE ISPD in haemodialysis patients. Nephrol Dial Transplant 2004; 19: 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 2002; 17: Rao M, Guo D, Perianayagam MC, Tighiouart H, Jaber BL, Pereira BJ, et al. Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 2005; 45: Tripepi G, Mallamaci F, Zoccali C. Inflammation markers, adhesion molecules, and all-cause and cardiovascular mortality in patients with ESRD: searching for the best risk marker by multivariate modeling. J Am Soc Nephrol 2005; 16(Suppl 1):S Honda H, Qureshi AR, Heimbürger O, Bárány P, Wang K, Pecoits Filho R, et al. Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis 2006; 47: Liu Y, Berthier Schaad Y, Fallin MD, Fink NE, Tracy RP, Klag MJ, et al. IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort. J Am Soc Nephrol 2006; 17: Block GA, Hulbert Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31: Noordzij M, Korevaar JC, Bos WJ, Boeschoten EW, Dekker FW, Bossuyt PM, et al. Mineral metabolism and cardiovascular morbidity and mortality risk: peritoneal dialysis patients compared with haemodialysis patients. Nephrol Dial Transplant 2006; 21: Wang AY, Woo J, Sea MM, Law MC, Lui SF, Li PK. Hyperphosphatemia in Chinese peritoneal dialysis patients with and without residual kidney function: what are the implications? Am J Kidney Dis 2004; 43: Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001; 38: Wang AY, Wang M, Woo J, Lam CW, Li PK, Lui SF, et al. Cardiac valve calcification as an important predictor for allcause mortality and cardiovascular mortality in long-term peritoneal dialysis patients: a prospective study. J Am Soc Nephrol 2003; 14: Haydar AA, Covic A, Colhoun H, Rubens M, Goldsmith DJ. Coronary artery calcification and aortic pulse wave velocity in chronic kidney disease patients. Kidney Int 2004; 65: London GM, Marchais SJ, Guerin AP, Metivier F, Adda H. Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 2002; 17: Amann K, Tornig J, Kugel B, Gross ML, Tyralla K, El- Shakmak A, et al. Hyperphosphatemia aggravates cardiac fibrosis and microvascular disease in experimental uremia. Kidney Int 2003; 63: Wang AY, Ho SS, Wang M, Liu EK, Ho S, Li PK, et al. Cardiac valvular calcification as a marker of atherosclerosis and arterial calcification in end-stage renal disease. Arch Intern Med 2005; 165: Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 1996; 27: Raggi P, Boulay A, Chasan Taber S, Amin N, Dillon M, Burke SK, et al. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 2002; 39: Moe SM, O Neill KD, Fineberg N, Persohn S, Ahmed S, Garrett P, et al. Assessment of vascular calcification in ESRD patients using spiral CT. Nephrol Dial Transplant 2003; 18: Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: Stompor T, Pasowicz M, Sullowicz W, Dembinska Kiec A, Janda K, Wojcik K, et al. An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003; 41: Stompor TP, Pasowicz M, Sulowicz W, Dembinska Kiec A, Janda K, Wojcik K, et al. Trends and dynamics of changes in calcification score over the 1-year observation period in patients on peritoneal dialysis. Am J Kidney Dis 2004; 44: Chertow GM, Raggi P, Chasan Taber S, Bommer J, Holzer H, Burke SK. Determinants of progressive vascular calcification in haemodialysis patients. Nephrol Dial Transplant 2004; 19: Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62: Wang AY, Woo J, Wang M, Sea MM, Ip R, Li PK, et al. Association of inflammation and malnutrition with cardiac valve calcification in continuous ambulatory peritoneal dialysis patients. J Am Soc Nephrol 2001; 12: Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, et al. Association of low fetuin-a (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003; 361: Wang AY, Woo J, Lam CW, Wang M, Chan IH, Gao P, et al. Associations of serum fetuin-a with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol Dial Transplant 2005; 20: Jung HH, Kim SW, Han H. Inflammation, mineral metabolism and progressive coronary artery calcification in patients on haemodialysis. Nephrol Dial Transplant 2006; 21: S227