Peritoneal Dialysis International, Vol. 26, pp. 523–539 Printed in Canada. All rights reserved. 0896-8608/06 $3.00 + .00 Copyright © 2006 International Society for Peritoneal Dialysis IN-DEPTH REVIEW STATINS FOR TREATMENT OF DYSLIPIDEMIA IN CHRONIC KIDNEY DISEASE Sabin Shurraw1 and Marcello Tonelli1,2,3 Dyslipidemia is a potent cardiovascular (CV) risk factor in the general population. Elevated low-density lipoprotein cholesterol (LDL-C) and/or low high-density lipoprotein (HDL-C) are well-established CV risk factors, but more precise determinants of risk include increased apoprotein B (ApoB), lipoprotein(a) [Lp(a)], intermediate and very lowdensity lipoprotein (IDL-C, VLDL-C; “remnant particles”), and small dense LDL particles. Lipoprotein metabolism is altered in association with declining glomerular filtration rate such that patients with non dialysis-dependent chronic kidney disease (CKD) have lower levels of HDL-C, higher triglyceride, ApoB, remnant IDL-C, remnant VLDL-C, and Lp(a), and a greater proportion of oxidized LDL-C. Similar abnormalities are prevalent in hemodialysis (HD) patients, who often manifest proatherogenic changes in LDL-C in the absence of increased levels. Patients treated with peritoneal dialysis (PD) have a similar but more severe dyslipidemia compared to HD patients due to stimulation of hepatic lipoprotein synthesis by glucose absorption from dialysate, increased insulin levels, and selective protein loss in the dialysate analogous to the nephrotic syndrome. In the dialysis-dependent CKD population, total cholesterol is directly associated with increased mortality after controlling for the presence of malnutrition–inflammation. Treatment with statins reduces CV mortality in the general population by approximately one third, irrespective of baseline LDL-C or prior CV events. Statins have similar, if not greater, efficacy in altering the lipid profile in patients with dialysis-dependent CKD (HD and PD) compared to those with normal renal function, and are well tolerated in CKD ≤≤ mg/day atorvastatin or patients at moderate doses (≤ ≤20 Correspondence to: M. Tonelli, Division of Nephrology, University of Alberta, 7-129 Clinical Science Building, 8440 112 Street, Edmonton, Alberta, T6G 2G3 Canada. [email protected] Received 29 March 2006; accepted 15 June 2006. simvastatin). Statins reduce C-reactive protein as well as lipid moieties such as ApoB, remnants IDL and VLDL-C, and oxidized and small dense LDL-C fraction. Large observational studies demonstrate that statin treatment is independently associated with a 30% – 50% mortality reduction in patients with dialysis-dependent CKD (similar between HD- and PD-treated patients). One recent randomized controlled trial evaluated the ability of statin treatment to reduce mortality in type II diabetics treated with HD (“4D”); the primary end point of death from cardiac cause, myocardial infarction, and stroke was not significantly reduced. However, results of this trial may not apply to other endstage renal disease populations. Two ongoing randomized controlled trials (SHARP and AURORA) are underway evaluating the effect of statins on CV events and death in patients with CKD (including patients treated with HD and PD). Recruitment to future trials should be given a high priority by nephrologists and, until more data are available, consideration should be given to following published guidelines for the treatment of dyslipidemia in CKD. Additional consideration could be given to treating all dialysis patients felt to be at risk of CV disease (irrespective of cholesterol level), given the safety and potential efficacy of statins. This is especially relevant in patients treated with PD, given their more atherogenic lipid profile and the lack of randomized controlled trials in this population. Perit Dial Int 2006; 26:523–539 www.PDIConnect.com KEY WORDS: HMG-CoA reductase inhibitor; statin; chronic kidney disease; hemodialysis. T he tremendous burden of cardiovascular (CV) morbidity and mortality in hemodialysis (HD) and peritoneal dialysis (PD) patients has been well documented (1,2). Dyslipidemia contributes significantly to CV death in 523 Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 Division of Nephrology1 and Division of Critical Care Medicine,2 University of Alberta; Institute of Health Economics,3 Edmonton, Alberta, Canada SHURRAW and TONELLI OVERVIEW OF LIPOPROTEIN METABOLISM AND ATHEROSCLEROSIS LIPID CLASSIFICATION Lipids [triglycerides (TGs) and cholesterol] are insoluble in plasma and must therefore associate with phospholipid and apoproteins (also referred to as apolipoproteins) to form dissolvable particles called lipoproteins. Apoproteins function not only as lipid carriers, but may possess enzymatic activity and may serve as cofactors for other enzymes or as ligands for receptors in various tissues. Five classes of apoprotein exist: ApoA to ApoE, with several subclasses within each. The most important subclasses are ApoA-I (activator of lecithin cholesterol acyltransferase), ApoB-100 [promotes low- density lipoprotein (LDL) uptake by LDL-receptor], ApoB-48 (promotes chylomicron binding to remnant liver receptors), and ApoC-III (inhibits lipoprotein lipase). Lipoproteins are categorized by their density, which is directly proportional to their ratio of protein to lipid and to the ratio of cholesterol to TG (Figure 1). Each lipoprotein contains a unique array of apoproteins that allow the particle to carry out its specific physiological functions. PRO-ATHEROSCLEROTIC LIPIDS Dyslipidemia is a key contributor to atherosclerosis when kidney function is normal. The detrimental effect of high LDL and/or low high-density lipoprotein (HDL) cholesterol (LDL-C; HDL-C) on CV risk is well established from early studies of dietary cholesterol on atheroscle524 PDI Figure 1 — Major classes of lipoproteins with predominant apoprotein components. Small, dense, low-density lipoprotein (LDL) and lipoprotein(a) [Lp(a)] may be more atherogenic. A subset of LDL contains a unique apoprotein, Apo(a), which is covalently bound to ApoB-100; this complex is called lipoprotein(a), or Lp(a). TG = triglyceride; VLDL = very lowdensity lipoprotein; IDL = intermediate-density lipoprotein; HDL = high-density lipoprotein. rotic progression in animal models, and by large epidemiological studies (4). Apoprotein B-containing lipoproteins are key to the atherosclerotic process and include not only cholesterol-rich LDL and lipoprotein(a) [Lp(a)], but also TG-rich very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). Apoprotein Bcontaining lipoproteins can initiate atherosclerosis by infiltrating the subendothelial space of the arterial wall, where they are sequestered by ionic interactions and subsequently oxidized. LDL-C is a heterogeneous group of lipoproteins; for a given serum LDL concentration, there may be a small number of large particles, or a large number of small, dense, cholesterol-poor particles. The size and shape of the latter particles allow them to more easily pass through the endothelial barrier and bind with stronger affinity to the subendothelial matrix (5), perhaps explaining why predominance of this small dense LDL is associated with increased CV risk (6,7). Since each LDL particle contains one ApoB lipoprotein, ApoB levels may be useful for refining risk estimation within a given stratum of LDL-C level. Oxidized LDL can be taken up by macrophages, which then become cholesterol-laden foam cells that form fatty streaks (8). Foam cells and oxidized LDL in turn play a direct role in the progression of atherosclerosis and plaque rupture (9). Elevated Lp(a) is an independent CV risk factor in most but not all studies. A meta-analysis of 27 prospective studies showed that an elevated baseline Lp(a) (top tertile versus bottom) independently increased the 10-year risk of a coronary event by 70% (10). The in- Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 patients with normal renal function, and cholesterol lowering with statins is effective for primary or secondary prevention of CV disease (3). If pharmacological treatment even modestly lowers the risk of CV events in patients with end-stage renal disease (ESRD), the overall benefit in this high-risk group would be substantial. However, the relation between dyslipidemia and CV risk in patients with renal disease is less clear than in those with normal renal function, as is the efficacy of statins for preventing CV risk. This article reviews the physiology of lipoprotein metabolism, the effect of lipoproteins on atherosclerosis, and how statins might interact with these processes. A review of the literature pertaining to dyslipidemia, statins, and CV risk will follow, discussing patients with normal renal function, non dialysis-dependent chronic kidney disease (CKD), and ESRD in turn, with special emphasis on issues relating to PD. SEPTEMBER 2006 – VOL. 26, NO. 5 PDI SEPTEMBER 2006 – VOL. 26, NO. 5 ANTI-ATHEROSCLEROTIC LIPIDS In contrast to other lipoproteins, increasing levels of HDL independently reduce CV risk in humans in a graded fashion (17). One important protective mechanism may be HDL’s ability to remove cholesterol from atherosclerotic plaques and cells (reverse cholesterol transport), a process mediated by ApoA-I, the predominant apoprotein in HDL (18). Other potential mechanisms may include a direct antioxidant effect, maintenance of blood viscosity by promotion of er ythrocyte membrane deformability, maintenance of endothelial function, and prevention of the transbilayer shift of anionic phospholipids to the outside surface of erythrocytes (thereby impeding their ability to activate the coagulation cascade) (19,20). DYSLIPIDEMIA AND CV RISK IN PATIENTS WITH PRESERVED RENAL FUNCTION The relationship between total cholesterol (TC) and mortality is clearly illustrated in an analysis of 356 222 men screened for the Multiple Risk Factor Intervention prospective cohort study (21). At the 6-year analysis, a continuous graded relation between initial TC and sub- sequent death from coronary artery disease was evident. The age-adjusted relative risk (RR) of death in quintiles 2 through 5 of TC, compared to the lowest cholesterol quintile, was 1.29, 1.73, 2.21, and 3.42, respectively. Similar findings were found in a recent case-control study involving approximately 15 000 persons in 52 countries (22). About half the population’s attributable risk of first myocardial infarction in both men and women was attributed to dyslipidemia (defined as an elevated ApoB/ ApoA-I ratio). DYSLIPIDEMIA IN NON DIALYSIS-DEPENDENT CKD LIPID ABNORMALITIES IN CKD Lipoprotein metabolism appears to be substantially influenced by the severity of renal dysfunction and proteinuria. HDL-C, TC, and LDL-C decrease with declining glomerular filtration rate (GFR) and, on average, are similar or lower in people with stage 3–5 CKD than in the general population (23). The prevalence of various “nontraditional” CV risk factors was studied in a cross-sectional analysis of 16 471 NHANES III participants, stratified by estimated GFR > 90, 60 – 89, and 15 – 59 mL/minute (24). After adjustment for age, sex, and race, mean ApoA-I (found mostly in HDL) was lower and ApoB higher at lower GFR. This clustering of low HDL-C with elevated ApoB and Lp(a) characterizes the more atherogenic lipid profile of CKD. Patients with CKD have elevated TG, including the atherogenic TG-rich ApoB-containing VLDL and IDL (25), due perhaps to decreased activity of hepatic TG lipase and peripheral lipoprotein lipase. These abnormalities in turn may be due to an inhibitory effect of hyperparathyroidism (26), calcium accumulation in islet cells resulting in impaired insulin action (27), elevated ApoC-III which acts as a direct lipase inhibitor, or a putative circulating inhibitor detected in uremic plasma (28). Although elevated LDL-C is not a characteristic feature of CKD, serum LDL-C levels may underestimate the atherogenic effect of LDL in CKD for several reasons. First, patients with CKD may have a greater proportion of LDL-C existing in the more atherogenic oxidized form (29,30). Second, routine LDL-C measurement does not measure the subfraction that exists as the more atherogenic Lp(a) particle. Although most studies have focused on elevated Lp(a) levels in the ESRD population, it is likely that levels are also increased in non-dialysis CKD (31). Furthermore, there is an increase in the small, dense LDL-C phenotype in patients with non dialysisdependent CKD versus healthy controls (32). Multiple 525 Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 creased risk was similar when studies that exclusively involved patients with vascular disease were excluded. Lipoprotein(a) may promote atherosclerosis by inhibiting fibrinolysis via competition with plasminogen binding sites (11), promoting oxidation of LDL (12), and recruiting monocytes into the vessel wall (13). The independent relation between serum TG levels and CV risk is controversial, since this association is potentially confounded by low HDL-C (14). A more precise determinant of risk than TG levels may be VLDL particles, which have a large TG component. A prospective casecontrol substudy of the Cholesterol and Recurrent Events (CARE) study found, by direct measurements, that plasma VLDL and ApoC-III (found in VLDL and LDL) levels were independently associated with increased coronary risk; whereas, overall, TG itself did not increase risk (14). NonHDL cholesterol (TC-HDL) may be used in clinical practice as a simple and accurate estimate of VLDL and IDL; this parameter may be a more powerful predictor of CV mortality than LDL-C alone (15). These TG-rich “remnant particles” may mediate atherosclerosis by ApoC-III’s direct inhibition of VLDL lipolysis preventing its clearance from the plasma, or by direct effects on plasma viscosity (16). Thus, hypertriglyceridemia in itself may be atherogenic only in specific circumstances where VLDL and IDL metabolism is altered. STATINS FOR TREATMENT OF DYSLIPIDEMIA IN CKD SHURRAW and TONELLI DOES DYSLIPIDEMIA IN NON DIALYSIS-DEPENDENT CKD CONTRIBUTE TO CV MORTALITY? Few data describe the contribution of dyslipidemia toward CV morbidity and mortality in the non-dialysis CKD population. Although one could extrapolate from data in the general population, the pathophysiology of CV disease in CKD may be influenced by other factors, such as the effect of anemia, uremic toxins, increased calcium intake, abnormal mineral metabolism, malnutrition/inflammation, and proteinuria (39–42). Thus, it is plausible that dyslipidemia per se contributes differently to overall risk in the setting of CKD, especially at lower levels of GFR. 526 PDI A recent study of 14856 participants with no coronary disease at baseline examined the contribution of various risk factors toward CV mortality in the non-dialysis CKD population over a mean follow-up period of 10.5 years (43). In this prospective cohort study, the presence and severity of dyslipidemia was associated with future CV events to a similar degree among those with normal renal function (Modification of Diet in Renal Disease GFR > 90 mL/min) compared to those with mild and moderate-to-severe CKD (GFR 60 – 89 and 15 – 59 mL/ min, respectively) (Figure 2). The authors predicted that, for every 1.1 mmol/L (1 SD) reduction in TC, there would be a 19.7% reduction in associated incident CV events. This compared favorably to their predicted 18% reduction associated with a systolic blood pressure reduction of 20 mmHg. Although this study shows that dyslipidemia is associated with excess CV risk in patients with non dialysis-dependent CKD, it does not demonstrate that treatment of dyslipidemia reduces CV mortality in this population. PREVALENCE AND NATURE OF DYSLIPIDEMIA IN ESRD HEMODIALYSIS Patients treated with HD typically have relatively normal TC and LDL-C accompanied by high TG and low HDL, similar to CKD patients who are not dialysis dependent. Approximately 20% – 40% of chronic HD patients have elevated TGs and reduced HDL-C (44–46). In a cross-sectional analysis of 1047 HD patients from the United States Renal Data System (USRDS) Wave II study, 28% of patients had TG > 2.26 mmol/L, and 57% had non-HDL cholesterol > 3.36 mmol/L. The apoprotein profile in HD patients is also similar to that of patients with less severe renal failure: moderately increased ApoB and ApoE, significantly increased in ApoC-III, and depressed ApoA-I and ApoA-II (47). The increase in ApoB is accounted for by TG-rich ApoB-containing lipoproteins in the VLDL and IDL range, as opposed to cholesterol-rich LDL (48). Increased VLDL and IDL is likely due to diminished activity of lipoprotein lipase, as in patients with non dialysisdependent CKD (49). In a study of 183 HD patients on no cholesterol medications, approximately one third were found to have increased plasma level of CETP, which may contribute to the low level of HDL-C found in this population (50). Hemodialysis patients can also have an atherogenic lipid profile in the absence of hyperlipidemia per se, as shown by a study that compared 210 chronic HD patients to 223 age- and sex-matched healthy controls (51). The HD group had lower TC than controls (4.44 vs 5.33, p < Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 studies have shown small dense LDL-C to be a strong independent predictor of coronary artery disease (7). Finally, the lower levels of HDL-C in CKD may exaggerate the pathogenic effect of lower-density lipoproteins for any given level of LDL-C. The dyslipidemia in CKD patients with nephrotic syndrome is distinct from that in patients with non-nephrotic CKD. From a quantitative standpoint, both hypercholesterolemia and hypertriglyceridemia (by definition) are common in the nephrotic syndrome (23,33). Nephrotic patients typically have significantly elevated levels of all ApoB-containing lipoproteins, including VLDL, IDL, and LDL, as well as normal or slightly depressed HDL, although the mechanisms for these abnormalities are not completely elucidated. Early work suggested enhanced lipoprotein synthesis as the major mechanism, but more recent studies suggest an important role for decreased catabolism. Delipidation from TG-rich VLDL to IDL to LDL is impaired (the degree of impairment positively correlating with the amount of proteinuria), with a trend toward slightly increased hepatic ApoB production (34). Delipidation is carried out via lipoprotein lipase and hepatic lipase; level of an activator cofactor protein required for this enzymatic activity may be decreased due to its loss in the urine (35). Low HDL-C may be secondary to increased activity of cholesteryl ester transfer protein (CETP) (36). This enzyme facilitates clearance of HDL-C from the circulation by transferring cholesterol ester from HDL to ApoB-containing lipoproteins, which are then taken up by the liver. Patients with nephrotic syndrome also appear to have slower LDL clearance, mediated by decreased hepatic LDL receptor function (37). Finally, the levels of Lp(a) are almost uniformly and severely elevated: one study found median Lp(a) in nephrotic patients to be about 7 times higher than in healthy controls, and 5 times higher than in patients with CKD and minimal proteinuria (38). SEPTEMBER 2006 – VOL. 26, NO. 5 SEPTEMBER 2006 – VOL. 26, NO. 5 STATINS FOR TREATMENT OF DYSLIPIDEMIA IN CKD Relative Risk of Major Coronary Event PDI Total Cholesterol (Quartile) Triglyceride (Quartile) 0.0001) and higher TG (1.30 vs 1.10, p < 0.0006). Compared with controls, the HD patients also had higher VLDL-C (0.89 vs 0.57 mmol/L) and IDL-C (0.40 vs 0.18 mmol/L), and lower HDL-C (1.01 vs 1.39 mmol/L) and LDL-C (2.12 vs 2.81 mmol/L); p < 0.0001 for all comparisons. These differences remained significant when groups were compared on the basis of similar TG and TC levels. Despite lower mean LDL-C in the HD patients, their cholesterol/TG ratio was significantly decreased (2.8 vs 4.10, p < 0.00001), reflecting a preponderance of small dense LDL (52). Other studies have shown that HD patients tend to have elevated Lp(a) and oxidized LDL-C, even if LDL-C levels are relatively normal (32,53–55). In summary, the dyslipidemia in HD is similar to that in the non dialysis-dependent CKD population, characterized by relatively normal TC and LDL-C, elevated TG, and low HDL-C. While these quantitative abnormalities may themselves contribute to atherosclerosis and CV mortality, the qualitative forms of dyslipidemia of HD patients may also play a role. PERITONEAL DIALYSIS Peritoneal dialysis patients also exhibit a form of “uremic dyslipidemia,” but the lipid profile in this group is more overtly abnormal than in HD patients. Multiple cross-sectional studies demonstrate higher TC, LDL-C, and TG in PD patients compared to HD patients (48,56– 60). One study compared 31 patients on continuous ambulatory peritoneal dialysis (CAPD), 30 patients treated with HD, and 27 healthy controls. Compared to HD, patients treated with CAPD had significantly higher mean TC (6.8 vs 5.1 mmol/L, p < 0.001), LDL-C (4.6 vs 3.2, p < 0.001), VLDL-C (1 vs 0.7, p < 0.05), and TG (2.3 vs 1.5, p < 0.01), with a nonsignificant difference in HDL (1.1 vs 1.3 in HD, p = NS) (48). Atherogenic ApoB was 47% higher in CAPD compared to HD patients (p < 0.001), and CAPD patients had both a higher TG-rich ApoB fraction (mainly VLDL, IDL) and a higher cholesterol-rich ApoB fraction (LDL) than HD patients. Further data supporting the concept of a more atherogenic lipid profile in CAPD were provided by a large multicenter cross-sectional study that compared 564 HD patients with 168 CAPD patients (53). Compared to HD, patients treated with CAPD had higher TC (6.0 vs 4.8 mmol/L), LDL-C (4.0 vs 3.0 mmol/L), TC/HDL-C ratio (7.0 vs 5.5), TG (2.1 vs 1.8 mmol/L), and Lp(a) (1.2 vs 0.9 µmol/L); p < 0.001 for all comparisons. HDL-C was similar between groups (0.95 in CAPD vs 0.97 mmol/L in HD, p = NS). There were twice as many CAPD than HD patients with a TC > 5.2 mmol/L (67% vs 34%), and 1.7 times as many with a TG > 4.7 mmol/L (47% vs 28%). Approximately half of CAPD patients, compared to only a quarter of HD patients, possessed three or more dyslipidemic risk factors (elevated LDL-C, TC, Lp(a), or low HDL-C). However, PD patients were more than twice as likely to have diabetes mellitus, which may have accounted for some of these differences. Patients treated with PD, like those on HD, have increased specific activity of CETP, which may contribute to the low HDL-C and increased ApoB-containing lipoproteins observed in this population (61,62). Other qualitative lipid abnormalities may further contribute to the CV risk of CAPD patients. For example, Lp(a) is elevated to an even greater degree than in HD patients. Analysis of data from the 702 HD and CAPD 527 Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 Figure 2 — Relationship of total cholesterol and triglyceride levels with major coronary events in 17898 participants followed for 10.5 years. The Figure shows that participants with increased total cholesterol or triglyceride suffered more coronary events irrespective of baseline estimated glomerular filtration rate (GFR). Data from Muntner et al. (43). SHURRAW and TONELLI IS DYSLIPIDEMIA ASSOCIATED WITH INCREASED MORTALITY IN PATIENTS WITH ESRD? Data describing the association between dyslipidemia and death in dialysis patients may seem contradictory. For instance, large cross-sectional studies have found no association between baseline TC or TG and CV disease in dialysis patients (72,73), and two prospective studies in HD patients showed no association between baseline TG, TC, LDL-C, or HDL-C and future atherosclerotic events (74,75). In contrast, several cross-sectional studies of HD patients have shown dyslipidemia to be positively associated with coronary artery disease or death (76–78), as has a prospective study that followed 412 patients (317 HD, 95 PD) for 9 years (77). Finally, some 528 PDI studies have shown a paradoxical (inverse) relation between cholesterol levels and mortality in HD patients (79–82), or both HD and PD patients (83). To make sense of this seemingly conflicting data, one must consider the potential role of malnutrition/inflammation on mortality. In a retrospective study of 12000 HD patients in 1995, the relation between TC and death took the form of a U-shaped curve, which appeared more linear after adjustment for serum albumin (80). This apparently paradoxical relation may be wholly or partially due to increased mortality among patients with evidence of inflammation/malnutrition, which typically results in lower cholesterol levels (41). Alternatively, it may result from “reverse causation,” wherein coexisting CV disease leads to inflammation/malnutrition, and thus lowers cholesterol level. Two large prospective studies help to clarify this issue. In a prospective report of 1167 Japanese HD patients, low cholesterol was found to be independently associated with higher C-reactive protein (CRP) and mortality at 10 years in those with low albumin (79). However, in the subgroup of patients with albumin >45 g/L, high cholesterol was associated with increased mortality. A second prospective study performed in the USA followed 823 patients starting HD (80%) or PD (20%) for a median of 2.4 years (84). Patients were classified by the presence or absence of inflammation and/or malnutrition at baseline, based on serum levels of albumin (<36 g/L: <10th percentile in the general population), CRP (>10 mg/L: >90th percentile), or interleukin-6 (>3.09 pg/mL: >75th percentile). An increment in baseline TC of 1 mmol/L decreased all-cause mortality in the presence of inflammation/malnutrition [relative hazard (RH) 0.89, 0.84 – 0.95], but in the absence of inflammation/malnutrition, there was a strong, positive, graded relation of TC with all-cause mortality (RH 1.32, 1.07 – 1.63) and CV mortality (RH 1.41, 1.04 – 1.89) (Figure 3). These studies both demonstrate that hypercholesterolemia is a risk factor for all-cause and CV mortality in patients with ESRD, but the association can be masked by concomitant inflammation and/or malnutrition. As in the general population, Lp(a) has been positively associated with atherosclerotic CV disease in HD patients (42,74,85,86). This was best demonstrated in a study of 390 HD patients and 105 normal controls who had baseline Lp(a) measured and were then prospectively followed for 28 months (85). Lipoprotein(a) level was twice as high in HD patients compared to controls and was independently associated with CV death. There are few data describing the effect of other, less traditional, lipid risk factors (such as small dense LDL, oxidized LDL, and VLDL/ IDL) on mortality in dialysis patients. Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 patients in the aforementioned cross-sectional study revealed that 34% of HD patients and 42% of CAPD patients had serum Lp(a) greater than the 75th percentile of the healthy control group (>0.92 µmol/L, p < 0.005 for HD vs PD) (63). Mean Lp(a) was 0.82 µmol/L in HD patients and 1.25 µmol/L in CAPD patients, versus 0.64 µmol/L in controls (p < 0.005 for comparisons of patients to controls). Finally, small dense LDL-C (32,64) and oxidized LDL-C (55,65) are increased to a greater extent in CAPD patients compared to HD patients. Several mechanisms have been proposed to explain the more atherogenic lipid profile in patients undergoing PD. It has been suggested that absorption of glucose from the dialysate solution may stimulate hepatic lipoprotein synthesis (66), or increase insulin levels and thus TG synthesis (67). Consistent with this is the observation that the lipid profile improves when the overnight dwell is switched from a dextrose-based solution to icodextrin (68). The daily loss of protein in the dialysate solution may also promote dyslipidemia by mechanisms similar to those relating to protein loss in the nephrotic syndrome. Finally, smaller sized proteins, including various lipoproteins, are preferentially lost due to peritoneal sieving; for example, HDL is lost at a rate equivalent to 34% of its daily synthetic rate, while ApoB-containing lipoprotein loss is negligible (69–71). In summary, patients on PD typically have more severe dyslipidemia than those on HD, as reflected by increased TG, ApoB-containing VLDL and IDL, TC, LDL-C, Lp(a), and small dense LDL-C with a persistently low level of HDL-C. Although it is plausible that these apparent differences are due to PD per se, this association may be partially confounded by other characteristics related to selection of dialytic modality. Regardless of the etiology, it is indisputable that PD patients commonly have a highly atherogenic lipid profile. SEPTEMBER 2006 – VOL. 26, NO. 5 SEPTEMBER 2006 – VOL. 26, NO. 5 STATINS FOR TREATMENT OF DYSLIPIDEMIA IN CKD spective studies, 20% of dialysis patients enrolled in the largest prospective study were receiving PD (84). These data are consistent with the hypothesis that hypercholesterolemia is equally deleterious to patients treated with HD and PD. Since (as mentioned above) dyslipidemia is more prevalent in PD patients, this suggests that the population-attributable risk (i.e., the proportion of CV events that are due to dyslipidemia) may be higher compared to the HD population. However, whether pharmacological treatment of dyslipidemia will reduce CV risk in dialysis patients will require specific study. Mortality rate per 100 patients PDI STATINS: MECHANISM OF ACTION AND PLEIOTROPIC EFFECTS Cholesterol (mg/dL) Figure 3 — 823 patients starting hemodialysis (80%) or peritoneal dialysis (20%) were classified according to the presence (heavy dotted lines) or absence (light dotted lines) of malnutrition/inflammation at baseline. Total cholesterol is positively associated with all-cause (upper panel) and cardiovascular-specific (lower panel) mortality in patients without evidence of inflammation/malnutrition. Control: solid line. Adapted from Liu et al. (84). Statins compete with HMG-CoA for binding at the active site of the enzyme HMG-CoA reductase (96). Binding blocks the rate-limiting step of hepatic cholesterol biosynthesis, leading to enhanced surface expression and subsequent recycling of LDL receptors (97). The end result is a pronounced reduction in serum LDL-C, ranging from 30% to 60% depending on the potency and dose of the particular statin (98). Statins also shift the LDL profile away from the more atherogenic small dense form toward the larger, less dense and less atherogenic subtype (16). The effect of statins on other lipids is less marked, with HDL-C typically increasing 2% – 10%, and TG reduction ranging between 8% and 26% (99). In addition to directly improving the lipid profile, statins also exert a number of lipid-independent (“pleiotropic”) effects, including improvement in endothelial dysfunction by reducing endothelial permeability to LDL and enhancing vasodilatory response, a blunted inflammatory response, and reduced expression of endothelial adhesion molecules, antioxidant activity, and stabilization of atherosclerotic plaques (100). However, the clinical significance of these effects remains to be determined. PERITONEAL DIALYSIS LANDMARK STATIN TRIALS IN THE GENERAL POPULATION The majority of the aforementioned studies examined the relation between the serum lipid profile and CV events or death in HD patients. However, a similar relation between low cholesterol, malnutrition, and increased mortality in PD patients has been reported (46, 87,88), and a few retrospective studies also demonstrated an association between CV mortality and dyslipidemia in PD patients (89–92). There are also observational data confirming the association of elevated Lp(a) with atherosclerotic disease or death in CAPD patients (93–95). Although none of these were large pro- Four landmark randomized controlled trials (RCTs) published in the past decade demonstrate the benefits of statins in people with known coronary disease who were selected from the general population (101–104) (Table 1). Together, these trials clearly show that statins reduce the risk of CV death by 22% – 42% and all-cause mortality by 22% – 30%, in this population with acceptably low adverse events rates. In selected patients, aggressive lipid-lowering with higher doses of statin appears to further reduce CV event rates, but leads to slightly increased medication-related toxicity (104). 529 Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 Mortality rate per 100 patients Cholesterol (mg/dL) SHURRAW and TONELLI SEPTEMBER 2006 – VOL. 26, NO. 5 PDI TABLE 1 Landmark Randomized Controlled Trials of Statin Therapy in the General Population Study (Ref.) Duration Population/(total n) (years) Secondary prevention trials 4S (101) Previous angina/MI TC: >5.5 Age: 35–70 (n=4444) LIPID (102) Recent ACS TC: 4–7 Age: 31–75 (n=9014) CARE (103) Previous MI; TC<6.2 Age: 21–75 (n=4159) TNT (104) Stable CAD LDL: <3.4 (n=10001) High risk: MI, CAD, PVD, DM, HTN TC: >3.5 Age: 40–80 (n=20576) Primary prevention trials WOSCOPS (105) Male only TC: >7 Age: 45–64 (n=6595) AFCAPS (106) HDL: M: <1.16, F: <1.22 Average LDL & TC Age 45–73 (n=6605; 15% female) ASCOT (107) ≥3 CAD risk factors & HTN; TC: <6.5 Age 40–79 (n=10305) Statin 5.4 Simvastatin 20–40 mg/day 6.1 Pravastatin 40 mg/day 5 Pravastatin 40 mg/day Atorvastatin 80 mg/dayb 4.9 5.5 Simvastatin 40 mg/day 4.9 Pravastatin 40 mg/day 5.2 Lovastatin 20–40 mg/day 3.3 Atorvastatin 10 mg/day Absolute reduction in ACMc (control vs statind) 4.9→3.2 Death: 0.70 (0.58–0.85) 3.2% CV death: 0.58 (0.46– (11.5% vs 8.2%) 0.73) 3.9→2.9 Death: 0.78 (0.69–0.87) 3.1% CV death: 0.76 (0.65– 0.88) (14.1% vs 11%) 3.6→2.5 CV death or MI: Nonsignificant 0.76 (0.64–0.91) 2.6→2.0 CV death, MI, stroke Nonsignificant resuscitation after arrest: 0.78 (0.69–0.89) 3.3→2.3 Death: 0.87 (0.81–0.94) 1.8% Vascular death: 0.83 (14.7% vs 12.9%) (0.75–0.91) 5→4.1 CV death or nonfatal MI: 0.69 (0.57–0.83) 3.9→3.0 MI, unstable angina, or sudden cardiac death: 0.63 (0.50–0.79) 3.4→2.3 CV death or nonfatal MI: 0.64 (0.50–0.83) 0.9% (4.1 vs 3.2%) (p=0.051) Nonsignificant Nonsignificant (trial stopped early) MI = myocardial infarction; TC = total cholesterol; ACS = acute coronary syndrome; CAD = coronary artery disease; LDL = lowdensity lipoprotein cholesterol; PVD = peripheral vascular disease; DM = diabetes mellitus; HTN = hypertension; HDL = high-density lipoprotein cholesterol; CI = confidence interval; CV = cardiovascular; ACM = all-cause mortality. a In HPS, 2/3 of enrolled patients had known CAD, thus this was largely a trial of secondary prevention. b Control group received atorvastatin 10 mg/day. c Bold = 1° end point. d p < 0.001 for statin treatment versus control unless otherwise specified. Findings from three major primary prevention trials are consistent with those in secondary prevention, although absolute risk reductions tend to be smaller given the lower event rates (105–107). The largest statin trial published to date (HPS; see Table 1) enrolled patients with or at high risk for CV events (with and without coronary disease at baseline) who had a broad range of serum TC values (3.5 mmol/L and higher) (108). Since the RR reduction due to statin therapy was similar regardless of baseline LDL-C or prior CV events, results of this trial suggest that overall CV risk is the best determinant of benefit from statins, rather than individual factors, such as 530 cholesterol level. Given the high CV event rates in renal populations, this implies that CKD and ESRD patients would be particularly likely to benefit from statins. DO STATINS REDUCE CV RISK IN PATIENTS WITH NON DIALYSIS-DEPENDENT CKD? Post hoc analyses of several, large, randomized, placebo-controlled statin trials compared the effect of statins on CV outcomes in persons with and without renal insufficiency (Table 2) (107–109). In all three analyses, the RR reduction associated with statin therapy was simi- Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 HPSa (108) ∆ mean LDL (mmol/L) Relative riskc (95% CI) PDI SEPTEMBER 2006 – VOL. 26, NO. 5 STATINS FOR TREATMENT OF DYSLIPIDEMIA IN CKD TABLE 2 Effect of Statins on Cardiovascular Outcomes in Patients with Non Dialysis-Dependent Chronic Kidney Disease (Post Hoc Subgroup Analyses of Major Statin Trials) Study Renal function (mL/min or µmol/L) Patients in subgroup Duration (n) (years) Tonelli et al. (109)a CG-GFR: 30–59.99 4491 CG–GFR: 60–89.99 12 333 CG-GFR: ≥90 ASCOT (107) 3.3 5.5 3.9→2.7 CV death, MI, CABG, or 2.3% PTCA: 0.77 (0.68–0.86) (16.8% vs 14.5%) Death: 0.86 (0.74 – 1) (p=0.045) 4.3→3.1 CV death, MI, CABG, or — PTCA: 0.76 (0.70–0.83) Death: 0.76 (0.66–0.87) 4.3→3.2 CV death, MI, CABG, or — PTCA: 0.78 (0.55–0.94) Death: 0.93 (0.68–1.28) Atorvastatin — CV death or nonfatal — 10 mg/day MI: 0.61 (0.44–0.84) — CV death or nonfatal — MI: 0.70 (0.45–1.04) Simvastatin — Major vascular event: — 40 mg/day 0.77 (0.67–0.87)c — Major vascular event: — 0.86 (0.83–0.89)c CG-GFR = Cockroft–Gault estimated glomerular filtration rate; Cr = creatinine; LDL = low-density lipoprotein cholesterol; CI = confidence interval; CV = cardiovascular; MI = myocardial infarction; CABG = coronary artery bypass graft; PTCA = percutaneous transluminal coronary angioplasty; ACM = all-cause mortality. a Analysis of data from WOS-COPS, LIPID, and CARE trials. b Bold = 1° end point. c Relative risk rather than hazard ratio. lar in patients with and without CKD, and medicationrelated toxicity was no higher among those with impaired kidney function. However, due to the higher event rates in people with CKD, the absolute risk reduction due to statin treatment was markedly higher in the presence of impaired kidney function. Although these results are consistent with those from the general population, it is important to note that very few of these patients (<1%) had stage 4 CKD, and none were dialysis dependent. In addition, it is uncertain whether these patients are representative of those seen in nephrologists’ offices, given the inclusion criteria of the randomized trials. Therefore, definitive evidence of the benefits of statins in stage 2 – 3 CKD must await the results of RCTs conducted specifically in this patient population (discussed below). STATINS IN THE ESRD POPULATION SAFETY AND EFFICACY OF STATINS IN ESRD There have been seven published RCTs determining statins to be safe and efficacious in the treatment of dyslipidemia in both HD and PD patients (Table 3) (110–116). Overall, these studies show that statins reduce TC and LDL-C by 18% – 33% and 20% – 43% respectively, increase HDL-C from 0 to +7%, and decrease TG from nonsignificant to –40%. These changes are similar to those observed in patients with normal renal function in the major statin trials. With the doses used (generally not exceeding 20 mg of simvastatin or atorvastatin), there were no statistically significant differences in adverse events (including patient symptoms or elevation in creatine kinase or liver enzymes) between statin and placebo/control arms in any of the trials. Although the effect of statin on cholesterol levels was not statistically different between the three groups studied in the UK-HARP trial (dialysis patients, non dialysis-dependent CKD, and renal transplant; total n = 448) (114), the much larger number of patients studied in a pooled analysis of three pravastatin trials (n = 19727) showed that LDL-C was lowered to a significantly greater extent in participants with stage 3 CKD, compared to those with normal kidney function (109). A Cochrane meta-analysis of 6 RCTs was performed in 2004 that included some of the trials listed in Table 3, as well as abstracts (117). In their pooled analysis, statin treatment for at least 531 Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 HPS (108) Approx. 5 Pravastatin 40 mg/day 2876 Serum Cr: 6517 M: 130–200, F: 110–200 Serum Cr: 3788 M: <130, F: <110 Serum Cr: 1329 M: 130–200, F: 110–200 Serum Cr: 19 207 M: <130, F: <110 Statin Likelihood of reaching Absolute reduc∆ mean LDL clinical end pointb tion in ACM (mmol/L) [hazard ratio (95% CI)] (control vs statin) SHURRAW and TONELLI SEPTEMBER 2006 – VOL. 26, NO. 5 PDI TABLE 3 Randomized Controlled Trials of Statins in Dialysis Patients: Efficacy and Safety Duration treated Wanner et al. (110) HD 4 years Atorvastatin 20 mg/day 619 statin 636 placebo N/R –42c,d N/R N/R –1 Chang et al. (111) HD 2 months Harris et al. (112) CAPD 4 months Simvastatin 20 mg/day Atorvastatin 10–20 mg/day 31 statin 31 control 82 statin 94 placebo –29b +2 –29c –6 –41b +3 –41b +3 –3 +2 –40c +7c –14 –9 –3 +11 Simvastatin 16 statin 5–20 (median 10) 7 placebo mg/day 22 statin 11 placebo Simvastatin 38 statin 20 mg/day 35 placebo –22c –1 –21c –12 –18c N/R –36c 0 0 +5 –33c –5 –9 –3 –20c +2c N/R N/R Saltissi et al. (113) CAPD (n=23) 6 months HD (n=33) Baigent et al. (114)a CAPD (n=39) HD (n=34) Robson et al. (115) Lins et al. (116) 1 year CAPD (n=47) 6 months HD (n=60) HD 3 months Statin Simvastatin 10 mg/day Atorvastatin 10–40 mg/day Patients in %∆ %∆ %∆ %∆ each arm (n) TC LDL HDL TG 24 statin 29 placebo 23 statin 19 placebo –2 +4 –18 –13 –38c N/R –19c –24c 0 –11c –8 –9 –5 –3 –33c –43c –1 –12c –3 –8 –12 +21 Adverse eventse Myalgias: s: 7, c: 5 ↑CK 3–5×: s: 11, c: 3 ↑CK >5×: s: 1, c: 1 ↑ALT: s: 5, c: 1 None related to treatment Pain: s: 4, c: 0 ↑CK: s: 5, c: 3 ↑ALT: s: 1, c: 1 s=c for symptoms ↑CK: s: 1, c: 1 s=c for symptoms ↑CK/ALT: s: 0, c: 0 Myalgias: s: 65, c: 59 ↑CK: s: 2, c: 3 ↑ALT: s: 4, c: 2 Myalgias: s: 1, c: 0 CK/ALT: no ∆ Myalgias: s: 3, c: 1 ↑CK: s: 0, c: 0 ↑ALT: s: 1, c: 0 HD = hemodialysis; PD = peritoneal dialysis; CAPD = continuous ambulatory PD; TC = total cholesterol; N/R = data not reported; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol; TG = triglycerides; CK = creatine kinase; ALT = alanine aminotransferase. a UK-HARP I included 448 CKD patients: 242 non-dialysis, 73 dialysis (combined analysis of CAPD+HD), 133 transplant. b Statistically significant percent change from baseline (p < 0.01). c Statistically significant difference in percent change for statin versus placebo (p < 0.05). d Change in LDL-C as reported after 4 weeks of treatment. e s: n = number in statin group; c: n = number in control group. 12 weeks lowered TC by 1.4 mmol/L (1.7 in CAPD vs 1.4 in HD), LDL-C by 1.4 mmol/L (2.0 in CAPD vs 1.2 in HD), and TG by 0.4 mmol/L (0.5 mmol/L in CAPD vs nonsignif icant decrease in HD), and raised HDL-C by 0.13 mmol/L (nonsignificant in CAPD vs 0.13 in HD). Apolipoprotein B and remnant lipoproteins VLDL and IDL are similarly reduced with statin treatment in patients undergoing PD or HD (116,118,119). Conversely, statin treatment has little effect on Lp(a) concentration in patients with ESRD, as in patients with normal renal function (113). Treatment with statins lowers CRP in patients with normal renal function, independent of lipid lowering (120). Studies in HD patients confirm that statins retain many pleiotropic effects, including reducing CRP (by approximately half) and increasing serum albumin, decreasing oxidized LDL-C, and shifting LDL-C from the small dense to the larger, buoyant, less atherogenic form (116,121–123). Although it is tempting to 532 speculate that these pleiotropic effects are clinically beneficial (especially given the frequency of inflammation/malnutrition in ESRD), this remains to be proven. CAN STATINS REDUCE CV MORTALITY IN THE ESRD POPULATION? Two observational studies demonstrated that statin use in the ESRD population was independently associated with reduced mortality. The first study analyzed data from 3716 incident patients enrolled in the USRDS Dialysis Morbidity and Mortality Wave II cohort, which included all patients starting PD and a 20% random sample of patients starting HD in the United States during 1996 to 1997 (124). Of the total cohort, only 362 (approximately 10%) were using statins at the start of dialysis. Statin use was independently associated with a 32% reduction in total mortality [adjusted RR = 0.68, Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 HD or PD Study PDI SEPTEMBER 2006 – VOL. 26, NO. 5 cerebrovascular events or total mortality. The authors concluded that the apparent lack of benefit with statin treatment in HD patients could be due to nontraditional pathogenic pathways contributing to CV disease, making statin therapy unhelpful when postponed until dialysis is required. The available data are consistent with this hypothesis, but consideration of some of this study’s unique characteristics is worthwhile. First, as with most RCTs, the study population was highly specific (prevalent diabetic HD patients), and therefore findings may not be generalizable to all dialysis patients. Second, 15% of patients receiving atorvastatin required a dose reduction to 10 mg/day (as specified in the protocol if LDL-C in follow-up was <1.3 mmol/L); after 2 years of study, 16.6% of the atorvastatin users who remained alive and free of a primary event discontinued therapy altogether, and 15% of patients receiving placebo eventually received non-study statins. These factors probably led to the decreasing difference in LDL-C between atorvastatin and placebo groups over time, which may have reduced power to show a beneficial effect. Third, since many CV events in dialysis patients are due to sudden death (perhaps due to electrolyte abnormalities) (126–128) or to cardiomyopathy (perhaps from chronic extracellular fluid volume overload) (128,129), it is possible that a beneficial effect of statin therapy on atherosclerotic events might have been diluted. Although a relative risk reduction of 8% is not usually of major clinical significance, the high CV event rate in this patient population means that such a benefit, if it exists, would translate into a favorable absolute risk reduction of 1.7%. All of these factors point to the need to perform additional randomized trials of statins in dialysis patients. TREATMENT IMPLICATIONS Two subsequent large RCTs evaluating statin use in patients with ESRD commenced in 2003 and are currently underway. A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis (AURORA) has randomized 2700 patients from 190 sites in Australia, Canada, and Europe to rosuvastatin 10 mg/day or placebo. End points will be time to death from any cause and time to major CV event (nonfatal stroke, nonfatal myocardial infarction, or CV death). Results are expected in approximately 2 years. The multinational Study of Heart and Renal Protection (SHARP) will include about 9000 patients with CKD (3000 on PD or HD at randomization) and will compare the effect of simvastatin 20 mg/day plus ezetimibe 10 mg/day versus placebo on the end point of fatal and nonfatal cardiac events, fatal 533 Downloaded from http://www.pdiconnect.com/ by guest on June 9, 2014 95% confidence interval (CI) 0.54 – 0.87] and 37% lower CV-specific mortality (RR = 0.64, 95% CI 0.45 – 0.91). This result was similar in PD and HD treated patients. Fibrate use was not associated with a lower risk of allcause or CV-specific death. In patients with preexisting CV disease, statin use was associated with an even greater reduction in CV mortality of 50% (RR = 0.50, 95% CI 0.32 – 0.79). The second observational study analyzed data from 7365 prevalent HD patients enrolled in the multinational Dialysis Outcomes and Practice Patterns Study (DOPPS) (125). In multivariate analysis, statin users had a 31% lower adjusted risk of all-cause mortality than nonusers [hazard ratio (HR) = 0.69, 95% CI 0.60 – 0.79], a 23% reduction in CV-specific mortality (HR = 0.77, 95% CI 0.61 – 0.97), and a 44% reduction in non-cardiac mortality (HR = 0.56, 95% CI 0.46 – 0.69). Although these findings support the hypothesis that statins reduce mortality in both PD and HD patients, the possibility of residual confounding remains, given that statin therapy was not randomly assigned. The sole RCT designed to establish if statins reduce mortality in dialysis patients was recently published (Die Deutsche Diabetes Dialyse Studie: “4D”) (110). This was a rigorously conducted double-blind study of 1255 German HD patients with type II diabetes, comparing atorvastatin 20 mg/day with placebo on the composite primary outcome of death from cardiac causes, nonfatal myocardial infarction, and stroke. Adult patients were included if they had received HD for <2 years, had LDL-C between 2.1 and 4.9 mmol/L, and TG <11.3 mmol/L. The study had 90% power to detect a 27% reduction in the primary end point, and analysis was intention-to-treat. Baseline characteristics of the two patient groups were similar, including lipid profile (TC 5.7 mmol/L, LDL-C 3.3 mmol/L, HDL-C 0.93 mmol/L, TG 2.9 mmol/L in each group). During a median followup of 4 years, the primary end point was reached by 38.2% of patients randomized to placebo, versus 36.5% in those in the atorvastatin group, with no significant difference between groups (RR due to atorvastatin use 0.92, 95% CI 0.77 – 1.10, p = 0.37). Of the individual components of the composite primary end point, death from cardiac causes was of borderline statistical significance (RR = 0.81, 95% CI 0.64 – 1.03, p = 0.08) but was offset by an unexpected increase in fatal strokes in the atorvastatin group (RR of fatal stroke 2.03, 95% CI 1.05 – 3.93, p = 0.04). Of the secondary end points, atorvastatin significantly reduced the incidence of combined cardiac events (death from cardiac cause, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty) by 18% (RR 0.82, 95% CI 0.68 – 0.99, p = 0.03) but not combined STATINS FOR TREATMENT OF DYSLIPIDEMIA IN CKD SHURRAW and TONELLI Figure 4 — 2003 K/DOQI guidelines for the treatment of dyslipidemia in patients with dialysis-dependent chronic kidney disease. All units are mmol/L. TG = triglyceride; TLC = therapeutic lifestyle change; LDL = low-density lipoprotein cholesterol; HDL = high-density lipoprotein cholesterol. Adapted from K/DOQI, National Kidney Foundation (130). Note: If LDL is 2.6 – 3.4 mmol/L, consider a trial of therapeutic lifestyle change before initiating pharmacotherapy. 534 PDI CONCLUSION Dyslipidemia is quantitatively and qualitatively different in patients with CKD compared to those with normal renal function, but is associated with adverse outcomes regardless of kidney function after accounting for malnutrition and inflammation. While multiple RCTs have demonstrated statins to reduce all-cause and CV mortality in patients with normal renal function, only post hoc subgroup analyses support their use in patients with non dialysis-dependent CKD, and the sole randomized trial conducted in dialysis patients found no evidence of benefit. Two additional randomized trials of statin therapy in dialysis patients are underway, and results from these studies should help to clarify the role of statins in this population. In the interim, following practice guidelines for treatment of dyslipidemia in dialysis patients appears reasonable. 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