Reducing lipids for CV protection in CKD patients current evidence

Transcription

1 review & 2008 International Society of Nephrology Reducing lipids for CV protection in CKD patients current evidence Christoph Wanner 1,2 and Eberhard Ritz 1,2 1 Department of Internal Medicine, Division of Nephrology, University of Würzburg, Würzburg, Germany and 2 Department of Internal Medicine, Division of Nephrology, University of Heidelberg, Heidelberg, Germany Lipid parameters are altered in the earliest stages of primary kidney disease, some even when measured glomerular filtration rate (GFR) is still normal. The main problem is that routinely measured lipid parameters are deceivingly normal except low high-density lipoprotein (HDL) and moderately elevated triglycerides (TGs) (4150 mg per 100 ml). Behind this unimpressive spectrum, serious anomalies are hidden: increased very low-density lipoprotein (VLDL) and chylomicron remnants, accumulation of delipidated small dense low-density lipoprotein (LDL), post translational modification of lipoproteins, abnormal concentrations of Lp(a) and nonprotective HDL. A routine parameter with some predictive value is the concentration of non-hdl cholesterol. Several of these abnormal lipoprotein particles stimulate cellular free oxygen radical formation which in turn induce inflammation and impact on endothelial function. A bone of contention is the indication for treatment with statins in endstage renal disease. Poor survival is paradoxically predicted by low cholesterol. This appears to be the result of confounding by microinflammation. One controlled interventional study in hemodialysed type 2 diabetics, the 4-D study, failed to show a significant benefit on the primary cardiovascular endpoint. We discuss potential explanations for this negative outcome and the implications for statin treatment. ; doi: /ki KEYWORDS: chronic kidney disease; dyslipidemia; statins; cardiovascular disease Correspondence: Eberhard Ritz, Nierenzentrum, Im Neuenheimer Feld 162, Heidelberg 69120, Germany. prof.e.ritz@t-online.de Dyslipidemia in chronic kidney disease (CKD) with and without the nephrotic syndrome has recently been the subject of several overviews. 1,2 In the following, we discuss some selected topics, emphasizing the type of lipid abnormalities in different stages of CKD, their association with diabetes mellitus, inflammation, and cardiovascular disease (CVD), the relation to progression of CKD and the effect of lipidlowering interventions. Understanding the difficulties of interpreting the interventional data necessitates understanding of the underlying pathophysiology, which will be discussed first. LIPID PROFILE IN KIDNEY DISEASE Experimental evidence Experimental studies report that triglyceride (TG)-enriched very low-density lipoprotein (VLDL) activates nuclear factorkappa B (NF-kB), which plays a key role in activating a spectrum of pro-inflammatory genes, in turn leading to endothelial dysfunction and oxidative stress (Figure 1) (Fruchart et al. 3 ). Interestingly, apolipoprotein CIII (apoc- III), which is present on TG-rich lipoproteins, directly activates NF-kB. The adverse effects of TG-rich lipoproteins may have both direct 4,5 and indirect components, via potentiation of the response to inflammatory cytokines. Overall these actions induce inflammation and impair vasodilation in the microvascular and macrovascular environment. Typically, apociii is enriched in apob containing triglyceride-rich lipoproteins in CKD stages 3 and 4. 6 Clinical evidence In CKD patients without nephrotic syndrome, the routinely measured lipid values are misleadingly unobtrusive: highdensity lipoproteins (HDLs) are low and triglycerides are high but total cholesterol and low-density lipoprotein (LDL) cholesterol are normal or even low. At a first glance the type of dyslipidemia is similar in people with insulin resistance and the metabolic syndrome. Important abnormalities are hidden behind this spectrum (Table 1): the highly atherogenic VLDL remnants and chylomicron remnants are increased as a result of delayed catabolism. In addition, the concentration of LDL particles having undergone advanced delipidation, so-called small sense LDL, is increased. The concentration of apolipoproteins within LDL having S24

2 C. Wanner and E. Ritz: Reducing lipids for CV protection r e v i e w VLDL High LDL ApoCIII Free oxygen radical generation (O 2 ) Cytokines Prostaglandins Leukotrienes Table 2 Uninephrectomy accelerates atherogenesis in the apoe / mouse Maximal plaque diameter (lm) Plaque area per aortic circumference (lm ) Sham op 191± ±1.21 Uninephrectomy 322± ±15.5 Subtotal NX 473± ±30.1 Sham op, sham operated. Synthesis and release of pro-inflammatory factors (IL-6, COX-2, TNF-α, VCAM-1, ICAM-1, MCP-1) NFκB activation activated NFκB nucleus activation of genes of inflammation factors Figure 1 Triglyceride-enriched very low-density lipoprotein (VLDL) activates nuclear factor-kappa B (NF-jB), which plays a key role in activating a spectrum of pro-inflammatory genes, leading to endothelial dysfunction and oxidative stress. NFkB, nuclear factor kb; IL-6, interleukin 6; COX-2, cyclooxygenase-2; TNF-a, tumor necrosis factor-a; ICAM, intracellular adhesion molecule; VCAM, vascular cell adhesion molecule; ApoCIII, apolipoprotein CIII. Table 1 The spectrum of lipid changes and lipoprotein abnormalities in early and advanced stages of chronic kidney disease Lipids Abnormal Low HDL cholesterol High triglycerides Normal Total cholesterol LDL cholesterol Lipoproteins VLDL-remnants/IDL Chylomicron remnants small dense LDL modifications (glycation-oxidation-carbamylation) AGE-ApoB High lipoprotein(a) acute-phase HDL AGE, advanced glycation end products; ApoB, apolipoprotein B; HDL, high-density lipoprotein; IDL, intermediate-density lipoproteins; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein. undergone important post-translational modification is increased, an important aspect as such a post-translational modification of lipoproteins, specifically apolipoprotein B100, by glycation, oxidation, and carbamylation, favors uptake by the scavenger receptor and foam cell formation in atherosclerotic plaques. The concentration of lipoprotein(a) (Lp(a)) tends to be elevated. Finally, the HDL particle changes its composition during inflammation into paradoxically pro-atherogenic acute-phase HDL. Shoji et al. 7 proposed to complement the above-mentioned routine parameters by calculating non-hdl cholesterol, which turned out to be an acceptable predictor of cardiovascular events. The potential value of this parameter is illustrated by the findings in the 4D study. 8 Total mean cholesterol concentrations in hemodialysed type 2 diabetics were normal (221 mg per 100 ml), but the sum of LDL cholesterol and VLDL cholesterol (185 mg per 100 ml) was substantially higher than the normal value of 130 mg per 100 ml. The concentration of lipoprotein particles may not completely reflect the hazard conferred by the various particles. For instance, Ikewaki 9 showed no significant difference in the concentration of LDL apob concentrations between control patients and hemodialysed patients, yet a highly significant difference in the residence time was noted. The same was true for intermediate-density lipoproteinsapob particles. Prolonged residence time provides more opportunity for modification of lipoproteins by oxidation, glycation, and other types of modification, thus potentially increasing their atherogenicity. A similar prolongation of the residence time was also noted for Lp(a). 10 In the MMKD (Mild-to-Moderate Kidney Disease) study comprising 227 patients with primary kidney disease in various stages of CKD with a 7-year follow-up, 11 the evolution of lipid abnormalities was assessed as a function of measured glomerular filtration rate (GFR). Even in the absence of a low GFR, an increased Lp(a) and apolipoprotein A-IV 12 were found and an elevation of triglycerides in nonnephrotic patients was noted at a GFR of ml/min per 1.72 m 2. An association between mild impairment of kidney function and lipoprotein abnormalities was also noted in the multi-ethnic study of atherosclerosis. 13 ASSOCIATION WITH CARDIOVASCULAR DISEASE There is no doubt that in CKD and hemodialysis patients, atherogenesis is accelerated, as originally postulated by Scribner, 14 and reproduced in experimental studies in the apo E / mouse 15 (Table 2). Against this background, it was felt to be paradoxical that Degoulet 16 documented in hemodialysed patients that low total cholesterol was predictive of high mortality, as subsequently confirmed in numerous studies. 17 There is no doubt that this is the result of confounding by disease (or reverse causality), that is, the impact of an activated acutephase response or in other words profound inflammation or even infection. Liu 18 showed that in patients without inflammation the same positive progressive relationship between cholesterol and mortality is seen as in the general population. Total and LDL cholesterol, however, provides too narrow a view of the cardiovascular risk. Extensive evidence supports the argument that, in addition, low HDL cholesterol and elevated TG are individual independent predictors of CVD in S25

3 r e v i e w C. Wanner and E. Ritz: Reducing lipids for CV protection the general population. The observational Framingham Heart Study reported that people with HDL cholesterol levels of o35 mg per 100 ml had an eight-fold higher incidence of CVD compared with those with HDL cholesterol levels of 465 mg per 100 ml. 19 The Atherosclerosis Risk in Communities (ARIC) study based on 10-year follow-up in 2339 middle-aged patients free of coronary heart disease (CHD) at baseline showed a continuous inverse relationship between HDL cholesterol and CHD risk, independent of other lipids. 20 Furthermore evidence supporting the relationship between HDL cholesterol and CVD risk has been extensively reviewed in a recent consensus group paper. 21 Elevated TG are also associated with increased risk of atherosclerotic events. In a meta-analysis of 29 prospective studies including 262,525 patients of whom 10,158 were CHD cases, the odds ratio for coronary risk was 1.72 (95% CI: ) when individuals in the highest tertile were compared with those in the lowest tertile of usual logtriglyceride values (adjusted for age, sex, smoking history, lipid levels, and blood pressure). Recent long-term prospective studies 22,23 highlight the importance of non-fasting triglyceride levels as a significant risk factor for CHD events, rather than the usual values measured after a h fast. 22 The former timing captures the peak of postprandial triglyceridemia, and hence exposure of the vasculature to triglyceride-rich remnant particles. 23 This is all the more important because hemodialysis patients exhibit severe postprandial dyslipidemia with prolonged clearance deficits for triglycerides. 24 PROGRESSION OF KIDNEY DISEASE AND STATIN THERAPY Why the effect of lipids and lipid lowering on progression of kidney disease are of interest? The importance is obvious, as renal dysfunction is one of the most potent cardiovascular risk factors. Dyslipidemia, in part explained by its association with proteinuria, predicts progressive loss of renal function, 25 particularly in diabetes. This was seen even in early stages of diabetic nephropathy. 26,27 In the Care study, intervention with pravastatin was associated with an admittedly small reduction in the rate of loss of renal function. 28 This issue is currently investigated by the interventional LORD study (lipid lowering and onset of renal disease). 29 Other lipid parameters apparently also play a role. In the MMKD study, a significant relationship was found between apo(a)iv and progression: 30 12% of patients with apo(a)iv below the median of 26 mg per 100 ml experienced doubling of serum creatinine, whereas not less than 51% of patients above the median experienced progression, but this may not be a causal effect. Other lipids are also implicated in the high microvascular risk of diabetic patients. 31 In diabetic patients, elevated levels of triglycerides and triglyceride-rich VLDL are implicated in driving the progression of albuminuria 32 and elevated triglycerides are also predictive of the development and progression of diabetic nephropathy, 33 retinopathy and need for future renal replacement therapy. 34 Conversely, higher levels of HDL cholesterol apparently protect against the development of albuminuria in type 1 diabetes. 35 What is the effect of lowering cholesterol by statins on progression? Uncontrolled evidence suggests that statin treatment is beneficial in preventing albuminuria and the decline in renal function. Meta-analyses in patients with and without diabetes indicate that statins improve renal outcomes, particularly in patients with CVD. However, the studies included in these analyses were heterogeneous with respect to patient populations 36,37 and at least in diabetic patients a significant effect could not be documented. In the Heart Protection study, treatment with simvastatin (40 mg/day) led to a significantly smaller decline in GFR in patients at high risk of CVD, with a more marked effect among patients with diabetes. 38 A post hoc analysis from the Treating to New Targets study suggest that the benefit is more marked with high doses (80 mg/day) compared with conventional doses (10 mg/day) of atorvastatin. 39 CARDIOVASCULAR EVENTS AND STATIN THERAPY Even minor reduction of renal function causes an elevated risk of cardiovascular events. This excess burden appears to be because of a higher prevalence of traditional cardiovascular risk factors, but possibly also of non-traditional risk factors such as hyperphosphatemia, hyperparathyroidism, or chronic inflammation. The issue, whether in secondary prevention cardiovascular events can be reduced by statins, was addressed by a subanalysis of the randomized double-blind placebo-controlled CARE study. All participants had entry serum cholesterol of o240 mg per 100 ml. In the 1711 participants who had an entry egfr o70 ml/min per 1.73 m 2, patients treated with pravastatin had, after a median follow-up of 58.9 months, significantly lower hazard ratios (HR) for coronary events (HR 0.72; CI: ; P ¼ 0.001) and coronary revascularization (HR 0.65; CI: ; P ¼ 0.001), but not for total mortality and stroke. There was no excess of side effects. 40 Therefore, statins are effective in pre-end-stage renal patients, but the question that has been raised is: why are they not more effective? Is it possible that statin therapy fails to adequately address the above-discussed vascular risk attributable to elevated TG and low HDL cholesterol? Findings from the Cholesterol Treatment Trialists Collaborators meta-analysis of 14 prospective statin studies showed that both lipid abnormalities markedly increased vascular risk. Among people with diabetes and low HDL cholesterol (p35 mg per 100 ml) at baseline, vascular event rates were 50% higher than in those with values above target (22.8 vs 11.5%). In the presence of elevated TG (4177 mg per 100 ml) vascular event rates were 24% higher compared with those observed in people with values p150 mg per 100 ml. 41 Even if patients achieve LDL cholesterol levels below current targets, the presence of low HDL cholesterol or elevated TG limits reduction in vascular events. S26

4 C. Wanner and E. Ritz: Reducing lipids for CV protection r e v i e w EVIDENCE FROM LIPID-LOWERING INTERVENTIONS IN END- STAGE RENAL DISEASE The situation is even less clear in patients with end-stage renal disease and on renal replacement therapy. In observational studies, statin users had lower mortality than non-statin users in hemodialysed 42 as well as in peritoneal dialysis patients. It should be noted, however, that in Fathi s 43 study, patients with CKD stage 4, as compared with non-renal patients with coronary artery disease, the same degree of lowering of LDL cholesterol reduced maximum intima media thickness of the carotid artery in patients with CHD, whereas it was completely ineffective in CKD patients after 2 years. This observation suggests that the response of the vascular wall to lipid lowering by statins is much less marked in advanced CKD. In view of such uncertainties, the 4D study 8 was performed in hemodialysed type 2 diabetic patients who at entry had total cholesterol of 221±42 mg per 100 ml, triglycerides 257±157 mg per 100 ml, LDL cholesterol 128±30 mg per 100 ml, VLDL cholesterol 57±34 mg per 100 ml and HDL cholesterol 37±18 mg per 100 ml. A total of 1255 patients were randomized to receive placebo or atorvastatin (20 mg daily). After 4 years in atorvastatintreated patients the primary composite endpoint was reduced only by 8%, which was not statistically significant (95% CI: , P ¼ 0.37). A potential explanation is that adjudicated CHD was found in only 9% of the patients whereas 35% died from other cardiac causes such as sudden death (26%), heart failure (6%), and other cardiac causes (3%). Although often interpreted as negative, the results of 4D are in line with the results of other statin trials, the results of which are summarized in a meta-analysis of individual participant data by the Cholesterol Treatment Trialists (CTT) Collaborators assessing the efficacy and safety of cholesterol-lowering treatment in a prospective meta-analysis of data from 90,056 participants in 14 randomized trials. 41 Reducing LDL cholesterol by 1 mmol/l (40 mg per 100 ml) reduced the risk of major vascular events by about one-fifth, with similar reductions of about one-fifth in each separate component of the primary outcome. Estimates of the effects of statin therapy on the causes of death revealed that CHD mortality was reduced by about one-fifth per mmol/l lower LDL cholesterol, but non-vascular causes of death were not significantly reduced. Therefore, the results of the CTT metaanalysis predict what might have been expected if the effects of lowering cholesterol among dialysis patients were similar to those observed in non-renal populations. With the exception of stroke, which occurred more frequently in the 4D study, an excess that remains unexplained, the results predicted by the meta-analysis in non-renal patients closely matched those observed in hemodialysed type 2 diabetics in the 4D study. 44 The 4D study also documented the excellent side effect profile of atorvastatin: no significant difference between placebo and atorvastatin was found with respect to myalgia or myopathy. Table 3 Statin use in dialysis patients Statins in dialysis patients Hazard ratio USRDS Total death 0.68 ( ) CV death 0.63 ( ) DOPPS Total death 0.69 ( ) CV events 0.63 ( ) CV death 0.77 ( ) CV, cardiovascular. Data from the United States Renal Data System (USRDS) and Dialysis Outcomes Prospective Population (DOPPS) Study. Does the lack of a significant benefit with respect to the composite endpoint in the 4D study constitute a contraindication against statins in diabetic or non-diabetic hemodialysis patients? Obviously, with the wisdom of hindsight the study was underpowered. In addition, observational data, such as USRDS (United States Renal Data System) and DOPPS (Dialysis Outcomes Prospective Population) data, showed a markedly lower rate of cardiovascular death in statin-treated patients, 45 (Table 3) which led the authors to the conclusion that clinicians should not be discouraged from continuing or initiating statin therapy in hemodialysis patients by the results of the 4D study. We agree and hope that the final answer will be given by the ongoing AURORA study in non-diabetic hemodialysis patients 46 and by the large SHARP study. 47 DISCLOSURE Christoph Wanner has received consulting fees from Genzyme and Nova Nordisk as well as lecture fees from Genzyme, Nova Nordisk, and Abbott. Christoph Wanner has also received grant support from Gezyme. The remaining author has declared no financial interests. REFERENCES 1. Ritz E, Wanner C. Lipid abnormalities and cardiovascular risk in renal disease. J Am Soc Nephrol 2008; 19: Kaysen GA. Hyperlipidemia in chronic kidney disease. Int J Artif Organs 2007; 30: Fruchart JC, Duriez P, Staels B. Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 1999; 10: Dichtl W, Nilsson L, Goncalves I et al. Very low-density lipoprotein activates nuclear factor-kappab in endothelial cells. Circ Res 1999; 84: Kawakami A, Aikawa M, Nitta N et al. Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein and protein kinase C alpha-mediated nuclear factor-kappab activation. Arterioscler Thromb Vasc Biol 2007; 27: Attman PO, Samuelsson O, Alaupovic P. Lipoprotein metabolism and renal failure. Am J Kidney Dis 1993; 21: Shoji T, Nishizawa Y, Kawagishi T et al. Intermediate-density lipoprotein as an independent risk factor for aortic atherosclerosis in hemodialysis patients. J Am Soc Nephrol 1998; 9: Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: Ikewaki K, Schaefer JR, Frischmann ME et al. Delayed in vivo catabolism of intermediate-density lipoprotein and low-density lipoprotein in hemodialysis patients as potential cause of premature atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: S27

5 r e v i e w C. Wanner and E. Ritz: Reducing lipids for CV protection 10. Frischmann ME, Kronenberg F, Trenkwalder E et al. In vivo turnover study demonstrates diminished clearance of lipoprotein(a) in hemodialysis patients. Kidney Int 2007; 71: Becker B, Kronenberg F, Kielstein JT et al. Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the mild and moderate kidney disease study. J Am Soc Nephrol 2005; 16: Kronenberg F, Kuen E, Ritz E et al. Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol 2000; 11: de Boer IH, Astor BC, Kramer H et al. Lipoprotein abnormalities associated with mild impairment of kidney function in the multi-ethnic study of atherosclerosis. Clin J Am Soc Nephrol 2008; 3: Lindner A, Charra B, Sherrard DJ et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974; 290: Buzello M, Tornig J, Faulhaber J et al. The apolipoprotein e knockout mouse: a model documenting accelerated atherogenesis in uremia. JAm Soc Nephrol 2003; 14: Degoulet P, Legrain M, Reach I et al. Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron 1982; 31: Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15: Liu Y, Coresh J, Eustace JA et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004; 291: Gordon T, Castelli WP, Hjortland MC et al. High-density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977; 62: Sharrett AR, Ballantyne CM, Coady SA et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001; 104: Chapman MJ, Assmann G, Fruchart JC et al. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004; 20: Bansal S, Buring JE, Rifai N et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298: Nordestgaard BG, Benn M, Schnohr P et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007; 298: Weintraub M, Burstein A, Rassin T et al. Severe defect in clearing postprandial chylomicron remnants in dialysis patients. Kidney Int 1992; 42: Ozsoy RC, van der Steeg WA, Kastelein JJ et al. Dyslipidaemia as predictor of progressive renal failure and the impact of treatment with atorvastatin. Nephrol Dial Transplant 2007; 22: Ficociello LH, Perkins BA, Silva KH et al. Determinants of progression from microalbuminuria to proteinuria in patients who have type 1 diabetes and are treated with angiotensin-converting enzyme inhibitors. Clin J Am Soc Nephrol 2007; 2: Earle KA, Harry D, Zitouni K. Circulating cholesterol as a modulator of risk for renal injury in patients with type 2 diabetes. Diabetes Res Clin Pract 2008; 79: Tonelli M, Moye L, Sacks FM et al. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003; 14: Fassett RG, Ball MJ, Robertson IK et al. The Lipid lowering and Onset of Renal Disease (LORD) Trial: a randomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression of kidney disease. BMC Nephrol 2008; 9: Boes E, Fliser D, Ritz E et al. Apolipoprotein A-IV predicts progression of chronic kidney disease: the mild to moderate kidney disease study. JAm Soc Nephrol 2006; 17: Jenkins AJ, Rowley KG, Lyons TJ et al. Lipoproteins and diabetic microvascular complications. Curr Pharm Des 2004; 10: Misra A, Kumar S, Kishore Vikram N et al. The role of lipids in the development of diabetic microvascular complications: implications for therapy. Am J Cardiovasc Drugs 2003; 3: Hadjadj S, Duly-Bouhanick B, Bekherraz A et al. Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes. Diabetes Metab 2004; 30: Cusick M, Chew EY, Hoogwerf B et al. Risk factors for renal replacement therapy in the Early Treatment Diabetic Retinopathy Study (ETDRS), Early Treatment Diabetic Retinopathy Study Report No. 26. Kidney Int 2004; 66: Molitch ME, Rupp D, Carnethon M. Higher levels of HDL cholesterol are associated with a decreased likelihood of albuminuria in patients with long-standing type 1 diabetes. Diabetes Care 2006; 29: Douglas K, O Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006; 145: Sandhu S, Wiebe N, Fried LF et al. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 2006; 17: Collins R, Armitage J, Parish S et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: Shepherd J, Kastelein JJ, Bittner V et al. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol 2008; 51: Tonelli M, Moye L, Sacks FM et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003; 138: Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: Seliger SL, Weiss NS, Gillen DL et al. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 2002; 61: Fathi R, Isbel N, Short L et al. The effect of long-term aggressive lipid lowering on ischemic and atherosclerotic burden in patients with chronic kidney disease. Am J Kidney Dis 2004; 43: Baigent C, Landray MJ, Wheeler DC. Misleading associations between cholesterol and vascular outcomes in dialysis patients: the need for randomized trials. Semin Dial 2007; 20: Kwan BC, Kronenberg F, Beddhu S et al. Lipoprotein metabolism and lipid management in chronic kidney disease. J Am Soc Nephrol 2007; 18: Fellstrom B, Zannad F, Schmieder R et al. Effect of rosuvastatin on outcomes in chronic haemodialysis patients design and rationale of the AURORA study. Curr Control Trials Cardiovasc Med 2005; 6: Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003; 84: S207 S210. S28