LDL cholesterol in CKD to treat or not to treat?

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1 & 2013 International Society of Nephrology review LDL cholesterol in CKD to treat or not to treat? Ziad A. Massy 1 and Dick de Zeeuw 2 1 Division of Nephrology, Ambroise Paré Hospital, Paris Ile de France Ouest (UVSQ) University, Boulogne Billancourt/Paris, and INSERM U-1088, Amiens, France and 2 Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands In the majority of patients with chronic kidney disease (CKD) the total and low-density lipoprotein (LDL) cholesterol are usually normal, with the exception of patients with nephrotic-range proteinuria and in peritoneal dialysis patients. Moreover, epidemiological evidence shows that the link between serum total cholesterol or LDL cholesterol and cardiovascular disease (CVD) in CKD is not as straightforward as in the general population. In addition, atherosclerosisrelated events are responsible for only B30% of CVD in these patients. Nevertheless, intervention trials, particularly the Study of Heart and Renal Protection, and meta-analyses showed a proportional reduction of cardiovascular risk associated with the absolute reduction in LDL cholesterol in patients with CKD similar to the general population, with apparent attenuation of this relationship in end-stage kidney disease. Therefore, the use of cholesterol-lowering agents appears to be indicated in early CKD stages to prevent atherosclerosis-related risk. However, uncertainty persists as to the optimal management of this risk in end-stage kidney disease patients. In the present review, we discuss these issues and end up with a practical plan aimed to help the nephrologist in managing atherosclerosis-related risk using cholesterol-lowering therapies in CKD patients. Kidney International (2013) 84, ; doi: /ki ; published online 22 May 2013 KEYWORDS: cardiovascular disease; CKD; dyslipidemia; LDL cholesterol; randomized controlled trials; statins Lipid patterns in CKD Lipid abnormalities, also referred to as dyslipidemia, are common in patients with chronic kidney disease (CKD). However, the pattern of lipid abnormalities is not uniform among different CKD categories and stages, as different lipoprotein spectra are observed in patients with nephrotic syndrome, those with CKD not yet on dialysis, those receiving hemodialysis, and those receiving peritoneal dialysis treatment (Table 1). 1 Increased serum total and low-density lipoprotein (LDL) cholesterol that is associated or not associated with hypertriglyceridemia is invariably found in patients with nephrotic-range proteinuria. High-density lipoprotein levels are often normal in nephrotic patients. The most prevalent pattern in CKD patients without nephrotic syndrome and in hemodialysis patients is an increase in serum triglyceride concentration, due to the accumulation of triglyceride-enriched apolipoprotein-b particles, and a decrease in serum high-density lipoprotein concentration. Peritoneal dialysis patients usually have an increase in total and LDL cholesterol concentrations. Moreover, pro-atherogenic changes of lipoprotein composition, such as modifications induced by oxidative stress and advanced glycation end products, have also been repeatedly documented in association with CKD. 2,3 With regard to the cause of the reported complex lipoprotein abnormalities in CKD, the fact that highly variable patterns are observed in different patient categories suggests a multifactorial pathogenesis. Several causes have been implicated, including insulin resistance, inflammation, glycoxidation, secondary hyperparathyroidism, and dialysis-related factors (e.g., dialysis membranes and use of heparin). 1 Correspondence: Ziad A. Massy, Division of Nephrology, Ambroise Paré Hospital, Paris Ile de France Ouest (UVSQ) University, 09 Avenue Charles de Gaulle 92100, Boulogne Billancourt/Paris, France. ziad.massy@apr.aphp.fr Received 20 January 2013; accepted 31 January 2013; published online 22 May 2013 Cardiovascular disease in CKD Individuals with CKD have high rates of cardiovascular disease (CVD), particularly when proteinuria is present. 4 According to a recent report, CKD could be added to the list of criteria defining individuals at highest risk of future coronary events. 5 The contribution of atherosclerosis to the CVD associated with CKD remains unclear. The prevalence of atherosclerosis increases with age and is aggravated by CKD, although it does not appear to be specifically induced by it. 6,7 However, the cardiovascular events associated with atherosclerosis are more often fatal in patients with CKD than in individuals without CKD. 5 On the basis of clinical and experimental findings, it appears that the initial Kidney International (2013) 84,

2 review ZA Massy and D de Zeeuw: LDL cholesterol in CKD Table 1 Common lipid abnormalities in patients with renal disease LDL and cholesterol Triglycerides HDL Nephrotic syndrome mm m N CKD without nephrotic syndrome Nk m k Hemodialysis Nk m k Peritoneal dialysis m mm k Abbreviations: CKD, chronic kidney disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein. cardiovascular abnormalities in the CKD setting include nonatherosclerotic changes, in particular arterial stiffness, left ventricular diastolic dysfunction, and left ventricular hypertrophy. 6,7 In adult CKD patients, these abnormalities are often accompanied by atherosclerosis, which may aggravate them secondarily. It is noteworthy that in the general population there is no obvious clinical benefit in treating LDL cholesterol with respect to the above non-atherosclerosis-linked abnormalities. 8 Treatment goals From a practical point of view, guidelines for lipid-lowering treatment mainly base the initiation of treatment and therapeutic goals for LDL cholesterol on projected risk of atherosclerotic events. The US National Cholesterol Education Program Adult Treatment Panel III recommends that LDL cholesterol be reduced to levels lower than 2.6 mmol/l in patients with CVD or an equivalent disorder. The nephrology community assumed that the numerous quantitative and qualitative abnormalities of LDL cholesterol metabolism should contribute to the pathogenesis of CVD in patients with CKD, similar to what is known in the general population. 9,10 Therefore, several randomized, double-blind interventional trials were performed aiming to reduce serum LDL cholesterol and to prevent CVD in patients with CKD, initially only in those receiving dialysis treatment but subsequently also in those not yet on dialysis therapy. 13 Surprisingly, however, the results did not meet expectations. Could it be that nephrology tried to cut corners and did not follow the natural, classical approach in developing an appropriate therapy for a given disease condition? Traditionally, one starts by generating a hypothesis linking circulating biomarkers to a disease, based on the results of observational studies. The following step is to explore the potential toxicity of the incriminated compound in experimental in vitro and in vivo models. Once solid experimental data have become available, it is possible to plan interventional trials to confirm any postulated causality link (Figure 1). Could the apparent failure of several large intervention trials using cholesterol-lowering agents in CKD patients, except the Study of Heart and Renal Protection (SHARP), be explained by the fact that the nephrology community did not follow the above steps? In this review, we discuss the evidence and the lack of evidence, respectively, in favor of atherosclerosis-related risk by LDL cholesterol lowering in CKD patients and end up Chronic kidney disease Experimental evidence (?) Epidemiological evidence (+/ ) Interventional studies - 4D, AURORA ( ) - SHARP (+) Normal (low) LDL Cardiovascular events and mortality Figure 1 Classical methodological approach. Schematic representation of the classical methodological approach to establish a causality link between biomarker low-density lipoprotein (LDL) cholesterol and cardiovascular and mortality risk in chronic kidney disease (CKD) patients; þ positive effect; negative effect;? uncertain effect. with a practical plan aimed at helping the nephrologists manage this risk. DIFFERENT LINKS BETWEEN LDL CHOLESTEROL AND CVD IN CKD AS COMPARED WITH NON-CKD CONDITIONS Epidemiological evidence Observational studies among apparently healthy individuals or patients with preexisting CVD have repeatedly demonstrated a roughly linear relationship between serum total and LDL cholesterol and risk of death from CVD. 14,15 Among patients with CKD, however, this relationship is much less obvious. Several large studies reported a negative relationship of serum total or LDL cholesterol with CVD at very low total cholesterol levels (which are common in malnourished, inflamed dialysis patients) and a flat relationship at total cholesterol levels within the range of normal to slightly above normal values. 16,17 Low total and LDL cholesterol levels were also associated with higher mortality in patients with moderate to advanced stages of CKD, who were not yet on dialysis. 18,19 The inverse association between low total and LDL cholesterol levels and mortality may be explained in part by the presence of the so-called malnutrition inflammation syndrome. 18,19 This phenomenon has been inappropriately named reverse causality, with both malnutrition and chronic inflammatory disease lowering total and LDL cholesterol and, independently, increasing the risk of death. It is, however, less likely to explain the absence or only weak association observed among those with normal to slightly high total and LDL cholesterol levels. Moreover, although the risk of myocardial infarction in individuals with CKD is high, it has been recently shown that it is not increased to the same extent as in individuals with a history of coronary disease in the absence of CKD. 5 Therefore, these observations do not support the use of the term coronary heart disease risk equivalent for CKD. However, observational studies often have several biases unless confirmed by controlled intervention trials. 20 Experimental evidence Evidence that high total and LDL cholesterol concentrations may be toxic for the vessel wall under non-ckd conditions 452 Kidney International (2013) 84,

3 ZA Massy and D de Zeeuw: LDL cholesterol in CKD review has been obtained in laboratory experiments both in vitro and in vivo. 21,22 Mice with apoe / (apolipoprotein E deficiency), as generated by gene targeting technique, develop hypercholesterolemia and atherosclerotic vascular lesions in a reproducible manner while being fed on regular mouse chow. 22 Other gene knockout models, such as the one created by an LDL receptor gene deletion, confirmed these findings in mice with normal kidney function. In contrast, in vitro evidence exploring the toxicity of total and LDL cholesterol on vascular cells exposed to uremic milieu is rather limited. 23,24 However, in in vivo animal models with CKD, several groups were able to show that the atherosclerotic process is aggravated by the uremic state Importantly, even in this particular CKD animal model the impact of the uremic state on vascular lesion development was shown to be more important than that of high serum cholesterol. 7,25 Recent works have shown that elevated urea levels induced the formation of potentially atherogenic carbamylated LDL, and that high plasma carbamylated LDL may represent an independent risk factor for CKD-induced atherosclerosis in apoe / mice. 28 Thus, the pathogenic events that link total and LDL cholesterol to CKD-associated atherosclerosis remain poorly understood. They appear to be different from those involved in the non-ckd setting. If indeed the relationship between cholesterol and CVD is different in CKD, one could question whether statins are able to modify the levels of carbamylated LDL and thereby modify cardiovascular risk. This has not been described so far in experimental models. Evidence from interventional trials (cholesterol-lowering treatment and cardiovascular risk reduction) In the general population with normal or slightly altered kidney function, there is clear evidence of the beneficial effects of LDL cholesterol lowering on major cardiovascular events and mortality, particularly in patients at high cardiovascular risk. Thus, the Cholesterol Treatment Trialists Collaboration performed a meta-analysis of available statin trials and concluded that a 1-mmol/l reduction of LDL cholesterol led to a reduction in the annual incidence of heart attacks, revascularization, and ischemic stroke by roughly 20% independently of the baseline LDL cholesterol levels. 29 It is noteworthy that numerous post-hoc analyses of some of these trials have shown that LDL lowering may also be beneficial in CKD stage 1 and 2 patients. 29 In CKD patients, only three large interventional randomized trials have been conducted to date. Two studies were conducted in hemodialysis patients (i.e., Die Deutsche Diabetes Dialysis (4D) and An Assessment of Survival and Cardiovascular Events (AURORA) studies). Both failed to find a reduction in cardiovascular events or mortality with atorvastatin or rosuvastatin despite significant LDL cholesterol lowering. 11,12 However, the power of these two studies was probably insufficient (o3000 patients). Both had a mixed end point, including atherosclerosis and non-atherosclerosis events. This may have been partly responsible for the negative results. Recently, the SHARP trial reported on the effects of lipid lowering with both ezetimibe and simvastatin on cardiovascular outcomes in patients with different CKD stages, including end-stage kidney disease (on dialysis treatment) in the absence of a history of coronary heart disease. 13 This trial showed a significant, 17% reduction in major atherosclerosis events and a 15% reduction in major cardiovascular events in the entire cohort (more than 9000 patients). It is noteworthy that approximately one-third of the patients in the SHARP trial were on dialysis. There was no statistical trend to show that lipid-lowering therapy affected the dialysis patients in a manner different from the CKD stage 3 5 patients who were not treated by dialysis (Figure 2). However, if one looks at the efficacy of LDL cholesterol lowering therapy in the different stages of CKD in the SHARP trial, one cannot escape from the impression that LDL cholesterol lowering therapy is highly effective in normal epidermal growth factor receptor ranges, but progressively loses its efficacy when moving toward end-stage kidney disease, becoming completely ineffective in patients with no kidney function, who are undergoing dialysis treatment (Figure 2). However, the SHARP trial was not powered to test the potential differences between patient subgroups. Therefore, the question of the efficacy of simvastatin combined with ezetimibe in preventing major atherosclerosis events in dialysis patients remains unsettled to date. In any case, the benefit achieved in CKD patients related to cardiovascular events or mortality remains overall low in comparison with that observed in the general population (Figure 3), particularly so for the incidence of mortality. As patients with a history of coronary heart disease were excluded from SHARP, the relative benefit of LDL cholesterol lowering in CKD patients might be higher than 17%. In addition, the relatively modest efficacy in the CKD setting may be related to the reported low frequency of atherosclerotic events compared with other cardiovascular pathologies, particularly so in advanced stages of CKD. 6 It is noteworthy that the LDL cholesterol lowering achieved in the Statin (n = 4650) CKD3 (n = 2086) CKD4 (n = 2552) CKD5 (n = 1236) Dialysis (n = 2776) 230 (15%) 87 (7.9%) 127 (10.2%) 67 (10.9%) Atherosclerotic events Placebo (n = 4620) 110 (10.4%) 168 (12.7%) 81 (13.3%) 246 (16.5%) Risk ratio (95% CI) Cholesterol reduction better 16.5% SE 5.4 reduction (P = ) Placebo better Figure 2 Atherosclerotic events by chronic kidney disease (CKD) stage. Major atherosclerotic events by CKD stage at randomization, as adapted from the Study of Heart and Renal Protection (SHARP) study. No significant heterogeneity between CKD stages 3 5 patients and dialysis patients (P ¼ 0.25). Kidney International (2013) 84,

4 review ZA Massy and D de Zeeuw: LDL cholesterol in CKD Proportional reduction (%) in major cardiovascular event rate (95% CI) General population (statin vs. control) (21 trials) 25% risk reduction # SHARP 15% Risk reduction # 4D 8% Risk reduction Mean LDL cholesterol difference between treatment groups (mmol/l) # AURORA 4% Risk reduction Figure 3 Reduction in major cardiovascular event rates. Schematic representation of the reduction in major cardiovascular event rates according to the mean difference of serum low-density lipoprotein (LDL) cholesterol achieved between treated and nontreated patient groups in the Study of Heart and Renal Protection (SHARP), Die Deutsche Diabetes Dialysis (4D), and An Assessment of Survival and Cardiovascular Events (AURORA) studies in comparison with those observed in the Cholesterol Treatment Trialists Collaboration meta-analysis. above three trials carried out in CKD patients was not associated with an overt increase of side effects, except the fact that the 4D study showed a significant increase in fatal stroke incidence in the statin arm. Although this higher incidence may have happened by chance owing to the small number of fatal stroke events, it nevertheless cautions against the liberal use of statins in dialysis patients, in particular if there is no further cardiovascular protection to be expected. To address the persistent uncertainties about the usefulness of LDL cholesterol lowering across the large spectrum of CKD, two recent meta-analyses incorporated published trial data of LDL cholesterol lowering, essentially by statins, to allow for sufficient power to quantify treatment effects per stage of CKD. The first one provided moderate- to highquality evidence indicating that statins (generally at doses equivalent to simvastatin, 20 mg) reduced all-cause and cardiovascular mortality and major cardiovascular events in persons with CKD not receiving dialysis, by about one-fifth to one-quarter during B5 years of treatment. In contrast, moderate- to high-quality evidence indicated that in persons receiving dialysis, statins had little or no effect on all-cause mortality, cardiovascular mortality, or major cardiovascular events (including myocardial infarction and stroke), despite marked decreases in serum cholesterol levels (1.0 mmol/l (40 mg/dl)). 30 The second meta-analysis found that lipid lowering with statins was safe and effective in preventing cardiac mortality and cardiovascular events, especially myocardial infarction and revascularization procedures, in patients with CKD. The benefit was also seen for all-cause mortality, but this was limited to studies in patients with CKD not receiving dialysis, and the results were highly heterogenous. 31 In the latter study, no benefit for cardiovascular events was seen when the need for revascularization procedures was excluded from the composite outcome. It should be noted that the discrepancies between the results of these two meta-analyses may be due to methodological issues, including potential misclassification of cardiovascular events, and differences in the adjudication of coronary heart events between different studies, which is not easy in CKD patients, and/or the impact and validity of including revascularization procedures within composite primary end points. In addition, the interpretation becomes more complicated if one takes into account the starting level of LDL cholesterol in the different trials. If the starting level is too low, one cannot ascribe the cardiovascular risk to lipid changes, and thus cannot expect a beneficial effect of statin therapy. Indeed, in contrast to what has been observed in the Treatment Trialists Collaboration meta-analysis in general population, a recent post-hoc analysis of 4D study showed that in patients with type 2 diabetes mellitus undergoing hemodialysis, atorvastatin significantly reduced the risk of fatal and nonfatal cardiac events and death from any cause only when pretreatment LDL cholesterol was higher than 3.76 mmol/l, but not with lower levels. 32 Therefore, the benefit of LDL cholesterol lowering therapies in dialysis patients in atherosclerosis risk prevention could be restricted to those with high starting levels of LDL cholesterol, but this has not been studied and the issue thus remains unsettled. From literature evidence to clinical application As pointed out above, clinical trials should be performed on the basis of solid evidence from observational clinical studies and experimental animal experiments, suggesting a causal relationship between changes in serum total and LDL cholesterol and cardiovascular morbidity and mortality in the setting of CKD. As we have seen, the evidence for a relationship between total and LDL cholesterol and CVD is not as straightforward in CKD patients as it is in non-ckd patients. This may have to do with the fact that additional factors are more important in the pathogenesis of CVD than disturbances of cholesterol metabolism. In addition, experimental evidence in favor of a causal link between LDL cholesterol and CVD in CKD models is limited. If one extrapolates these experimental findings to the human situation, it is no surprise to see a heavy debate among the experts concerning the interpretation of the contradictory results obtained in the large randomized controlled trials on LDL cholesterol in patients with CKD. Finally, as high serum levels of triglycerides and low levels of high-density lipoprotein are the two cardinal features of lipid abnormalities in CKD patients, administration of fibrates in appropriate doses has been proposed as an alternative treatment approach. 33 Recently, Jun et al. 34 performed a meta-analysis of fibrate treatment trials in a subgroup of patients with baseline CKD, which showed a reduction in the risk of cardiovascular events, including protection against cardiovascular death. At the same time, there was a 14% reduction in the progression of 454 Kidney International (2013) 84,

5 ZA Massy and D de Zeeuw: LDL cholesterol in CKD review microalbuminuria, although this was associated with an acute reduction in epidermal growth factor receptor. However, this meta-analysis had limitations, including the relative paucity of data for patients with CKD stages 4 5D and lack of information on baseline triglyceride concentrations in the CKD subgroups of these trials. Nevertheless, the place of fibrates in the treatment and prevention of atherosclerosisassociated risk remains an uncertain one, and its place, similar to that of other lipid-lowering drugs such as niacin or cholesteryl ester transfer protein inhibitors, to prevent CVD risk remains to be defined in patients with CKD. CONCLUSIONS AND PRACTICAL TREATMENT STRATEGIES Data from recent interventional trials and meta-analyses in CKD patients would plead in favor of reducing atherosclerosis risk by cholesterol-lowering treatment strategies. Most importantly, although the state of CKD is not considered as a coronary heart disease risk equivalent, cardiovascular events associated with atherosclerosis appear to be more often fatal in patients with CKD than in individuals without CKD. 5 This evidence constitutes an additional argument for the treatment of atherosclerosis-associated risk, although the experimental data and other epidemiological evidence are less convincing. In patients with end-stage kidney disease, we have no definitive evidence in favor of beneficial cholesterol-lowering therapies on cardiovascular risk, together with a potential increase in the risk of stroke in those with diabetes. From a practical point of view, we are inclined to propose a pragmatic strategy for daily patient management while waiting for the results of a meta-analysis of dialysis patients included in the 4D, AURORA, and SHARP studies. Our proposition has been adapted and extended from the treatment strategy proposed by the European Society of Cardiology and the European Atherosclerosis Society guidelines, 35 which were limited to CKD stages 2 4, considering them at very high cardiovascular risk: (1) LDL cholesterol lowering strategies include either statins or ezetimibe, or both, and target the reduction of LDL to o1.8 mmol/l as recommended for patients with CVD or an equivalent disorder in the general population. 35 (2) We propose to start LDL cholesterol lowering treatment in stages 1 4 CKD patients with preexisting cardiovascular events or those with multiple risk factors and at high risk for coronary heart disease and LDL cholesterol 41.8 mmol/l. 5,35 (3) We propose to continue LDL cholesterol lowering strategies in patients developing CKD stage 1 or more, or those starting dialysis therapy (CKD stage 5D), who were previously on such treatment. (4) At present, we propose not to use LDL cholesterol lowering strategies in CKD patients with inflammation and/or malnutrition, 36 nor to start such treatment in dialysis patients who are treatment naive, until additional literature data in favor of a different therapeutic approach become available. DISCLOSURE ZAM and DdZ both are members of the SHARP Steering Committee. ZAM declares having received speaking fees from MSD. REFERENCES 1. Kaysen GA. Lipid and lipoprotein metabolism in chronic kidney disease. J Ren Nutr 2009; 19: Massy ZA, Nguyen-Khoa T. Oxidative stress and chronic renal failure: markers and management. J Nephrol 2002; 15: Keane WF, Tomassini JE, Neff DR. Lipid abnormalities in patients with chronic kidney disease: implications for the pathophysiology of atherosclerosis. J Atheroscler Thromb 2012; 20: Chronic Kidney Disease Prognosis Consortium. 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