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Lipid Management in Chronic Kidney Disease, Hemodialysis, and Transplantation
Lipid Ma nagement in Chronic Kidney Dis eas e, Hemo dialysis, a nd Tra nspla nt ation Terri Montague, MDa,*, Barbara Murphy, MDb KEYWORDS Chronic kidney disease Hyperlipidemia Statin Hemodialysis Renal transplantation
The optimal management of lipid abnormalities in patients who have chronic kidney disease (CKD) remains controversial. There are limited data to guide the use of lipid-lowering drugs in this population, because most of the landmark trials that showed benefits of lipid-lowering therapy on cardiovascular mortality in the general population included few patients who had CKD.1–3 This issue is important, because cardiovascular morbidity and mortality are high in the CKD population. If pharmacologic therapy lowers the risk of cardiovascular events even modestly, the impact in this high-risk group is substantial. The high rates of cardiovascular disease in the CKD, end-stage renal disease (ESRD), and renal transplant population are multifactorial; risk factors include general risk factors, such as diabetes, hypertension, and smoking, and also factors unique to renal disease, such as vascular calcification and chronic low-grade inflammation. The impact of dyslipidemia and lipid-lowering therapy in this population is unclear. Recent studies have shown the spectrum of dyslipidemia in patients who have CKD or ESRD to be different from that of the general population. There seems to be a shift to a uremic profile as the renal function deteriorates.4,5 The magnitude of the abnormalities is not disclosed fully by routine laboratory chemistries that test only total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. Other modifications such as oxidation and glycation of lipoproteins may promote further atherosclerosis.6 The few trials aimed at studying dyslipidemia in the ESRD and renal transplant population have shown mixed benefits from lipid-lowering therapy.7,8 This article discusses the pathophysiology of dyslipidemia in CKD, dialysis, and renal transplant patients, the therapeutic options, and their association with clinical a
Division of Kidney Disease and Hypertension, 593 Eddy Street, APC 9, Brown Medical School, Providence, RI 02903, USA b Division of Nephrology, Mount Sinai School of Medicine, 1468 Madison Avenue, Annenberg Building, New York, NY 10029, USA * Corresponding author. E-mail address: [email protected] (T. Montague). Endocrinol Metab Clin N Am 38 (2009) 223–234 doi:10.1016/j.ecl.2008.11.004 0889-8529/08/$ – see front matter ª 2009 Published by Elsevier Inc.
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outcomes. Whenever possible, comparisons are made to outcomes in the general population. PATHOPHYSIOLOGY AND PREVALENCE OF DYSLIPIDEMIA IN CHRONIC KIDNEY DISEASE, DIALYSIS, AND TRANSPLANTATION
Lipids are insoluble in plasma and thus require association with proteins (apolipoproteins) to form dissolvable particles called ‘‘lipoproteins.’’ These lipoproteins function mainly in transporting cholesterol or triglycerides from sites of absorption (gut) or synthesis (liver) to sites of use (peripheral tissues) or metabolism. Lipoprotein profiles seem to be affected by the severity of renal dysfunction and proteinuria.9 High-density lipoprotein (HDL), total cholesterol, and low-density lipoprotein (LDL) levels tend to decrease with declining renal function and on average are lower in patients who have stage 3 to stage 5 CKD than in the general population.10 As CKD advances to renal failure and dialysis, the levels of total cholesterol and LDL cholesterol tend to decrease. Despite this decrease, more than 50% of dialysis patients have LDL cholesterol levels greater than 100 mg/dL or non–high-density (non-HDL) lipoprotein cholesterol levels greater than 130 mg/dL.11 The prevalence of LDL cholesterol levels greater than 100 mg/dL is 85%, 70%, and 90%, respectively, in patients who have nephrotic syndrome, patients who are being treated with peritoneal dialysis, and renal transplant patients.12 In general, patients treated with peritoneal dialysis tend to have a more atherogenic lipid profile, with increased LDL cholesterol and oxidized LDL levels, than patients treated with hemodialysis.12 This difference may result in part from the use of dextrose-containing peritoneal dialysate and glucose absorption across the peritoneal membrane.13 Measurements of serum LDL cholesterol in patients who have kidney disease also may underestimate the atherogenic potential if it does not measure the LDL subfractions, such as small, dense LDL particles and lipoprotein (a), which are increased in these patients.14 Small, dense LDL particles tend to penetrate the vascular endothelium, become oxidized, and be taken up by scavenger receptors on macrophages and vascular smooth muscle cells. Once overloaded with cholesterol esters, these macrophages transform into foam cells, further accelerating atherosclerosis.15 The increased levels of oxidative stress and inflammation in CKD may promote the conversion of LDL to this more atherogenic form.16 Lipoprotein (a), a modified form of LDL that exists in different isoforms, has been found to be a risk factor for cardiovascular disease (CVD) in the general population and is highly atherogenic.17 Structurally it resembles plasminogen and interferes with fibrinolysis,18 and it also binds to macrophages, promoting foam cell formation. Plasma lipoprotein (a) levels are affected by renal function. In patients who have large lipoprotein (a) isoforms, levels have been found to increase as the glomerular filtration rate (GFR) decreases.19 After successful kidney transplantation, a decrease in large isoforms of plasma lipoprotein (a) is noted in patients previously treated with hemodialysis, and a decrease in all isoforms is seen in patients previously treated with peritoneal dialysis.20,21 Elevated lipoprotein (a) is an independent risk factor for CVD in patients treated with hemodialysis and has been associated with vascular events.22,23 Triglyceride levels tend to increase early in CKD and are particularly high in patients who have nephrotic syndrome and patients treated with dialysis.14 In the plasma, triglycerides are found predominantly in chylomicrons and in very-low-density lipoproteins (VLDLs). Chylomicrons are assembled in the intestine and transport dietary fatty acids, whereas VLDLs are produced in the live rand transport endogenous fatty acids. The increase in triglycerides is caused partly by the decreased catabolic rate of these
Lipid Management in Chronic Kidney Disease
lipoproteins resulting from the decreased activity of vascular endothelium-associated lipases such as lipoprotein lipase and hepatic triglyceride lipase.24 Impaired lipase activity may be caused by an inhibitor effect of hyperparathyroidism, calcium accumulation in islet cells leading to impaired insulin secretion, or depletion of the enzyme pool by frequent heparinization during hemodialysis.25,26 This decreased catabolism leads to prolonged exposure of the arterial vasculature to triglyceriderich lipoprotein remnants that are atherogenic.18 Studies in the general population have shown elevated triglyceride levels to be an independent risk factor for CVD.27 Patients who have CKD and patients treated with dialysis tend to have lower plasma HDL cholesterol levels than common in the general population.28 HDL plays a role in the reverse cholesterol transport, moving cholesterol from peripheral cells to the liver. This decrease leads to increased cholesterol levels peripherally and in the vasculature, thereby promoting atherosclerosis. These relative differences in the lipid profiles of uremic patients render questionable the extrapolation of data on the benefits of lipid-lowering therapy derived from the general population. In addition, given the relatively lower levels of total cholesterol and LDL cholesterol on standard lipid profile measurements that do not measure small, dense LDL particles, lipoprotein (a), VLDL, and chylomicron, potentially beneficial therapy may be withheld if guidelines for initiation are not met (ie, LDL cholesterol level >100 mg/dL). DYSLIPIDEMIA AND CARDIOVASCULAR MORTALITY IN CHRONIC KIDNEY DISEASE, DIALYSIS, AND TRANSPLANTATION
In the general population, clinical trials have demonstrated that cardiovascular mortality decreases proportionally with the rate of LDL cholesterol reduction.3,29,30 There are few data on the contribution of dyslipidemia toward cardiovascular morbidity and mortality in the CKD population. It is possible that in the setting of CKD with contributing factors such as anemia, inflammation, and proteinuria, dyslipidemia may contribute differently to the overall risk. In a prospective cohort study, Muntner and colleagues31 evaluated the contribution of different risk factors to cardiovascular mortality in the nondialysis CKD population. The study involved 14,856 participants with a mean follow-up period of 10.5 years. The association between the severity of dyslipidemia and future cardiovascular events was similar to that in patients who had normal renal function. The study included patients who had mild (GFR 60–90 mL/min/1.73 m2 body surface area [bsa]) and moderate to severe CKD (GFR 15–59 mL/min/1.73 m2 bsa). Based on their data, the authors predicted that for every 42-mg/dL (1.1-mmol/L) reduction in total cholesterol, there would be a 19.7% reduction in cardiovascular events. This study, however, did not show that treatment of dyslipidemia actually decreases cardiovascular mortality in the CKD population. The data in the dialysis population are conflicting. Two prospective studies in patients treated with hemodialysis showed no relationship between total cholesterol, triglyceride, LDL cholesterol, or HDL cholesterol levels and future cardiovascular events, but a cross-sectional and a prospective study showed a positive association.19,22,32–35 In 1995, Lowrie and colleagues,36 in a retrospective study involving 12,000 patients undergoing hemodialysis, found a U-shaped relationship between cholesterol levels and mortality. Patients who had low total cholesterol levels (<100 mg/dL) had more than four times the mortality risk of patients who had total cholesterol levels between 200 and 250 mg/dL. Once adjusted for albumin, the relationship became more linear, suggesting a potential role of malnutrition. In
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a 10-year prospective study of 1167 Japanese patients undergoing hemodialysis, low cholesterol was associated independently with higher C-reactive protein levels and mortality in patients who had low albumin levels.37 In a subgroup of patients who had albumin levels higher than 4.5 mg/dL, however, higher levels of cholesterol were associated with increased mortality. Liu and colleagues,38 in a prospective study of 823 patients starting hemodialysis or peritoneal dialysis in the United States, found that an increase in total cholesterol levels in the setting of inflammation and malnutrition decreased all-cause mortality. In the absence of inflammation and malnutrition, however, higher total cholesterol levels were associated positively with all-cause mortality. Both these studies show hypercholesterolemia to be a risk factor for allcause mortality in the dialysis population, which is modified in the presence of inflammation and malnutrition. In the renal transplant population, the incidence of both hyperlipidemia and CVD is high. The hyperlipidemia is multifactorial, and causes include previously discussed factors such as renal dysfunction, proteinuria, obesity, and diabetes as well as risk factors unique to transplant recipients, including immunosuppressive medications. In this population studies have not demonstrated conclusively a causal relationship between hyperlipidemia and CVD. Several small studies, however, have shown that treatment leads to decreased rates of mortality, rejection, and chronic allograft nephropathy.39,40
CURRENT TREATMENT GUIDELINES
The National Kidney Foundation has established guidelines that recommend aggressive therapy of dyslipidemia in patients who have kidney disease.41 These guidelines are based on the risk reductions achieved in the general population in patients who have or are at high risk for CVD, on the high risk of CVD in patients who have kidney disease, and on the overall safety of most pharmacologic therapies. These guidelines, however, also acknowledge the paucity of data in this population. In keeping with the National Cholesterol Education Program (NCEP) guidelines for hyperlipidemia in the general population, the National Kidney Foundation guidelines recommend lifestyle modifications with diet and exercise.42 Both sets of guidelines endorse therapeutic lifestyle changes including reduced intake of saturated fat, trans fats, and cholesterol, increased intake of fiber, weight loss, increased exercise, avoidance of (or moderation in the use of) alcohol, and treatment of high blood glucoses. The work group also concluded that, with a few notable differences, many of the NCEP guidelines are applicable to stage 1 to stage 5 CKD, including patients who have received a renal transplant (regardless of whether the GFR is >90 mL/min/1.73 m2 bsa). One guideline places all patients who have renal insufficiency, including renal transplant recipients, in the highest category of cardiovascular risk. As a result, a target LDL cholesterol level of less than 100 mg/dL is recommended for all renal patients. Furthermore, for renal patients who have an LDL cholesterol level between 100 and 129 mg/dL, pharmacologic therapy should be used after only 3 months of lifestyle changes, although this guideline is considered optional in the general population. For renal patients whose LDL cholesterol is greater than 120 mg/dL, lifestyle changes should be initiated concurrently with pharmacologic therapy. The National Kidney Foundation guidelines also suggest that fibrates may be used in stage 5 CKD for patients who have triglyceride levels higher than 500 mg/dL or patients who have triglyceride levels higher than 200 mg/dL, non-HDL cholesterol levels greater than 130 mg/dL, and who cannot tolerate statins. This guideline is in
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contrast to the NCEP Adult Treatment Panel guidelines, in which fibrates are contraindicated in stage 5 CKD.
PHARMACOLOGIC MANAGEMENT OF DYSLIPIDEMIA IN CHRONIC KIDNEY DISEASE, DIALYSIS, AND TRANSPLANTATION Antioxidants
Oxidative stress, as discussed previously, plays a role in promoting atherosclerosis in patients who have CKD. As a result, antioxidants such as vitamin E have been used in attempts to decrease atherogenic oxidized lipid levels. Randomized trials in the general population did not demonstrate any cardiovascular benefits.43,44 Boaz and colleagues,45 however, in a trial of 196 patients treated with hemodialysis who had pre-existing cardiovascular disease, found that vitamin E given for median time of 519 days resulted in a 54% reduction in the composite end point of myocardial infarction, peripheral vascular disease, and ischemic stroke as compared with placebo. In another study, vitamin E was found to increase HDL cholesterol levels in patients treated with dialysis.46 Larger randomized studies are needed to validate these results.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (Statins)
In the general population, studies have shown a direct correlation between increasing levels of total and LDL cholesterol and cardiovascular mortality.47,48 Treatment with lipid-lowering therapy has shown clear benefits in cardiac outcomes in both primary and secondary prevention studies.1,49,50 Studies of statin use in patients treated with peritoneal dialysis or hemodialysis and in renal transplant recipients have shown that statins are effective in reducing LDL cholesterol levels, but few studies have evaluated the correlation between statin use and a reduction in cardiovascular mortality.7,8,51,52 Stage 2 through stage 4 chronic kidney disease
In large, randomized trials in the general population, there have been several post hoc analyses of subgroups with impaired renal function. The Pravastatin Pooling Project combined patient results of three randomized trials of pravastatin versus placebo in the general population.53 The three trials were the West of Scotland Coronary Prevention Study, the Cholesterol and Recurrent Events study, and the Long-term Intervention with Pravastatin in Ischemic Disease study.2,3,54 The primary outcome studied was time to myocardial infarction, coronary death, or cardiac intervention. Of the 19,700 patients included, 4491 had moderate CKD defined by a GFR between 30 and 60 mL/min/1.73 m2 bsa. CKD was associated with increased risk for the primary outcome with a hazard ratio of 1.26 (95% confidence interval, 1.07–1.49). In the patients who had CKD, 40 mg of pravastatin was associated with a 23% reduction in the composite outcome over 5 years. This result was similar to those obtained in patients who did not have CKD. In the Anglo-Scandinavian Cardiac Outcomes Trial, subgroup analysis of 6517 patients who had kidney dysfunction followed for a median of 3.3 years revealed that 10 mg of atorvastatin led to a significant (39%) reduction in nonfatal myocardial infarction and cardiac death.55 Both these studies included patients who had or who were at high risk for coronary artery disease. It is unknown whether there is a benefit to patients who have moderate CKD without coronary artery disease.
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Dialysis
In patients treated with dialysis, Seliger and colleagues,56 in the Dialysis Morbidity and Mortality wave 2 study, studied the effect on mortality of starting statins at the initiation of dialysis. The cohort of 3716 prospective study participants included patients treated with peritoneal dialysis and a random sample of 20% of the patients treated with hemodialysis from the US Renal Data System. The rate of statin use at the initiation of dialysis was low, at 9.7%, and recipients tended to have pre-existing coronary artery disease and diabetes. In this study cardiovascular mortality decreased by 37% in the statin recipients. This trial was not a randomized, controlled study, however, and it is uncertain if the results are generalizable to the entire dialysis population. These findings were not confirmed by the Die Deutsche Diabetes-Dialyse (4D) study.8 This controlled trial randomly assigned 1255 diabetic patients treated with hemodialysis to atorvastatin, 20 mg, or placebo. Despite a 42% reduction in the LDL cholesterol level in the atorvastatin group, the rate of the composite end point of death from cardiac causes, fatal stroke, nonfatal myocardial infarction, and nonfatal stroke was similar in the two groups at 3 years. The rate of coronary interventions was 18% lower in the atorvastatin group, but the risk of fatal stroke was doubled. Statin drugs may have limited benefit in advanced CVD, but further studies are needed to establish this benefit firmly. Renal transplantation
To date, only one trial has examined the mortality benefits of statin treatment in renal transplant recipients. The Assessment of Fluvastatin in Renal Transplantation study evaluated the effect of fluvastatin, 40 mg, compared with placebo on the cardiac outcomes of renal transplant recipients.7 This study, which enrolled 2102 stable transplant recipients 6 months after transplantation, is notable for its size. The follow-up duration was 5 to 6 years. Fluvastatin lowered LDL cholesterol levels by 32%, but no significant reduction was seen in the combined primary end points of cardiac death, definite or probable myocardial infarction, or coronary intervention. A post hoc analysis examining the effect of fluvastatin on definite myocardial infarction or cardiac death (omitting the end point of coronary intervention) showed that fluvastatin was associated with a statistically significant risk reduction of 35%.57 Overall there may be a benefit of statin use in early CKD that decreases as renal failure advances. Two ongoing randomized trials are evaluating statin use in patients who have CKD. The Study of Heart and Renal Protection (SHARP) will evaluate the combined effect of simvastatin and ezetimibe versus placebo in the primary prevention of heart disease and stroke.58 Six thousand patients who have CKD with plasma creatinine levels greater than 1.7 mg/dL in men and greater than 1.5 mg/dL in women and 3000 patients being treated with dialysis will be recruited. A second trial, the Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: an Assessment of Survival and Cardiovascular Events (AURORA), will evaluate the effect of rosuvastatin on the incidence of cardiovascular deaths, heart attacks, and strokes in patients with and without diabetes who are being treated with hemodialysis.59,60 Neither study has lipid inclusion criteria. A serious and common complication of statin therapy is myositis, the importance of which was emphasized by the recall of cerivastatin in 2001. This concern was not recognized in either the 4D study or the other large studies. Most statins are metabolized by the cytochrome P450 (CYP) 3A4, and myotoxicity is increased if they are taken with medications that inhibit this metabolism (eg, immunosuppressive medications such as cyclosporine, tacrolimus, and sirolimus and other medications such as verapamil, diltizaem, erythromycin, and several antidepressants).61 Exceptions among
Lipid Management in Chronic Kidney Disease
statins include fluvastatin, which is metabolized by CYP2C9, and pravastatin and rosuvastatin, which are metabolized by a non–cytochrome-dependent mechanism. The potential for drug–drug interactions are substantial, and thus caution and close monitoring are recommended. Current recommendations are that, except for atorvastatin and pravastatin, the statin dose be reduced by 50% in patients being treated with dialysis.62,63 In transplant recipients, the current recommendations are that a lower initial dose of statin be used, particularly with concomitant use of cyclosporine.41 Studies involving rosuvastatin in patients who had severe renal insufficiency noted higher rosuvastatin levels than seen in patients who had normal renal function, and thus a lower starting dose of 5 mg is recommended.64 Statin and additional effects
Statins may exert additional effects independent of the effect on LDL cholesterol. The results of one small observational study in patients treated with hemodialysis suggest that statins may have anti-inflammatory properties, because significant decreases were seen in C-reactive protein levels after 8 weeks of simvastatin treatment.65 Other small, randomized trials suggest that statins also may help slow the decline in GFR.66,67 Bianchi and colleagues66 studied the effect of atorvastatin, 10 to 40 mg/d, versus placebo in 56 patients who had CKD. They found that after 1 year the rate of proteinuria decreased significantly with atorvastatin compared with placebo. In a post hoc analysis of a subgroup of 690 patients who had moderate CKD (GFR < 60 mL/min/1.73 m2 bsa), statin therapy slowed the decline in GFR, especially in patients who had proteinuria.67
Fibrates
In the general population, fibrates reduce plasma triglyceride levels and modestly increase HDL cholesterol concentrations. They are indicated when a triglyceride level greater than 500 mg/dL is the primary lipid abnormality and may reduce these levels by up to 50%.11 Gemfibrozil was associated with 20% reduction in cardiovascular events in patients who had mild to moderate renal insufficiency (GFR 30–75 mL/ min/1.73 m2 bsa).68 In patients who had dyslipidemia who were treated with continuous ambulatory peritoneal dialysis, gemfibrozil led to significant reductions in triglyceride levels without myositis or liver toxicity.69,70 The dose used in these studies was less than that used in the general population (600 mg/d or 600 mg every other day). There have been case reports of rhabdomyolysis associated with use of fibrates in ESRD and hypothyroidism, however.71,72 There also have been reports of worsening kidney function associated with the use of clofibrate, bezafibrate, and fenofibrate in patients who had mild to moderate CKD.73 Recent guidelines discourage the use of fibrates in patients who have a GFR of less than 15 mL/min/1.73m2 bsa.11
Bile Acid Sequestrants
Treatment with cholestyramine in asymptomatic individuals who had normal kidney function reduced cardiovascular mortality by 19%.29 In the general population, bile acid sequestrants used in combination with statins lower LDL cholesterol levels by up to 20%. Because these drugs are not absorbed in the gastrointestinal tract, in theory no dose adjustments are needed for patients who have reduced kidney function. Bile acid sequestrants do interfere with cyclosporine absorption, however, and also may cause increases in triglyceride levels. There are few data on the safety and cardiac outcomes of these agents in the CKD population.
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Nicotinic Acid
Nicotinic acid reduces the secretion of VLDL by the liver.74 The National Kidney Foundation guidelines recommend nicotinic acid as an alternative second agent for LDL cholesterol reduction in combination with a statin.11 The side effects associated with the administration of niacin, such as flushing, hyperglycemia, and hepatoxicity, decrease its tolerability, leading to high rates of noncompliance. One study compared the results of nicotinic acid, clofibrate, and pravastatin on LDL cholesterol levels in patients treated with continuous ambulatory peritoneal dialysis or hemodialysis.75 There were no adverse effects with any of the treatments, but statins were superior in reducing LDL cholesterol levels. Sevelamer Hydrochloride
Sevelamer is a cationic polymer that binds phosphates via ion exchange. It also has been found to reduce plasma total cholesterol levels by 18% to 22% and plasma LDL cholesterol levels by 30% to 37% by binding bile acids in the intestine.76 An open-label study involving 192 patients treated by hemodialysis who used sevelamer for 46 weeks showed a 36% reduction in LDL cholesterol level and an 18% increase in HDL cholesterol level.77 In the Treat to Goal Study, patients receiving sevelamer were found to have significantly lower rates of coronary artery calcification and an associated decrease in LDL cholesterol levels.78 There have been no long-term outcome studies of the cardiovascular benefits of sevelamer. SUMMARY
Commonly used clinical assays that measure only triglyceride, LDL cholesterol, HDL cholesterol, and total cholesterol levels may not measure the additional lipid abnormalities prevalent in uremia. Post hoc analysis of large clinical trials in the general population seems to support the beneficial effects of statins in renal transplant recipients and patients in the early stages of CKD, but the evidence is unclear in the latter stages of CKD. Data on the use of statins in the ESRD population are sparse, and the results have been discouraging in the one completed study, the 4D trial. Patients who have CKD, in particular the subset treated by dialysis, are at high risk for cardiovascular morbidity and mortality, and thus this lack of data represents a significant gap in knowledge. It is hoped that the results of the ongoing SHARP and AURORA trials will help guide the use of statins in this population. REFERENCES
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5. Weintraub M, Burstein A, Rassin T, et al. Severe defect in clearing postprandial chylomicron remnants in dialysis patients. Kidney Int 1992;42(5):1247–52. 6. Galle J, Wanner C. Modification of lipoproteins in uremia: oxidation, glycation and carbamoylation. Miner Electrolyte Metab 1999;25(4–6):263–8. 7. Holdaas H, Fellstrom B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361(9374):2024–31. 8. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353(3):238–48. 9. Molitch ME. Management of dyslipidemias in patients with diabetes and chronic kidney disease. Clin J Am Soc Nephrol 2006;1(5):1090–9. 10. Kasiske BL. Hyperlipidemia in patients with chronic renal disease. Am J Kidney Dis 1998;32(Suppl 3):S142–56. 11. K/DOQI clinical practice guidelines for management of dyslipidemias in patients with kidney disease. Am J Kidney Dis 2003;41(Suppl 3):S1–91. 12. Weiner DE, Sarnak MJ. Managing dyslipidemia in chronic kidney disease. J Gen Intern Med 2004;19(10):1045–52. 13. Attman PO, Samuelsson O, Johansson AC, et al. Dialysis modalities and dyslipidemia. Kidney Int 2003;84:S110–2. 14. Kwan BC, Kronenberg F, Beddhu S, et al. Lipoprotein metabolism and lipid management in chronic kidney disease. J Am Soc Nephrol 2007;18(4):1246–61. 15. Zioncheck TF, Powell LM, Rice GC, et al. Interaction of recombinant apolipoprotein (a) and lipoprotein (a) with macrophages. J Clin Invest 1991;87(3):767–71. 16. Maggi E, Bellazzi R, Falaschi F, et al. Enhanced LDL oxidation in uremic patients: an additional mechanism for accelerated atherosclerosis? Kidney Int 1994;45(3): 876–83. 17. Craig WY, Neveux LM, Palomaki GE, et al. Lipoprotein (a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies. Clin Chem 1998; 44(11):2301–6. 18. Nogueira J, Weir M. The unique character of cardiovascular disease in chronic kidney disease and its implications for treatment with lipid-lowering drugs. Clin J Am Soc Nephrol 2007;2(4):766–85. 19. Kronenberg F, Neyer U, Lhotta K, et al. The low molecular weight apo(a) phenotype is an independent predictor for coronary artery disease in hemodialysis patients: a prospective follow-up. J Am Soc Nephrol 1999;10(5):1027–36. 20. Kerschdorfer L, Konig P, Neyer U, et al. Lipoprotein(a) plasma concentrations after renal transplantation: a prospective evaluation after 4 years of follow-up. Atherosclerosis 1999;144(2):381–91. 21. Kronenberg F, Konig P, Lhotta K, et al. Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation. Arterioscler Thromb 1994;14(9):1399–404. 22. Cressman MD, Heyka RJ, Paganini EP, et al. Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients. Circulation 1992;86(2): 475–82. 23. Longenecker JC, Klag MJ, Marcovina SM, et al. High lipoprotein(a) levels and small apolipoprotein(a) size prospectively predict cardiovascular events in dialysis patients. J Am Soc Nephrol 2005;16(6):1794–802. 24. Arnadottir M. Pathogenesis of dyslipoproteinemia in renal insufficiency: the role of lipoprotein lipase and hepatic lipase. Scand J Clin Lab Invest 1997;57(1):1–11. 25. Arnadottir M, Nilsson-Ehle P. Has parathyroid hormone any influence on lipid metabolism in chronic renal failure? Nephrol Dial Transplant 1995;10(12):2381–2.
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26. Nishizawa Y, Shoji T, Kawagishi T, et al. Atherosclerosis in uremia: possible roles of hyperparathyroidism and intermediate density lipoprotein accumulation. Kidney Int Suppl 1997;62:S90–2. 27. Assmann G, Schulte H, Funke H, et al. The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J 1998; 19(Suppl M):M8–14. 28. Farbakhsh K, Kasiske BL. Dyslipidemias in patients who have chronic kidney disease. Med Clin North Am 2005;89(3):689–99. 29. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251(3):365–74. 30. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-thanaverage cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Drugs 2004;64(Suppl 2):43–60. 31. Muntner P, He J, Astor BC, et al. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study. J Am Soc Nephrol 2005;16(2):529–38. 32. Cheung AK, Sarnak MJ, Yan G, et al. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int 2000;58(1):353–62. 33. Hahn R, Oette K, Mondorf H, et al. Analysis of cardiovascular risk factors in chronic hemodialysis patients with special attention to the hyperlipoproteinemias. Atherosclerosis 1983;48(3):279–88. 34. Koch M, Kutkuhn B, Grabensee B, et al. Apolipoprotein A, fibrinogen, age, and history of stroke are predictors of death in dialysed diabetic patients: a prospective study in 412 subjects. Nephrol Dial Transplant 1997;12(12):2603–11. 35. Stack AG, Bloembergen WE. Prevalence and clinical correlates of coronary artery disease among new dialysis patients in the United States: a cross-sectional study. J Am Soc Nephrol 2001;12(7):1516–23. 36. 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(5):458–82. 37. Iseki K, Yamazato M, Tozawa M, et al. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002;61(5):1887–93. 38. 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(4):451–9. 39. Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333(10):621–7. 40. Wenke K, Meiser B, Thiery J, et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation 1997;96(5):1398–402. 41. Kasiske B, Cosio FG, Beto J, et al. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant 2004;4(Suppl 7):13–53. 42. Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106(25):3143–421.
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43. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347(9004):781. 44. Yusuf S, Dagenais G, Pogue J, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study investigators. N Engl J Med 2000;342(3):154–60. 45. Boaz M, Smetana S, Weinstein T, et al. Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356(9237):1213–8. 46. Khajehdehi P. Effect of vitamins on the lipid profile of patients on regular hemodialysis. Scand J Urol Nephrol 2000;34(1):62–6. 47. Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322(24):1700–7. 48. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256(20):2823–8. 49. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350(15):1495–504. 50. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279(20):1615–22. 51. Harris KP, Wheeler DC, Chong CC. A placebo-controlled trial examining atorvastatin in dyslipidemic patients undergoing CAPD. Kidney Int 2002;61(4):1469–74. 52. Saltissi D, Morgan C, Rigby RJ, et al. Safety and efficacy of simvastatin in hypercholesterolemic patients undergoing chronic renal dialysis. Am J Kidney Dis 2002;39(2):283–90. 53. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation 2004;110(12):1557–60. 54. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998;339(19):1349–57. 55. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-thanaverage cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361(9364):1149–58. 56. Seliger SL, Weiss NS, Gillen DL, et al. HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 2002;61(1):297–304. 57. Jardine AG, Holdaas H, Fellstrom B, et al. Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT study. Am J Transplant 2004;4(6):988–95. 58. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP). Kidney Int Suppl 2003;84:S207–10. 59. Fellstrom B, Holdaas H, Jardine AG, et al. Effect of rosuvastatin on outcomes in chronic haemodialysis patients: baseline data from the AURORA study. Kidney Blood Press Res 2007;30(1):314–22.
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60. 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(5):9. 61. Bilchick KC, Henrikson CA, Skojec D, et al. Treatment of hyperlipidemia in cardiac transplant recipients. Am Heart J 2004;148(2):200–10. 62. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol 2004;44(3):720–32. 63. Stern RH, Yang BB, Horton M, et al. Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin. J Clin Pharmacol 1997;37(9):816–9. 64. Launay-Vacher V, Izzedine H, Deray G. Statins’ dosage in patients with renal failure and cyclosporine drug-drug interactions in transplant recipient patients. Int J Cardiol 2005;101(1):9–17. 65. Chang JW, Yang WS, Min WK, et al. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002;39(6):1213–7. 66. Bianchi S, Bigazzi R, Caiazza A, et al. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003;41(3):565–70. 67. 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(2):98–104. 68. Tonelli M, Collins D, Robins S, et al. Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int 2004;66(3):1123–30. 69. Lee MS, Kim SM, Kim SB, et al. Effects of gemfibrozil on lipid and hemostatic factors in CAPD patients. Perit Dial Int 1999;19(3):280–3. 70. Lucatello A, Sturani A, Di Nardo AM, et al. Safe use of gemfibrozil in uremic patients on continuous ambulatory peritoneal dialysis. Nephron 1998;78(3):338. 71. Clouatre Y, Leblanc M, Ouimet D, et al. Fenofibrate-induced rhabdomyolysis in two dialysis patients with hypothyroidism. Nephrol Dial Transplant 1999;14(4): 1047–8. 72. Schonfeld G. The effects of fibrates on lipoprotein and hemostatic coronary risk factors. Atherosclerosis 1994;111(2):161–74. 73. Broeders N, Knoop C, Antoine M, et al. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent? Nephrol Dial Transplant 2000;15(12):1993–9. 74. Kamionna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008; 101(8A):20B–6B. 75. Nishizawa Y, Shoji T, Tabata T, et al. Effects of lipid-lowering drugs on intermediatedensity lipoprotein in uremic patients. Kidney Int Suppl 1999;71:S134–6. 76. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002;62(1):245–52. 77. Chertow GM, Burke SK, Dillon MA, et al. Long-term effects of sevelamer hydrochloride on the calcium phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 1999;14(12):2907–14. 78. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005; 68(5):1815–24.
The optimal management of lipid abnormalities in patients who have chronic kidney disease (CKD) remains controversial. There are limited data to guide the use of lipid-lowering drugs in this population, because most of the landmark trials that showed benefits of lipid-lowering therapy on cardiovascular mortality in the general population included few patients who had CKD.1–3 This issue is important, because cardiovascular morbidity and mortality are high in the CKD population. If pharmacologic therapy lowers the risk of cardiovascular events even modestly, the impact in this high-risk group is substantial. The high rates of cardiovascular disease in the CKD, end-stage renal disease (ESRD), and renal transplant population are multifactorial; risk factors include general risk factors, such as diabetes, hypertension, and smoking, and also factors unique to renal disease, such as vascular calcification and chronic low-grade inflammation. The impact of dyslipidemia and lipid-lowering therapy in this population is unclear. Recent studies have shown the spectrum of dyslipidemia in patients who have CKD or ESRD to be different from that of the general population. There seems to be a shift to a uremic profile as the renal function deteriorates.4,5 The magnitude of the abnormalities is not disclosed fully by routine laboratory chemistries that test only total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. Other modifications such as oxidation and glycation of lipoproteins may promote further atherosclerosis.6 The few trials aimed at studying dyslipidemia in the ESRD and renal transplant population have shown mixed benefits from lipid-lowering therapy.7,8 This article discusses the pathophysiology of dyslipidemia in CKD, dialysis, and renal transplant patients, the therapeutic options, and their association with clinical a
Division of Kidney Disease and Hypertension, 593 Eddy Street, APC 9, Brown Medical School, Providence, RI 02903, USA b Division of Nephrology, Mount Sinai School of Medicine, 1468 Madison Avenue, Annenberg Building, New York, NY 10029, USA * Corresponding author. E-mail address: [email protected] (T. Montague). Endocrinol Metab Clin N Am 38 (2009) 223–234 doi:10.1016/j.ecl.2008.11.004 0889-8529/08/$ – see front matter ª 2009 Published by Elsevier Inc.
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outcomes. Whenever possible, comparisons are made to outcomes in the general population. PATHOPHYSIOLOGY AND PREVALENCE OF DYSLIPIDEMIA IN CHRONIC KIDNEY DISEASE, DIALYSIS, AND TRANSPLANTATION
Lipids are insoluble in plasma and thus require association with proteins (apolipoproteins) to form dissolvable particles called ‘‘lipoproteins.’’ These lipoproteins function mainly in transporting cholesterol or triglycerides from sites of absorption (gut) or synthesis (liver) to sites of use (peripheral tissues) or metabolism. Lipoprotein profiles seem to be affected by the severity of renal dysfunction and proteinuria.9 High-density lipoprotein (HDL), total cholesterol, and low-density lipoprotein (LDL) levels tend to decrease with declining renal function and on average are lower in patients who have stage 3 to stage 5 CKD than in the general population.10 As CKD advances to renal failure and dialysis, the levels of total cholesterol and LDL cholesterol tend to decrease. Despite this decrease, more than 50% of dialysis patients have LDL cholesterol levels greater than 100 mg/dL or non–high-density (non-HDL) lipoprotein cholesterol levels greater than 130 mg/dL.11 The prevalence of LDL cholesterol levels greater than 100 mg/dL is 85%, 70%, and 90%, respectively, in patients who have nephrotic syndrome, patients who are being treated with peritoneal dialysis, and renal transplant patients.12 In general, patients treated with peritoneal dialysis tend to have a more atherogenic lipid profile, with increased LDL cholesterol and oxidized LDL levels, than patients treated with hemodialysis.12 This difference may result in part from the use of dextrose-containing peritoneal dialysate and glucose absorption across the peritoneal membrane.13 Measurements of serum LDL cholesterol in patients who have kidney disease also may underestimate the atherogenic potential if it does not measure the LDL subfractions, such as small, dense LDL particles and lipoprotein (a), which are increased in these patients.14 Small, dense LDL particles tend to penetrate the vascular endothelium, become oxidized, and be taken up by scavenger receptors on macrophages and vascular smooth muscle cells. Once overloaded with cholesterol esters, these macrophages transform into foam cells, further accelerating atherosclerosis.15 The increased levels of oxidative stress and inflammation in CKD may promote the conversion of LDL to this more atherogenic form.16 Lipoprotein (a), a modified form of LDL that exists in different isoforms, has been found to be a risk factor for cardiovascular disease (CVD) in the general population and is highly atherogenic.17 Structurally it resembles plasminogen and interferes with fibrinolysis,18 and it also binds to macrophages, promoting foam cell formation. Plasma lipoprotein (a) levels are affected by renal function. In patients who have large lipoprotein (a) isoforms, levels have been found to increase as the glomerular filtration rate (GFR) decreases.19 After successful kidney transplantation, a decrease in large isoforms of plasma lipoprotein (a) is noted in patients previously treated with hemodialysis, and a decrease in all isoforms is seen in patients previously treated with peritoneal dialysis.20,21 Elevated lipoprotein (a) is an independent risk factor for CVD in patients treated with hemodialysis and has been associated with vascular events.22,23 Triglyceride levels tend to increase early in CKD and are particularly high in patients who have nephrotic syndrome and patients treated with dialysis.14 In the plasma, triglycerides are found predominantly in chylomicrons and in very-low-density lipoproteins (VLDLs). Chylomicrons are assembled in the intestine and transport dietary fatty acids, whereas VLDLs are produced in the live rand transport endogenous fatty acids. The increase in triglycerides is caused partly by the decreased catabolic rate of these
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lipoproteins resulting from the decreased activity of vascular endothelium-associated lipases such as lipoprotein lipase and hepatic triglyceride lipase.24 Impaired lipase activity may be caused by an inhibitor effect of hyperparathyroidism, calcium accumulation in islet cells leading to impaired insulin secretion, or depletion of the enzyme pool by frequent heparinization during hemodialysis.25,26 This decreased catabolism leads to prolonged exposure of the arterial vasculature to triglyceriderich lipoprotein remnants that are atherogenic.18 Studies in the general population have shown elevated triglyceride levels to be an independent risk factor for CVD.27 Patients who have CKD and patients treated with dialysis tend to have lower plasma HDL cholesterol levels than common in the general population.28 HDL plays a role in the reverse cholesterol transport, moving cholesterol from peripheral cells to the liver. This decrease leads to increased cholesterol levels peripherally and in the vasculature, thereby promoting atherosclerosis. These relative differences in the lipid profiles of uremic patients render questionable the extrapolation of data on the benefits of lipid-lowering therapy derived from the general population. In addition, given the relatively lower levels of total cholesterol and LDL cholesterol on standard lipid profile measurements that do not measure small, dense LDL particles, lipoprotein (a), VLDL, and chylomicron, potentially beneficial therapy may be withheld if guidelines for initiation are not met (ie, LDL cholesterol level >100 mg/dL). DYSLIPIDEMIA AND CARDIOVASCULAR MORTALITY IN CHRONIC KIDNEY DISEASE, DIALYSIS, AND TRANSPLANTATION
In the general population, clinical trials have demonstrated that cardiovascular mortality decreases proportionally with the rate of LDL cholesterol reduction.3,29,30 There are few data on the contribution of dyslipidemia toward cardiovascular morbidity and mortality in the CKD population. It is possible that in the setting of CKD with contributing factors such as anemia, inflammation, and proteinuria, dyslipidemia may contribute differently to the overall risk. In a prospective cohort study, Muntner and colleagues31 evaluated the contribution of different risk factors to cardiovascular mortality in the nondialysis CKD population. The study involved 14,856 participants with a mean follow-up period of 10.5 years. The association between the severity of dyslipidemia and future cardiovascular events was similar to that in patients who had normal renal function. The study included patients who had mild (GFR 60–90 mL/min/1.73 m2 body surface area [bsa]) and moderate to severe CKD (GFR 15–59 mL/min/1.73 m2 bsa). Based on their data, the authors predicted that for every 42-mg/dL (1.1-mmol/L) reduction in total cholesterol, there would be a 19.7% reduction in cardiovascular events. This study, however, did not show that treatment of dyslipidemia actually decreases cardiovascular mortality in the CKD population. The data in the dialysis population are conflicting. Two prospective studies in patients treated with hemodialysis showed no relationship between total cholesterol, triglyceride, LDL cholesterol, or HDL cholesterol levels and future cardiovascular events, but a cross-sectional and a prospective study showed a positive association.19,22,32–35 In 1995, Lowrie and colleagues,36 in a retrospective study involving 12,000 patients undergoing hemodialysis, found a U-shaped relationship between cholesterol levels and mortality. Patients who had low total cholesterol levels (<100 mg/dL) had more than four times the mortality risk of patients who had total cholesterol levels between 200 and 250 mg/dL. Once adjusted for albumin, the relationship became more linear, suggesting a potential role of malnutrition. In
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a 10-year prospective study of 1167 Japanese patients undergoing hemodialysis, low cholesterol was associated independently with higher C-reactive protein levels and mortality in patients who had low albumin levels.37 In a subgroup of patients who had albumin levels higher than 4.5 mg/dL, however, higher levels of cholesterol were associated with increased mortality. Liu and colleagues,38 in a prospective study of 823 patients starting hemodialysis or peritoneal dialysis in the United States, found that an increase in total cholesterol levels in the setting of inflammation and malnutrition decreased all-cause mortality. In the absence of inflammation and malnutrition, however, higher total cholesterol levels were associated positively with all-cause mortality. Both these studies show hypercholesterolemia to be a risk factor for allcause mortality in the dialysis population, which is modified in the presence of inflammation and malnutrition. In the renal transplant population, the incidence of both hyperlipidemia and CVD is high. The hyperlipidemia is multifactorial, and causes include previously discussed factors such as renal dysfunction, proteinuria, obesity, and diabetes as well as risk factors unique to transplant recipients, including immunosuppressive medications. In this population studies have not demonstrated conclusively a causal relationship between hyperlipidemia and CVD. Several small studies, however, have shown that treatment leads to decreased rates of mortality, rejection, and chronic allograft nephropathy.39,40
CURRENT TREATMENT GUIDELINES
The National Kidney Foundation has established guidelines that recommend aggressive therapy of dyslipidemia in patients who have kidney disease.41 These guidelines are based on the risk reductions achieved in the general population in patients who have or are at high risk for CVD, on the high risk of CVD in patients who have kidney disease, and on the overall safety of most pharmacologic therapies. These guidelines, however, also acknowledge the paucity of data in this population. In keeping with the National Cholesterol Education Program (NCEP) guidelines for hyperlipidemia in the general population, the National Kidney Foundation guidelines recommend lifestyle modifications with diet and exercise.42 Both sets of guidelines endorse therapeutic lifestyle changes including reduced intake of saturated fat, trans fats, and cholesterol, increased intake of fiber, weight loss, increased exercise, avoidance of (or moderation in the use of) alcohol, and treatment of high blood glucoses. The work group also concluded that, with a few notable differences, many of the NCEP guidelines are applicable to stage 1 to stage 5 CKD, including patients who have received a renal transplant (regardless of whether the GFR is >90 mL/min/1.73 m2 bsa). One guideline places all patients who have renal insufficiency, including renal transplant recipients, in the highest category of cardiovascular risk. As a result, a target LDL cholesterol level of less than 100 mg/dL is recommended for all renal patients. Furthermore, for renal patients who have an LDL cholesterol level between 100 and 129 mg/dL, pharmacologic therapy should be used after only 3 months of lifestyle changes, although this guideline is considered optional in the general population. For renal patients whose LDL cholesterol is greater than 120 mg/dL, lifestyle changes should be initiated concurrently with pharmacologic therapy. The National Kidney Foundation guidelines also suggest that fibrates may be used in stage 5 CKD for patients who have triglyceride levels higher than 500 mg/dL or patients who have triglyceride levels higher than 200 mg/dL, non-HDL cholesterol levels greater than 130 mg/dL, and who cannot tolerate statins. This guideline is in
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contrast to the NCEP Adult Treatment Panel guidelines, in which fibrates are contraindicated in stage 5 CKD.
PHARMACOLOGIC MANAGEMENT OF DYSLIPIDEMIA IN CHRONIC KIDNEY DISEASE, DIALYSIS, AND TRANSPLANTATION Antioxidants
Oxidative stress, as discussed previously, plays a role in promoting atherosclerosis in patients who have CKD. As a result, antioxidants such as vitamin E have been used in attempts to decrease atherogenic oxidized lipid levels. Randomized trials in the general population did not demonstrate any cardiovascular benefits.43,44 Boaz and colleagues,45 however, in a trial of 196 patients treated with hemodialysis who had pre-existing cardiovascular disease, found that vitamin E given for median time of 519 days resulted in a 54% reduction in the composite end point of myocardial infarction, peripheral vascular disease, and ischemic stroke as compared with placebo. In another study, vitamin E was found to increase HDL cholesterol levels in patients treated with dialysis.46 Larger randomized studies are needed to validate these results.
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (Statins)
In the general population, studies have shown a direct correlation between increasing levels of total and LDL cholesterol and cardiovascular mortality.47,48 Treatment with lipid-lowering therapy has shown clear benefits in cardiac outcomes in both primary and secondary prevention studies.1,49,50 Studies of statin use in patients treated with peritoneal dialysis or hemodialysis and in renal transplant recipients have shown that statins are effective in reducing LDL cholesterol levels, but few studies have evaluated the correlation between statin use and a reduction in cardiovascular mortality.7,8,51,52 Stage 2 through stage 4 chronic kidney disease
In large, randomized trials in the general population, there have been several post hoc analyses of subgroups with impaired renal function. The Pravastatin Pooling Project combined patient results of three randomized trials of pravastatin versus placebo in the general population.53 The three trials were the West of Scotland Coronary Prevention Study, the Cholesterol and Recurrent Events study, and the Long-term Intervention with Pravastatin in Ischemic Disease study.2,3,54 The primary outcome studied was time to myocardial infarction, coronary death, or cardiac intervention. Of the 19,700 patients included, 4491 had moderate CKD defined by a GFR between 30 and 60 mL/min/1.73 m2 bsa. CKD was associated with increased risk for the primary outcome with a hazard ratio of 1.26 (95% confidence interval, 1.07–1.49). In the patients who had CKD, 40 mg of pravastatin was associated with a 23% reduction in the composite outcome over 5 years. This result was similar to those obtained in patients who did not have CKD. In the Anglo-Scandinavian Cardiac Outcomes Trial, subgroup analysis of 6517 patients who had kidney dysfunction followed for a median of 3.3 years revealed that 10 mg of atorvastatin led to a significant (39%) reduction in nonfatal myocardial infarction and cardiac death.55 Both these studies included patients who had or who were at high risk for coronary artery disease. It is unknown whether there is a benefit to patients who have moderate CKD without coronary artery disease.
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Dialysis
In patients treated with dialysis, Seliger and colleagues,56 in the Dialysis Morbidity and Mortality wave 2 study, studied the effect on mortality of starting statins at the initiation of dialysis. The cohort of 3716 prospective study participants included patients treated with peritoneal dialysis and a random sample of 20% of the patients treated with hemodialysis from the US Renal Data System. The rate of statin use at the initiation of dialysis was low, at 9.7%, and recipients tended to have pre-existing coronary artery disease and diabetes. In this study cardiovascular mortality decreased by 37% in the statin recipients. This trial was not a randomized, controlled study, however, and it is uncertain if the results are generalizable to the entire dialysis population. These findings were not confirmed by the Die Deutsche Diabetes-Dialyse (4D) study.8 This controlled trial randomly assigned 1255 diabetic patients treated with hemodialysis to atorvastatin, 20 mg, or placebo. Despite a 42% reduction in the LDL cholesterol level in the atorvastatin group, the rate of the composite end point of death from cardiac causes, fatal stroke, nonfatal myocardial infarction, and nonfatal stroke was similar in the two groups at 3 years. The rate of coronary interventions was 18% lower in the atorvastatin group, but the risk of fatal stroke was doubled. Statin drugs may have limited benefit in advanced CVD, but further studies are needed to establish this benefit firmly. Renal transplantation
To date, only one trial has examined the mortality benefits of statin treatment in renal transplant recipients. The Assessment of Fluvastatin in Renal Transplantation study evaluated the effect of fluvastatin, 40 mg, compared with placebo on the cardiac outcomes of renal transplant recipients.7 This study, which enrolled 2102 stable transplant recipients 6 months after transplantation, is notable for its size. The follow-up duration was 5 to 6 years. Fluvastatin lowered LDL cholesterol levels by 32%, but no significant reduction was seen in the combined primary end points of cardiac death, definite or probable myocardial infarction, or coronary intervention. A post hoc analysis examining the effect of fluvastatin on definite myocardial infarction or cardiac death (omitting the end point of coronary intervention) showed that fluvastatin was associated with a statistically significant risk reduction of 35%.57 Overall there may be a benefit of statin use in early CKD that decreases as renal failure advances. Two ongoing randomized trials are evaluating statin use in patients who have CKD. The Study of Heart and Renal Protection (SHARP) will evaluate the combined effect of simvastatin and ezetimibe versus placebo in the primary prevention of heart disease and stroke.58 Six thousand patients who have CKD with plasma creatinine levels greater than 1.7 mg/dL in men and greater than 1.5 mg/dL in women and 3000 patients being treated with dialysis will be recruited. A second trial, the Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: an Assessment of Survival and Cardiovascular Events (AURORA), will evaluate the effect of rosuvastatin on the incidence of cardiovascular deaths, heart attacks, and strokes in patients with and without diabetes who are being treated with hemodialysis.59,60 Neither study has lipid inclusion criteria. A serious and common complication of statin therapy is myositis, the importance of which was emphasized by the recall of cerivastatin in 2001. This concern was not recognized in either the 4D study or the other large studies. Most statins are metabolized by the cytochrome P450 (CYP) 3A4, and myotoxicity is increased if they are taken with medications that inhibit this metabolism (eg, immunosuppressive medications such as cyclosporine, tacrolimus, and sirolimus and other medications such as verapamil, diltizaem, erythromycin, and several antidepressants).61 Exceptions among
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statins include fluvastatin, which is metabolized by CYP2C9, and pravastatin and rosuvastatin, which are metabolized by a non–cytochrome-dependent mechanism. The potential for drug–drug interactions are substantial, and thus caution and close monitoring are recommended. Current recommendations are that, except for atorvastatin and pravastatin, the statin dose be reduced by 50% in patients being treated with dialysis.62,63 In transplant recipients, the current recommendations are that a lower initial dose of statin be used, particularly with concomitant use of cyclosporine.41 Studies involving rosuvastatin in patients who had severe renal insufficiency noted higher rosuvastatin levels than seen in patients who had normal renal function, and thus a lower starting dose of 5 mg is recommended.64 Statin and additional effects
Statins may exert additional effects independent of the effect on LDL cholesterol. The results of one small observational study in patients treated with hemodialysis suggest that statins may have anti-inflammatory properties, because significant decreases were seen in C-reactive protein levels after 8 weeks of simvastatin treatment.65 Other small, randomized trials suggest that statins also may help slow the decline in GFR.66,67 Bianchi and colleagues66 studied the effect of atorvastatin, 10 to 40 mg/d, versus placebo in 56 patients who had CKD. They found that after 1 year the rate of proteinuria decreased significantly with atorvastatin compared with placebo. In a post hoc analysis of a subgroup of 690 patients who had moderate CKD (GFR < 60 mL/min/1.73 m2 bsa), statin therapy slowed the decline in GFR, especially in patients who had proteinuria.67
Fibrates
In the general population, fibrates reduce plasma triglyceride levels and modestly increase HDL cholesterol concentrations. They are indicated when a triglyceride level greater than 500 mg/dL is the primary lipid abnormality and may reduce these levels by up to 50%.11 Gemfibrozil was associated with 20% reduction in cardiovascular events in patients who had mild to moderate renal insufficiency (GFR 30–75 mL/ min/1.73 m2 bsa).68 In patients who had dyslipidemia who were treated with continuous ambulatory peritoneal dialysis, gemfibrozil led to significant reductions in triglyceride levels without myositis or liver toxicity.69,70 The dose used in these studies was less than that used in the general population (600 mg/d or 600 mg every other day). There have been case reports of rhabdomyolysis associated with use of fibrates in ESRD and hypothyroidism, however.71,72 There also have been reports of worsening kidney function associated with the use of clofibrate, bezafibrate, and fenofibrate in patients who had mild to moderate CKD.73 Recent guidelines discourage the use of fibrates in patients who have a GFR of less than 15 mL/min/1.73m2 bsa.11
Bile Acid Sequestrants
Treatment with cholestyramine in asymptomatic individuals who had normal kidney function reduced cardiovascular mortality by 19%.29 In the general population, bile acid sequestrants used in combination with statins lower LDL cholesterol levels by up to 20%. Because these drugs are not absorbed in the gastrointestinal tract, in theory no dose adjustments are needed for patients who have reduced kidney function. Bile acid sequestrants do interfere with cyclosporine absorption, however, and also may cause increases in triglyceride levels. There are few data on the safety and cardiac outcomes of these agents in the CKD population.
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Nicotinic Acid
Nicotinic acid reduces the secretion of VLDL by the liver.74 The National Kidney Foundation guidelines recommend nicotinic acid as an alternative second agent for LDL cholesterol reduction in combination with a statin.11 The side effects associated with the administration of niacin, such as flushing, hyperglycemia, and hepatoxicity, decrease its tolerability, leading to high rates of noncompliance. One study compared the results of nicotinic acid, clofibrate, and pravastatin on LDL cholesterol levels in patients treated with continuous ambulatory peritoneal dialysis or hemodialysis.75 There were no adverse effects with any of the treatments, but statins were superior in reducing LDL cholesterol levels. Sevelamer Hydrochloride
Sevelamer is a cationic polymer that binds phosphates via ion exchange. It also has been found to reduce plasma total cholesterol levels by 18% to 22% and plasma LDL cholesterol levels by 30% to 37% by binding bile acids in the intestine.76 An open-label study involving 192 patients treated by hemodialysis who used sevelamer for 46 weeks showed a 36% reduction in LDL cholesterol level and an 18% increase in HDL cholesterol level.77 In the Treat to Goal Study, patients receiving sevelamer were found to have significantly lower rates of coronary artery calcification and an associated decrease in LDL cholesterol levels.78 There have been no long-term outcome studies of the cardiovascular benefits of sevelamer. SUMMARY
Commonly used clinical assays that measure only triglyceride, LDL cholesterol, HDL cholesterol, and total cholesterol levels may not measure the additional lipid abnormalities prevalent in uremia. Post hoc analysis of large clinical trials in the general population seems to support the beneficial effects of statins in renal transplant recipients and patients in the early stages of CKD, but the evidence is unclear in the latter stages of CKD. Data on the use of statins in the ESRD population are sparse, and the results have been discouraging in the one completed study, the 4D trial. Patients who have CKD, in particular the subset treated by dialysis, are at high risk for cardiovascular morbidity and mortality, and thus this lack of data represents a significant gap in knowledge. It is hoped that the results of the ongoing SHARP and AURORA trials will help guide the use of statins in this population. REFERENCES
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