Effects of Statins on Renal Function

REVIEW

EFFECTS OF STATINS ON RENAL FUNCTION

Effects of Statins on Renal Function RAJIV AGARWAL, MD Patients with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease than end-stage renal disease. Dyslipidemia is highly prevalent in patients with CKD and may contribute to the elevated cardiovascular risk as well as CKD progression. Statins are lipid-lowering drugs that appear to protect the kidneys via cholesterol reduction as well as noncholesterol-mediated mechanisms. Subgroup analyses of major clinical studies and meta-analyses of smaller trials indicate that statin therapy slows the decline of the glomerular filtration rate. Additionally, statins appear to reduce proteinuria in patients with CKD. Statins are well recognized to reduce cardiovascular morbidity and mortality in patients with and without documented cardiovascular disease and in certain high-risk populations, such as persons with diabetes mellitus. However, conclusive evidence for improved cardiovascular outcomes with statin therapy for CKD is not yet available. Several ongoing studies are evaluating the effect of statins on cardiovascular end points in patients with CKD and may provide data needed to support adjunctive use of these agents in this high-risk population.

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ALLIANCE = Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; CAD = coronary artery disease; CARE = Cholesterol and Recurrent Events; CI = confidence interval; CKD = chronic kidney disease; ESRD = end-stage renal disease; GFR = glomerular filtration rate; GREACE = GREek Atorvastatin and Coronary–heart-disease Evaluation; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LDL = low-density lipoprotein; L-FABP = liver-type fatty acid-binding protein; MI = myocardial infarction

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hronic kidney disease (CKD) affects an estimated 19 million people in the United States, representing 11% of the total adult population.1,2 Chronic kidney disease may be divided into 5 stages on the basis of glomerular filtration rate (GFR) and evidence of structural or functional renal abnormalities, such as persistent albuminuria or proteinuria.3 Stages 1 and 2 are characterized by evidence of kidney damage with normal or mildly reduced GFR, respectively, whereas stages 3 to 5 indicate progressively greater reductions in GFR below 60 mL/min per 1.73 m2 with or without known etiology of kidney damage. When both kidneys are involved, any GFR less than 60 mL/min per 1.73 m2 should be considered to be due to renal injury and therefore pathological. Rates of progression of CKD may differ; rarely, patients may even improve. In general, however, the condition of persons with CKD will deteriorate. The progressive course of CKD is a function of many factors, including the presence of concomitant disease, such as diabetes mellitus or proteinuric glomerular disease. Most patients with CKD have stage 1 to 3 disease; an estimated 7.6 million people Mayo Clin Proc.

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have stage 3 disease.1 However, nearly 500,000 people in the United States are in the most advanced stage of CKD, also known as end-stage renal disease (ESRD), and require regular dialysis treatment.4 Although the progressive course of CKD is well recognized, patients with CKD are likely to die of cardiovascular disease before they reach ESRD.5 In fact, CKD is an independent risk factor for cardiovascular disease, particularly in higher-risk populations.5 This point is illustrated in a post hoc analysis of pooled data from 4 major longitudinal, community-based studies: of 26,912 subjects, 4278 had preexisting cardiovascular disease.6 After adjusting for potential confounders, the risk for the composite outcome of myocardial infarction (MI), fatal coronary artery disease (CAD), stroke, and all-cause mortality was significantly higher in persons with than without CKD (hazard ratio, 1.35; 95% confidence interval [CI], 1.21-1.52). Notably, the increased risk associated with CKD was comparable to the risk associated with diabetes mellitus, hypertension, or left ventricular hypertrophy, each of which is well documented as a cardiovascular risk factor. Similar findings were obtained in a post hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) study, which enrolled 9297 patients with vascular disease or diabetes mellitus.7 The subset of patients with mild renal dysfunction had nearly twice the risk of cardiovascular mortality and all-cause mortality (both P<.001) as those with normal renal function. On the basis of a large body of evidence from these and other studies, the American Heart Association recommends that patients with CKD be placed in the highest risk group for subsequent cardiovascular events. Current treatment recommendations should take into account the highrisk status of this group of patients.5 ROLE OF DYSLIPIDEMIA IN CKD Many traditional and nontraditional cardiovascular risk factors are highly prevalent in CKD.8 In the Framingham From the Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Richard L. Roundebush VA Medical Center, Indianapolis. Dr Agarwal has received honoraria and served as a consultant and on the speakers’ bureau of Merck and AstraZeneca. Individual reprints of this article are not available. Address correspondence to Rajiv Agarwal, MD, Indiana University School of Medicine, Richard L. Roundebush VA Medical Center, 1481 W Tenth St (111N), Indianapolis, IN 46202. © 2007 Mayo Foundation for Medical Education and Research

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EFFECTS OF STATINS ON RENAL FUNCTION

Offspring Cohort, patients with CKD were significantly more likely to have low levels of high-density lipoprotein cholesterol (45% vs 29%; P<.001) and elevated triglycerides (40% vs 30%; P<.001) and tended to be more likely to have elevated low-density lipoprotein (LDL) cholesterol (61% vs 45%; P=.06) than those without CKD.8 In the Third National Health and Nutrition Examination Survey (NHANES III), participants with CKD (GFR <60 mL/min per 1.73 m2) had higher levels of apolipoprotein B and lower levels of apolipoprotein A than those with normal renal function (P=.003 and P=.021, respectively).9 Dyslipidemia is not only highly prevalent in CKD, but it also increases the risk of renal dysfunction in otherwise healthy individuals. The Physicians’ Health Study followed 4483 initially healthy men for a mean of 14.2 years.10 After adjustment for potential confounding factors (cardiovascular risk factors and development of hypertension and cardiovascular disease), men in the highest quartile of total cholesterol/high-density lipoprotein cholesterol ratio had a 92% higher risk (95% CI, 22%-204%) of developing CKD than those in the lowest quartile. The role of dyslipidemia in promoting kidney damage has been shown in experimental models. Rats fed a diet rich in cholesterol and fat exhibited increased numbers of glomeruli with sclerotic foci vs those on a low-fat, cholesterolfree diet.11 When administered to rats with kidney disease caused by unilateral nephrectomy, the cholesterol- and fatrich diet augmented the glomerular lesions in the remaining kidney.11 In rats fed a high-cholesterol diet, the severity of the hypercholesterolemia correlated with proteinuria (r=0.672) and was accompanied by increased numbers of glomeruli with lipid deposits.12 Lipid deposition can directly damage the glomerular basement membrane. It can also stimulate mesangial cell activation and proliferation, a process similar to smooth muscle cell proliferation in the evolution of atherosclerotic plaque13,14 (Figure 1). Mesangial cells then release chemokines that recruit monocytes to the mesangium, where they are transformed into resident macrophages that secrete proinflammatory and profibrotic mediators capable of augmenting the proliferative process.15-17 The macrophages also ingest lipids to become foam cells, which are commonly detected at early stages of glomerulonephritis.18 Each of these celltypes is capable of pr oducing reac tive oxygen species that oxidize LDL. Oxidized LDL, in turn, can cause further monocyte recruitment, endothelial dysfunction, and mesangial cell cytotoxicity.17,19,20 The endothelin system is also upregulated in hypercholesterolemia. Therefore, endothelin-A receptor blockade might protect the kidney from injury to the renal microvessels. In fact, in a porcine model, endothelin-A receptor blockade improved microvascular endothelial 1382

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function in the hypercholesterolemic kidney as well as microvascular remodeling and function.21 EFFECTS OF STATINS ON RENAL DAMAGE If dyslipidemia promotes renal injury, then reducing dyslipidemia should slow or prevent the progression of CKD. Indeed, experimental models show that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, decrease the severity of glomerular damage and preserve renal function.22-24 For example, New Zealand rabbits fed a diet rich in cholesterol became hypercholesterolemic, with evidence of endothelial dysfunction in renal segmental arteries as well as glomerular hypertrophy and diffuse glomerulosclerosis.24 In this model, atorvastatin attenuated the increase in plasma cholesterol and prevented renal artery endothelial dysfunction, glomerular hypertrophy, and most of the glomerulosclerosis. Statins lower serum cholesterol levels and may therefore be expected to reduce lipid deposits in the kidney. Nevertheless, the exact mechanism by which statins protect against renal damage is unclear. Statins inhibit the ratelimiting enzyme (HMG-CoA reductase) in cholesterol synthesis, but inhibition of this enzyme also leads to downstream inhibition of the synthesis of the isoprenoids farnesyl pyrophosphate and geranyl pyrophosphate.25,26 These isoprenoids normally attach to intracellular signaling proteins to facilitate a variety of cellular responses, including gene expression, membrane trafficking, cell proliferation and migration, and programmed cell death. By blocking isoprenoid synthesis, statins produce an array of antiinflammatory and vascular effects that are independent of cholesterol reduction. For example, stem cells govern numerous ischemic and degenerative disorders, and recent investigations have shown that statins may play a role in modulating stem cell functions.27 Similarly, impaired endothelial progenitor cell function is characteristic of vascular injury, and statin therapy may improve the regenerative capacity of progenitor cells.28 Levels of advanced glycation end products (the result of increasing oxidative stress) appear to increase as GFR decreases. In addition, renal insufficiency is associated with increased levels of inflammatory and procoagulant biomarkers, even in patients without cardiovascular disease.29 Attenuation of the inflammatory response to renal injury is considered another possible explanation for the renoprotective actions of statin therapy. In an open-label trial in which 91 patients with CKD were randomly assigned to treatment with 10 mg/d of rosuvastatin or no lipid-lowering treatment for 20 weeks, a 47% reduction in median highsensitivity C-reactive protein in treated patients was ac-

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EFFECTS OF STATINS ON RENAL FUNCTION

Lipid deposition in kidney

Direct injury to GBM

Mesangial cell activation

MCP-1, GM-CSF

Recruitment of monocytes Production of proinflammatory and profibrotic mediators

↑ Mesangial macrophages/foam cells

Oxidation of LDL and generation of reactive oxygen species

Endothelial dysfunction

Cytotoxic action on mesangial cells

Mesangial cell proliferation

Increased matrix production

Renal injury FIGURE 1. Schematic showing how lipid deposition can produce renal damage. GBM = glomerular basement membrane; LDL = low-density lipoprotein; MCP-1 = monocyte chemoattractant protein1; GM-CSF = granulocyte-macrophage colony–stimulating factor. Adapted from Lippincott Williams & Wilkins,14 with permission.

companied by a statistically significant improvement in GFR.30 CLINICAL EFFECTS OF STATINS ON RENAL FUNCTION The efficacy of statin therapy in reducing major cardiovascular events and mortality has been established in a series of large long-term outcome studies that enrolled patients with or without evidence of cardiovascular disease and a wide range of baseline cholesterol levels.31-35 Patients with renal dysfunction were excluded from early statin trials, limiting the availability of data on the efficacy of statin therapy in these patients. However, some secondary-prevention studies have reported the impact of statin therapy on renal function as part of a secondary or post hoc analysis (Table 1).36-44 The Heart Protection Study evaluated simvastatin vs placebo in 20,536 patients with occlusive arterial disease or Mayo Clin Proc.

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diabetes mellitus.34,39 Plasma creatinine levels were measured at baseline and again after 4 to 6 years of therapy. As expected, plasma creatinine levels increased as patients aged, but the increase in creatinine was smaller in the simvastatin vs the placebo group (7.1 vs 8.9 µmol/L [0.08 vs 0.1 mg/dL]; P<.0001).39 Using the plasma creatinine levels, GFR was estimated retrospectively with the simplified Modification of Diet in Renal Disease formula. The decline in GFR during follow-up was significantly smaller in patients assigned to treatment with simvastatin than in those receiving placebo (5.9 vs 6.7 mL/min; P=.0003), suggesting that statin therapy may slow the decline in renal function over time.39 Two trials—the GREek Atorvastatin and Coronary– heart-disease Evaluation (GREACE) study and the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) study—compared structured dose titration with atorvastatin to achieve specific LDL-cholesterol goals

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EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 1. Overview of Renal Outcomes in Major Statin Trials* Trial

No. of patients

Patient population

Secondary and post hoc analyses of renal outcomes in major statin trials Patients with CAD 690 Pravastatin CARE36 and moderate CKD (GFR (40 mg/d) vs <60 mL/min/1.73 m2) to placebo for severe CKD (GFR ≥3 y <40 mL/min/1.73 m2) (TC <240 mg/dL) GREACE37 Previously untreated 1600 Dose-titrated dyslipidemic patients with atorvastatin CAD (10-80 mg/d) vs usual care for 3 y (mean) ALLIANCE 38

Heart Protection Study39

Pravastatin Pooling Project (WOSCOPS, CARE, LIPID)40

Dyslipidemic patients with CAD and CrCl of 88.6 mL/min and 87.2 mL/min at baseline for participants receiving atorvastatin therapy and usual care, respectively Patients ≤80 y with occlusive arterial disease or DM Patients with and without CAD and with moderate CKD (GFR, 30-60 mL/min/1.73 m2)

Studies conducted in patients with kidney disease UK-HARP-I 41 Predialysis (n=242), dialysis (n=73), and renal transplant (n=133) patients

ALERT42

4D Study43

PREVEND-IT44

Renal transplant patients, with and without CAD (TC, 154-346 mg/dL) Hemodialysis patients with and without CAD, with type 2 DM and an LDL-C of 80-190 mg/dL (TG <1000 mg/dL) Patients ≤75 y with and without CAD and with microalbuminuria and CrCL <60% of normal age-adjusted value

2442

Atorvastatin (titrated to 80 mg/d) vs usual care for 4 y

5963

Simvastatin (40 mg/d) vs placebo for 4-8 y (mean)

4491†

Pravastatin

448

2102

1255

864

Primary outcome

Statin/dose

Results

Rate of change in GFR

Statin was significantly superior to placebo in slowing rate of decline of GFR (by 2.5 mL/min/1.73 m 2 per year; P=.0001) in patients with severe CKD, but was not superior in patients with mild CKD All-cause and coronary CrCl increased by 12% in atorvastatin mortality, coronary group ( P<.0001) and by 4.9% in the morbidity (nonfatal MI, usual care group that also took statins revascularization, UA, (P=.003), but declined by 5.3% and CHF), stroke (P=.0001) in usual care patients who did not take statins Deterioration in renal Mean decline of 4.4% in the usual care function in CAD group ( P=.0001 vs baseline). CrCl did patients not change in the atorvastatin group vs baseline. Highly significant difference between the statin and usual care groups in mean change from baseline (P=.0001) Major coronary event, Smaller increase in plasma creatinine stroke, or and smaller reduction in estimated revascularization GFR with statin therapy vs placebo ( P<.0001 and P=.0003, respectively)

Time to MI, coronary death, or PCR

Significant reduction in primary outcome in statin-treated patients with moderate CKD (hazard ratio, 0.77; 95% confidence interval, 0.68-0.86); reduction in total mortality in treated patients. Benefit seen in patients with and without CAD

Simvastatin Efficacy and safety Statin treatment lowered LDL-C by (20 mg/d) vs approximately 24%; no evidence pl acebo + aspirin of toxicity vs placebo (2 × 2 factorial design) for 1 y Fluvastatin vs Cardiac death, nonfatal No significant risk reduction in placebo for MI, or coronary statin-treated patients 5.1 y (mean) intervention Atorvastatin Composite of cardiac No significant difference in primary (20 mg/d) vs death, nonfatal MI, end point with statin treatment, but placebo for 4 y and stroke increased risk for fatal stroke ( P=.04) (mean) Fosinopril or placebo + pravastatin (40 mg/d) or placebo (2 × 2 factorial) for 4 y

CV mortality or CV hospitalization

No significant reduction in primary end point with statin treatment ( P=.649)

*ALERT = Assessment of Lescol in Renal Transplantation; ALLIANCE = Aggressive Lipid-Lowering Initiation Abates New Cardiac Even ts; CAD = coronary artery disease; CARE = Cholesterol and Recurrent Events; CHF = chronic heart failure; CKD = chronic kidney disease; Cr Cl = creatinine clearance; CV = cardiovascular; DM = diabetes mellitus; GFR = glomerular filtration rate; GREACE = GREek Atorvastatin and Coronary–heart-disease Evaluation; LDL-C = low-density lipoprotein cholesterol; LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease; MI = myocardial infarction; PCR = percutaneous coronary revascularization; PREVEND-IT = Prevention of Renal and Vascular Endstage Disease Inter vention Trial; TC = total cholesterol; TG = triglyceride; UA = unstable angina; UK-HARP-I = First United Kingdom Heart and Renal Protection st udy; WOSCOPS = West of Scotland Coronary Prevention Study; 4D Study = Die Deutsche Diabetes Dialyse Studie. †Of whom 3310 (74%) had CAD.

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EFFECTS OF STATINS ON RENAL FUNCTION

vs usual care in patients with CAD.35,45 GREACE enrolled 1600 consecutive patients with CAD seen at a hospital atherosclerosis clinic, whereas ALLIANCE studied 2442 patients enrolled in health maintenance organizations or Veterans Administration settings. In both studies, creatinine clearance declined by an average of 4.4% during 4 years in patients assigned to usual care.37,38 In contrast, patients assigned to atorvastatin therapy had an 11.6% increase in creatinine clearance in the GREACE study. Although creatinine clearance did not improve in the atorvastatin group in the ALLIANCE study, no decline was seen. The difference between treatments was highly significant in both studies (P<.0001). In contrast to these studies, a post hoc analysis of the Cholesterol and Recurrent Events (CARE) trial found no difference in the rate of decline in renal function with statin therapy vs placebo. CARE evaluated pravastatin therapy for 5 years in patients with previous MI who had average cholesterol levels.32 Pravastatin did not slow the rate of GFR decline relative to placebo in patients with a baseline GFR of 60 mL/min per 1.73 m2 or higher or in those with a baseline GFR lower than 60 mL/min per 1.73 m2.36 However, in the small subset of patients with a GFR of less than 40 mL/min per 1.73 m2 at baseline, pravastatin significantly reduced GFR decline by 2.5 mL/min per year (95% CI, 1.4-3.6; P=.0001) relative to placebo. The previously described studies reflect the effect of long-term statin therapy on renal function and therefore include any natural age-associated decreases in GFR. The effect of short-term rosuvastatin therapy on renal function was explored in a pooled analysis of 13 clinical studies involving nearly 4000 subjects.46 Creatinine levels were measured at baseline and then again after 6 to 8 weeks of treatment, and GFR was estimated by the Modification of Diet in Renal Disease formula. Overall, rosuvastatin at dosages of 5 to 40 mg/d increased GFR by a mean of 1.8 mL/min per 1.73 m2 (P<.01), with statistically significant increases seen at each of the tested doses. Notably, rosuvastatin increased GFR by a mean of 2.8 mL/min per 1.73 m2 (95% CI, 2.4-3.2) in the subgroup with a baseline GFR of less than 60 mL/min per 1.73 m2. Thus, short-term rosuvastatin therapy may modestly increase GFR, even among patients with CKD. Regarding long-term therapy, when more than 10,000 patients received 5 to 40 mg/d of rosuvastatin for 96 or more weeks, GFR remained unchanged or tended to increase when compared with baseline, irrespective of the level of renal function or hypertensive or diabetic status.47 The effect of statin therapy on CKD was evaluated prospectively in a study of 56 patients with a clinical diagnosis of idiopathic chronic glomerulonephritis.48 All patients in the study had proteinuria but no evidence of sysMayo Clin Proc.

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temic disease known to cause glomerulonephritis. Patients were randomly assigned to receive additional treatment with atorvastatin or no additional treatment. After 1 additional year of treatment, urinary protein excretion declined from 2.2 to 1.2 g/d in the group treated with atorvastatin (P<.01), whereas it remained essentially unchanged in the group that received no additional treatment. Moreover, the atorvastatin group showed a significantly smaller decline in creatinine clearance than the group that received no additional treatment (2.0% vs 11.6%; P<.05).48 Thus, this study provides evidence that statin therapy may reduce proteinuria and the rate of renal function decline in patients with CKD. Liver-type fatty acid-binding protein (L-FABP) is expressed in proximal renal tubules and is considered a marker of progression of glomerulonephritis. In a study of 58 persons with and 20 persons without diabetes mellitus, increased L-FABP levels were associated with the progression of diabetic nephropathy, the leading cause of ESRD.49 After 12 months, 1 mg/d of pitavastatin effectively decreased urinary L-FABP levels in patients with early diabetic nephropathy. The investigators speculated that the antioxidant effects of statins likely play a role in slowing the progression of tubulointerstitial lesions in diabetic nephropathy. Statin therapy has also been evaluated in other cohorts with proteinuria secondary to hypertension or type 2 diabetes mellitus. Pravastatin was compared with placebo in a randomized study of 63 normolipidemic patients with well-controlled hypertension and proteinuria.50 After 6 months, pravastatin at a dosage of 10 mg/d significantly reduced urinary protein excretion from 1.23 to 0.56 g/d (P<.0001), whereas the placebo group showed only a slight decline (from 1.19 to 1.10 g/d). The reduction in proteinuria with pravastatin was evident whether or not patients were cotreated with an angiotensin receptor blocker. However, despite the observed decrease in proteinuria, serum creatinine levels and creatinine clearance remained relatively stable in both groups during the 6month treatment period. Simvastatin was compared with cholestyramine in a cohort of 86 hypertensive type 2 diabetes patients with microalbuminuria, who had shown a decline in GFR of about 3 mL/min per 1.73 m2 each year during the previous 2 to 4 years.51 After 4 years of treatment, 40 mg/d of simvastatin and 30 g/d of cholestyramine similarly reduced lipid levels, but only simvastatin significantly reduced urinary albumin excretion and slowed the rate of GFR decline. The GFR declined by an average of 0.21 mL/min per 1.73 m2 during the 4 years of simvastatin therapy and by 2.75 mL/min per 1.73 m2 with cholestyramine (P<.01). Thus, the renoprotective effect of simvastatin in these patients appeared independent of the reduction in lipid levels. In the

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EFFECTS OF STATINS ON RENAL FUNCTION

study of 91 patients with CKD discussed earlier,30 treatment with 10 mg/d of rosuvastatin for 20 weeks produced a statistically significant improvement in GFR. Sandhu et al52 performed a systematic review and metaanalysis to better characterize the effect of statins on proteinuria and the rate of GFR decline. They identified 22 randomized controlled trials involving 38,867 participants in which the effect of statin therapy on estimated GFR was evaluated. Statins exhibited favorable effects in 18 of the 22 studies. Overall, the rate of decline in estimated GFR with statins was 1.22 mL/min per year (95% CI, 0.44-2.00 mL/min per year). This rate of decline in GFR was slower than that observed with the controls and corresponded to a 76% reduction in the rate of GFR loss. Interestingly, in this meta-analysis, statin therapy was found to positively affect the GFR in populations with cardiovascular disease but, in contrast to the results found by Nakamura et al,49 not in populations with diabetic or hypertensive kidney disease or glomerulonephritis. Comparable results were reported in an earlier, smaller meta-analysis that evaluated the impact of lipid-lowering therapy on GFR and proteinuria in patients with renal disease.53 The meta-analysis for GFR reviewed 12 studies (362 participants), 5 of which contained individual patient data. A total of 10 studies used statins and 2 used gemfibrozil and probucol. Lipid-lowering therapy was associated with a 1.9 mL/min per year (95% CI, 0.3-3.4 mL/min per year) slower decline in GFR vs controls (P=.008). Lipid-lowering therapy was also associated with a greater reduction in urinary protein or albumin excretion (P<.001). However, substantial heterogeneity among trials was seen in the latter analysis, calling into question the validity of combining the results for proteinuria and albuminuria. Nevertheless, this meta-analysis suggests that statins, which were used in most of the studies, may slow GFR decline in patients with CKD. Although statins usually appear to reduce proteinuria and slow the rate of GFR decline, discrepant findings have been reported in some studies. Short-term therapy with statins, particularly at high doses, has been reported to induce proteinuria. Of 120 hypercholesterolemic patients who were taking 40 mg/d of simvastatin, 10 developed proteinuria.54,55 After resolution, proteinuria recurred in 2 patients when 40 mg/d of simvastatin was resumed. During the clinical development of rosuvastatin, the highest studied dose (80 mg) was associated with dipstick-positive proteinuria. On urine dipstick analysis, proteinuria of 2+ or higher occurred at rates of 2%, 2%, and 4% at the currently approved dosages of 10, 20, and 40 mg/d, respectively, vs a rate of 3% with placebo.56 In many cases, rosuvastatintreated patients had normal urine dipstick findings when testing was repeated, even when rosuvastatin was contin1386

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ued at the same dosage.56 Urinary protein electrophoresis indicated that most of the protein excreted had a lower molecular weight than albumin.47 This finding suggests that the proteinuria was caused by reduced reabsorption of normally filtered protein in renal tubule cells rather than by glomerular leakage of albumin and other larger proteins. Protein uptake by renal proximal tubule cells occurs at megalin and cubulin receptors via receptor-mediated endocytosis.54 Many protein ligands bind to these receptors, but because cubulin lacks an endocytosis signaling sequence and binds to megalin, the megalin receptor is thought to be responsible for internalizing the ligands attached to both receptors.57 This endocytic process requires the presence of prenylated guanosine-5'-triphosphate– binding proteins.54 However, by inhibiting HMG-CoA reductase, statins reduce the amount of mevalonate, a key intermediate in the synthesis of the isoprenoids. This mechanism is supported by experimental studies conducted in primary cultures of human renal proximal tubule cells. When incubated with these cells, statins (simvastatin, pravastatin, rosuvastatin) inhibited protein uptake in a concentration-dependent manner; however, at the highest concentrations tested (50-500 µM), protein uptake was reduced by only 40% to 50%.58 However, statins were unable to inhibit protein uptake once mevalonate was added to the cultures. These findings suggest that the increase in urinary protein excretion associated with high statin doses in some patients is caused by reduction of prenylation and the consequent inhibition of protein reabsorption in proximal tubules. This scenario may help explain why statins can transiently increase protein excretion and simultaneously protect against renal damage. The National Lipid Association Statin Safety Assessment Task Force recently reported that “proteinuria is at least possible with all statins at some concentration, but is more likely to be seen with statins that are potent inhibitors of HMG-CoA reductase.”59 The report concludes that statin-induced proteinuria is not associated with either renal impairment or renal failure. In the aforementioned meta-analysis by Sandhu et al,52 the effects of statins on proteinuria and albuminuria were evaluated in 9 studies (350 participants) and 7 studies (904 participants), respectively. When proteinuria and albuminuria were considered separately, statin therapy did not significantly influence the rate of change in urinary protein or albumin excretion. However, when considered together, statins significantly reduced urinary protein and albumin excretion compared with controls (standardized mean difference between treatments, –0.58 units of SD; 95% CI, –0.98 to –0.17 units). These findings suggest that statin therapy modestly reduces proteinuria and slows the rate of

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EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 2. Overview of Ongoing Statin Studies in Patients With CKD* Trial

Design

Renal end points PLANET60 R, DB, MC PLANET II60

R, DB, MC

Cardiovascular end points SHARP61 R, DB, PC, MC AURORA62

R, DB, PC, MC

No. of patients

Treatment

Duration

Primary end point

345 (≥18 y) with diabetes who had proteinuria and hypercholesterolemia 345 (≥18 y) without diabetes who had proteinuria and hypercholesterolemia

Rosuvastatin (10 mg) or rosuvastatin (40 mg) vs atorvastatin (80 mg)

1y

Change in urinary protein excretion (urinary protein/creatinine ratio)

Rosuvastatin (10 mg) or rosuvastatin (40 mg) vs atorvastatin (80 mg)

1y

Change in urinary protein excretion (urinary protein/creatinine ratio)

9000, including 3000 receiving HD

Simvastatin (20 mg) + ezetimibe (10 mg) vs placebo

>2750 (50-80 y) receiving long-term HD

≥4 y

Rosuvastatin (10 mg) vs placebo

Until 620 primary events have occurred

Time to first major vascular event (cardiac death or nonfatal MI, fatal or nonfatal stroke, or revascularization); progression to ESRD in predialysis cohort (secondary end point) Time to major cardiovascular event (cardiovascular death, nonfatal MI, or nonfatal stroke)

*AURORA = A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an Assessment of survival and cardio CKD = chronic kidney disease; DB = double-blind; ESRD = end-stage renal disease; HD = hemodialysis; MC = multicenter; MI = myoc PC = placebo-controlled; PLANET = Prospective evaLuation of proteinuriA and reNal function in diabETic patients (with progressi randomized; SHARP = Study of Heart and Renal Protection.

GFR decline, particularly in patients with cardiovascular disease. EFFECTS OF STATINS IN PATIENTS WITH RENAL ALLOGRAFTS The effects of statin therapy on major adverse cardiac events in patients with renal allografts were examined in 2102 renal allograft recipients in the Assessment of Lescol in Renal Transplantation (ALERT)42 (Table 1). After a mean of 5.1 years, LDL cholesterol was reduced by 32% in patients who received 40 mg/d of fluvastatin. Risk reduction for the primary end point was not significant, possibly because the study was small and the total event rate was low; thus, the study was underpowered to detect significance. However, fewer deaths and nonfatal MI were observed in the fluvastatin group vs the placebo group (70 vs 104; P=.005). Coronary intervention procedures did not differ significantly between groups.42 EFFECTS OF STATINS ON CARDIOVASCULAR OUTCOME IN PATIENTS WITH CKD To date, no single trial has provided definitive evidence that statins reduce the risk of cardiovascular morbidity and mortality in patients with CKD. Die Deutsche Diabetes Dialyse Studie (4D Study) prospectively evaluated 20 mg/d of atorvastatin vs placebo in a cohort of 1255 patients with type 2 diabetes mellitus who were receiving maintenance hemodialysis.43 After a mean follow-up of 4 years, Mayo Clin Proc.

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vascular events; ardial infarction; ve renal disease); R =

atorvastatin did not significantly reduce the risk of the primary end point—a composite of death from cardiac causes, nonfatal MI, and stroke—compared with placebo (relative risk, 0.92; 95% CI, 0.77-1.10; P=.37). Atorvastatin did not reduce the risk of the individual components of the primary end point, but it did increase the relative risk of a fatal stroke (2.03; 95% CI, 1.05-3.93; P=.04). The negative findings in the 4D study raise the possibility that it may be too late to start statin therapy once patients with CKD require hemodialysis. A number of ongoing clinical trials, as summarized in Table 2,60-62 are further evaluating statin therapy in patients with impaired renal function. The Study of Heart and Renal Protection (SHARP)61 is comparing treatment with 20 mg/d of simvastatin plus 10 mg/d of ezetimibe vs placebo in approximately 9000 patients with CKD, 3000 of whom are undergoing dialysis. The study is designed to evaluate the effect of lowering LDL cholesterol on the time to a first major vascular event, defined as nonfatal MI or cardiac death, nonfatal or fatal stroke, or revascularization (primary end point). The study will also evaluate the impact of treatment on progression to ESRD in the predialysis cohort. Patients will be treated for at least 4 years.61 A study to evaluate the Use of Rosuvastatin in subjects On Regular hemodialysis: an Assessment of survival and cardiovascular events (AURORA)62 is a large-scale international study that is also evaluating an ESRD cohort. More than 2750 patients with ESRD who have been receiving chronic hemodialysis for at least 3 months, regardless of baseline lipid levels, are randomly assigned to treatment

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EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 3. Statins for Kidney Disease: Available Dosages, LDL-C Reductions, Metabolic Pathway, and Principal Drug Interactions* Reduction in LDL-C (%)

Dosage (mg/d)

Statin Atorvastatin

Fluvastatin

Pravastatin Rosuvastatin

Simvastatin

10 20 40 80 20 40 40† 80 10 20 40 5 10 20 40 5 10 20 40 80

39 43 50 60 22 25 36 35 22 32 34 45 52 55 63 26 30 38 41 47

Metabolic pathway

Clinically important drug interactions

CYP450 3A4

Cyclosporine, digoxin, fibric acid, niacin, erythromycin, azole antifungals Cimetidine, diclofenac, glibenclamide, omeprazole, phenytoin, ranitidine, rifampicin Gemfibrozil

CYP450 2C9

Minimally metabolized CYP450 2C9 (not extensively metabolized)

Cyclosporine, gemfibrozil

CYP450 3A4

Amiodarone, cyclosporine, gemfibrozil, itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, verapamil

*CYP450 = cytochrome P450; HIV = human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol. †Twice daily. Data from references 64-68.

with 10 mg/d of rosuvastatin or placebo. The primary end point is the time to a major cardiovascular event, defined as cardiovascular death, nonfatal MI, or nonfatal stroke. Treatment will be administered until 620 patients have a major cardiovascular event.62 SAFETY OF STATINS IN PATIENTS WITH NORMAL AND IMPAIRED RENAL FUNCTION Statin therapy is safe and well tolerated in most patients.63 Although statins increase liver function enzymes in a dosedependent manner in 0.5% to 2.0% of patients, it remains unclear whether this increase reflects true hepatotoxicity. In rare cases, statins produce severe myopathy characterized by muscle aches or weakness in combination with elevated creatine kinase levels more than 10 times the upper limit of normal. Myopathy is more likely to occur when statins are used at high doses or when those that are metabolized predominantly by the cytochrome P450 3A4 isoenzyme (atorvastatin and simvastatin) are administered in combination with other medications that use the same metabolic pathway (eg, macrolide antibiotics, azole antifungals). Table 3 summarizes the most common drug interactions with the currently available statins.64-68 Patients with diabetes mellitus–associated CKD are at increased risk of myopathy and should be monitored carefully.63 Other risk factors for myopathy include advanced 1388

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age, small body frame, frailty, and perioperative periods. The rate of fatal rhabdomyolysis with marketed statins is extremely low (<1 death per million prescriptions). To minimize such risk, patients with risk factors for myopathy should be monitored carefully during statin therapy. The Food and Drug Administration–approved package inserts for the available statins indicate the intervals at which liver function tests should be performed (Table 4).64-68 Because patients with kidney disease are at increased risk of toxicity, these guidelines should be strictly followed. All statins may be administered to patients with mild to moderate renal insufficiency, but, with the exception of atorvastatin and fluvastatin, all require modified dosing for patients with substantial or severe renal disease. Atorvastatin requires no dose adjustments for any degree of renal insufficiency; currently, fluvastatin has not been studied in severe renal disease.69 CONCLUSION Patients with CKD are at high risk of adverse cardiovascular outcomes. Dyslipidemia is highly prevalent in patients with CKD and may mediate progression of this disease. Lipids deposited in the kidney appear to cause renal damage in a manner analogous to the deposition of lipids in the vascular wall in the development of atherosclerosis. Statins may protect the kidney by reducing lipid levels as well as

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EFFECTS OF STATINS ON RENAL FUNCTION

TABLE 4. Recommendations for Statin Administration and Monitoring in Patients with Kidney Disease* Statin Atorvastatin Fluvastatin Pravastatin Rosuvastatin

Simvastatin

Dosage adjustment

Liver function tests

No dosage adjustment necessary. No studies in ESRD, Before and 12 wk after initiation of therapy and any dose elevat but drug is extensively bound to plasma proteins, so periodically thereafter. Reduce dose or discontinue with persistent hemodialysis should not substantially enhance clearance ALT or AST levels >3 times the upper limit of normal Not >40 mg in patients with severe renal impairment. Before and 12 wk after initiation of therapy and any dose elevation. Otherwise, no dosage adjustment necessary. No substantial Discontinue if persistent (2 consecutive liver function tests) (<6%) renal excretion ALT or AST levels >3 times the upper limit of normal At 20 mg, renal impairment had no effect on the Before initiation of therapy or elevation of dose, or when otherwise pharmacokinetics. Patients with renal impairment should indicated. Persistent transaminase elevations are indications for be closely monitored discontinuation At 20 mg, no effect on plasma concentrations in patients Before and 12 wk after initiation of therapy and any dose elevation; with CrCl ≥30 mL/min per 1.73 m2, but concentrations periodically thereafter. Reduce dose or discontinue with persistent increased substantially in patients with severe renal ALT or AST levels >3 times the upper limit of normal impairment (CrCl <30 mL/min/1.73 m2) vs healthy participants. Plasma concentrations were approximately 50% greater in hemodialysis patients than in healthy participants Does not undergo renal excretion, so no dosage modifi cation Before in itiation of treatment and when clinically indicated. Before is required in patients with mild to moderate renal titration to the 80-mg dose, 3 mo after titration, and insufficiency. Patients with severe renal insufficiency semiannually thereafter for the 1st year of treatment should be started at 5 mg/d and closely monitored

*ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; ESRD = end-stage renal disease. Data from references 64-68.

through nonlipid–dependent anti-inflammatory and vascular effects. Meta-analyses show that statins slow the rate of GFR decline and may also reduce proteinuria in patients with CKD. However, despite the well-recognized benefits of statins in primary and secondary prevention of cardiovascular disease, conclusive evidence that statins improve cardiovascular outcomes in patients with CKD is not yet available. Ongoing studies are addressing this issue and may provide the data needed to support adjunctive use of statins in the CKD population. REFERENCES 1. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41(1):1-12. 2. Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, and trends among US adults, 1999 to 2000. J Am Soc Nephrol. 2005 Jan;16(1):180-188. Epub 2004 Nov 24. 3. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1-S266. 4. US Renal Data System. USRDS 2006 Annual data report, part 2: incidence and prevalence. Available at: www.usrds.org/adr_2006.htm. Accessed September 21, 2007. 5. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108(17):2154-2169. 6. Weiner DE, Tighiouart H, Stark PC, et al. Kidney disease as a risk factor for recurrent cardiovascular disease and mortality. Am J Kidney Dis. 2004;44 (2):198-206. 7. Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S, HOPE Investigators. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134(8):629-636. 8. Parikh NI, Hwang SJ, Larson MG, Meigs JB, Levy D, Fox CS. Cardiovascular disease risk factors in chronic kidney disease: overall burden and rates of treatment and control. Arch Intern Med. 2006;166(17):1884-1891.

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