C L I N I C A L F O C U S : C A R D I O VA S C U L A R E V E N T S , U RO L O G Y F O R T H E P R I M A RY C A R E D O C T O R
Statins in Chronic Kidney Disease: Cardiovascular Risk and Kidney Function DOI: 10.3810/pgm.2014.01.2722
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Prakash C. Deedwania, MD University of California, San Francisco School of Medicine, Fresno, CA
Abstract: Chronic kidney disease (CKD) represents a serious public health concern. It has been associated with a significant burden of cardiovascular disease and studies have linked decreases in estimated glomerular filtration rate to higher incidences of cardiovascular events and mortality. Evidence from randomized clinical trials have shown that statins are a safe and effective treatment for improving cardiovascular outcomes in primary and secondary cardiovascular disease prevention in patients with CKD; despite this, statins are often underutilized in these patients. In addition to cardiovascular benefits, statin therapy may be associated with improvements in renal function in patients with kidney disease. Some statin treatment regimens have been shown to slow decline in kidney function, and some trials have found that intensive statin therapy improved kidney function. This review examines improved cardiovascular outcomes with statin treatment in patients with CKD (excluding end-stage renal disease) and investigates the effects of statin therapy on kidney function. Keywords: cardiovascular risk; statins; renal function; chronic kidney disease
Introduction
Correspondence: Prakash C. Deedwania, MD, Cardiology Division, Veterans Administration Central California Healthcare System, E224, 2615 E Clinton Ave, Fresno, CA 93703. Tel: 559-228-5325 Fax: 559-228-6961 E-mail: [email protected]
Chronic kidney disease (CKD) is defined by the National Kidney Foundation (NKF) clinical practice guidelines as the presence of kidney damage or reduced kidney function (estimated glomerular filtration rate [eGFR]) for $ 3 months.1 The guidelines stratify kidney disease into 5 clinical stages on the basis of pathologic abnormalities, markers of renal disease (such as proteinuria), measured GFR, or eGFR (Table 1). Chronic kidney disease represents a serious public health problem; the prevalence of any stage of CKD in the US population is estimated at 13% to 16%.2 The prevalence of CKD appears to be related to several patient risk factors, including age, diabetes mellitus, hypertension, and obesity. Kidney function declines naturally with age and prevalence of Stage 3 to 5 CKD has been estimated to be 26% in those aged $ 60 years.2 Type 2 diabetes mellitus (T2DM) is increasingly prevalent in the US population3 and # 40% of patients with T2DM may have concurrent CKD. As obesity and hypertension may be related to kidney disease, glycemic control and blood pressure reduction should be considered in the preservation of renal function. The presence of CKD is thought to be more prevalent among patients with established cardiovascular conditions, and CKD is considered a major risk factor for cardiovascular disease (CVD). Evidence has emerged highlighting the renoprotective effect of lipid management with statins. A recent study by the National Health and Nutrition Examination Survey (NHANES) III found that patients with CKD had higher levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) than those with normal renal function.4 Statins have been reported to slow or even reverse decline in renal function in patients with CKD, although the mechanism is not fully understood. Despite the NKF
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Prakash C. Deedwania
Table 1. NKF Kidney Disease Outcomes Quality Initiative Classification for Stages of CKD1 CKD Stage
eGFR (mL/min/1.73 m2)
1 (Early) 2 (Mild) 3 (Moderate) 4 (Severe) 5 (Kidney Failure)
$ 90 (plus kidney damage) 60–89 (plus kidney damage) 30–59 15–29 , 15
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Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NKF, National Kidney Foundation.
guidelines1 recommending their use, statins are underutilized in patients with CKD. This may, in part, be attributed to perceived safety and efficacy concerns associated with statin therapy in patients with CKD because many patients with CKD were excluded from early trials of statin therapy; additionally, trials in patients with end-stage renal disease (ESRD) failed to demonstrate cardiovascular benefit with statin therapy. Literature searches were performed using the PubMed MEDLINE database (www.ncbi.nlm.nih.gov) to identify English-language publications on: 1) risk of CVD in patients with CKD (excluding patients on dialysis); 2) the relation of LDL-C to risk of CKD; 3) the effect of statin therapy on renal function; and 4) CVD risk reduction with statins in patients with kidney disease. More than 1700 abstracts were reviewed for quantitative information on the relation between renal function and CVD or statin therapy, plus sufficient description of the population studied; however, no restrictions were made to the manner by which the relation was quantified. The full-length text of relevant abstracts was retrieved, and the references of these papers were reviewed. The link “Related citations in PubMed” was used to identify any additional publications. Additional references concerning the mechanisms of the effects of statins on the kidney were chosen based on the author’s knowledge on the subject.
Increased Risk of CVD in Patients With CKD
Patients with CKD are in the highest risk group for developing CVD, with cardiovascular mortality rates many times higher than in the general population.5 Studies have linked decreases in eGFR to increased risk of cardiovascular mortality.5 Indeed, the risk of CVD in patients with CKD is so great that these patients are even more likely to die from CVD than progress to ESRD.6 Traditional risk factors do not fully explain the increased cardiovascular risk; therefore CKD is now recognized as an independent risk factor for CVD.1 Investigations into the prevention of cardiovascular events have reported that the presence of CKD leads to an 30
increase in cardiovascular events.7–9 A longitudinal analysis of . 1 million adults in an integrated health care system reported an independent and graded association between patient eGFR and mortality, cardiovascular events, and hospitalization. The hazard ratio (HR) for cardiovascular events in patients with an eGFR of 45 to 59 mL/min/1.73 m2 was 1.40 (95% CI, 1.40–1.50) compared with patients who had an eGFR $ 60 mL/min/1.73 m2; rising to 3.40 (95% CI, 3.10–3.80) in patients with an eGFR , 15 mL/min/1.73 m2.5 Further, an analysis of the Kidney Early Evaluation Program (KEEP) and NHANES 1994–200410 reported that myocardial infarction (MI) and stroke were independently associated with CKD. The mortality rate in patients with CKD was higher than in participants without CKD (1.52 vs 0.33 deaths per 1000 patient-years, respectively), as was the risk of MI and stroke in KEEP (odds ratio [OR] 1.34; 95% CI, 1.25–1.43; P , 0.001) and NHANES 1999–2007 (OR 1.37; 95% CI, 1.10–1.70; P = 0.005).10
Effect of Statin Therapy on Markers of Renal Function
In addition to the potential to reduce LDL-C and cardiovascular events, statin therapy may have renal benefits in patients with kidney disease, independent of lipid lowering. Multiple landmark clinical trials have demonstrated modest renoprotection with statins (Table 2).7,9,11–18 Only a few prospective randomized studies have investigated the effect of a statin on kidney function; one of the studies demonstrated that addition of atorvastatin 10–40 mg/day to a regimen of antihypertensive medication slowed progression of kidney disease in patients with existing CKD and hypercholesterolemia.19 Likewise, a study investigating whether fluvastatin has renoprotective effects in patients with both hyperlipidemia and CKD, reported improvements in markers of renal function among patients treated with fluvastatin.20 A recent randomized controlled trial conducted in northern Tasmania investigated the effect of atorvastatin on kidney function in patients with Stage 2 to 4 CKD with all levels of proteinuria and serum cholesterol. The study reported a non-significant trend towards slower eGFR decline with atorvastatin 10 mg/ day compared with placebo.21 A key meta-analysis assessing how statins improve renal outcomes was conducted by Sandhu et al22 on 27 trials that were published before March 2005, which included a total of 39 704 patients. This meta-analysis detected a 1.22-mL/min/ 1.73 m2/year weighted mean difference in eGFR in patients receiving a statin compared with patients given placebo (95% CI, 0.44–2.00). The difference was equivalent to a 76%
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Statins in Chronic Kidney Disease
Table 2. Effect of Statin Use on Markers of Kidney Function in Clinical Trials Trial
Patients
Intervention
Follow-Up (Y)
Study N
Effect of Statin on Kidney Functiona
CHD
A10–80 vs UC
3
1600
ALLIANCE9 CARDS12 TNT13
CHD DM CHD
A10–80 vs UC A10 vs pbo A80 vs A10
4.5 3.9 4.9
2442 2838 10 001
ALLHAT-LLT14
HTN + $ 1 CHD RF
P40 vs UC
4.8
10 355
CARE15 PPP7 JUPITER16 4S17 HPS18
Previous MI CHD (or high risk) hsCRP $ 2.0 mg/L CHD CHD/OAD/DM
P40 vs pbo P40 vs pbo R20 vs pbo S20 vs pbo S40 vs pbo
∼5 ∼5 1.9 5.5 4.6
4159 19 768 17 802 4444 20 536
Increased by 12% with A10–80 and SC Increased by 4.9% with any statin and UC Increased by 0.8 mL/min/1.73 m2 with A10–80 Increased by 0.18 mL/min/1.73 m2/y with A10 Increased by 5.2 mL/min/1.73 m2 with A80 Increased by 3.5 mL/min/1.73 m2 with A10 No significant difference between P40 and UC (similar decline in both treatment arms) Slower decline by 2.5 mL/min/1.73 m2/y with P40b Slower decline by 0.1 mL/min/1.73 m2/y with P40 Slower decline by ∼0.5 mL/min/1.73 m2 with R20 Slower decline by 0.07 mL/min/1.73 m2/y with S20 Slower decline by 0.8 mL/min/1.73 m2 with S40
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GREACE
11
Marker of kidney function assessed in all trials except GREACE was eGFR; marker of kidney function assessed in GREACE was estimated CrCl. In patients with eGFR , 40 mL/min/1.73 m2. Abbreviations: 4S, Scandinavian Simvastatin Survival Study; A, atorvastatin; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial– Lipid-Lowering Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol and Recurrent Events; CHD, coronary heart disease; CKD, chronic kidney disease; CrCl, creatinine clearance; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HPS, Heart Protection Study; hsCRP, high-sensitivity C-reactive protein; HTN, hypertension; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; MI, myocardial infarction; OAD, occlusive arterial disease; P, pravastatin; pbo, placebo; R, rosuvastatin; RFs, risk factors; S, simvastatin; SC, structured care; TNT, Treating to New Targets; UC, usual care. a
b
reduction in rate of loss of kidney function in patients treated with a statin. A subpopulation of statin-treated patients with CVD also recorded a significantly slower decrease in eGFR, 0.93 mL/min/1.73 m2/year (95% CI, 0.10–1.76) compared with placebo. Much of the heterogeneity observed in this meta-analysis was ascribed to the benefit of atorvastatin treatment with respect to kidney function loss.22 However, in this meta-analysis the reduction in the rate of loss of kidney function in patients receiving statin versus placebo did not extend to the subpopulation of patients with diabetes.22 Although moderate statin regimes may slow decline in patient kidney function, such as in the Heart Protection Study (HPS), the eGFR of patients receiving simvastatin 40 mg/day decreased significantly less (by a mean of 0.8 mL/ min/1.73 m2) than that of patients allocated to placebo during 4.6 years.18 Other trials have found intensive statin therapy to improve kidney function.11,15 In the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, 1600 participants with coronary heart disease (CHD) were randomized to either usual care or structured care with atorvastatin (dose range 10–80 mg/day). Over 36 months, creatinine clearance (CrCl) in patients who were not treated with a statin (including those who discontinued atorvastatin in the structured-care group) fell by 5.2%. Patients treated with any statin in the usual-care arm achieved an average CrCl increase of 4.9%, whereas CrCl in the structured-care arm improved by 12%. The greatest improvement in CrCl during the course of the study was observed in patients with the lowest CrCl values at baseline.11 The findings were similar
to the trend observed with pravastatin use in the Cholesterol and Recurrent Events (CARE) study, where MI survivors with a baseline eGFR , 40 mL/min/1.73 m2 experienced eGFR decrease at a slower rate when treated with a statin compared with placebo.15 Recent clinical trials indicate that rosuvastatin and atorvastatin may have different effects on the kidney in patients with and without diabetes. In the Prospective Evaluation of Proteinuria and Renal Function in Diabetic/Nondiabetic Patients with Progressive Renal Disease Trial (PLANET) I/II trials, hyperlipidemic patients treated with atorvastatin 80 mg/day had significant reductions in proteinuria of 12.6% for those with diabetes, and 24.1% for non-diabetic patients. In contrast, rosuvastatin 10 and 40 mg/day had no significant effect on proteinuria in patients with or without diabetes. Additionally, substantial declines in renal function were found in patients treated with rosuvastatin 40 mg/day, but not in their counterparts treated with atorvastatin 80 mg/day.23,24 It should also be noted that some studies did not demonstrate renal benefits of statin treatment. For example, in a post hoc analysis of the lipid-lowering arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), during a mean follow-up of 4.8 years, pravastatin was not found to be superior to usual care in preventing the onset of ESRD or the composite endpoints of ESRD and 25% or 50% reductions in kidney function. This was consistent across eGFR strata; however, a considerable number of patients from the usual care arm received statin therapy, which may partially explain some
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Prakash C. Deedwania
of the observations.14 In the prospective Study of Heart and Renal Protection (SHARP) trial, no difference was found in the progression to ESRD between patients assigned to treatment with simvastatin plus ezetimibe or placebo.25 Although effects of statin therapy on CrCl or GFR have not been confirmed by earlier meta-analyses,26–28 in a metaanalysis published in August 2013, Nikolic et al29 reported that significant renoprotective effects of statins in patients with CKD may depend on treatment duration. The authors analyzed data from 6452 patients with CKD from 20 trials who were randomized to statin therapy or placebo. Significant effects of statin treatment on serum creatinine were only found for long-term (3-year) therapy (−0.65 mg/dL, 95% CI, −1.00 to −0.30; P = 0.0003). The summary of standardized effect size of mean differences of eGFR was 0.29 mL/min/ 1.73 m2 (95% CI, 0.01–0.58; P = 0.04), which was dependent on the treatment duration—for patients with CKD treated with statins for 1 to 3 years, the increase in eGFR was significant (0.50 mL/min/1.73 m2; 95% CI, 0.40–0.60; P , 0.0001), whereas for patients with CKD who received statin treatment for either shorter (# 1 year) or longer (. 3 years) periods, no significant increase was observed.29
Relationship Between Cholesterol and CKD
Whether or not a causal relationship exists between cholesterol and kidney disease, lipid control is of increased importance for patients with CKD as they are at increased risk of cardiovascular events. Although prospective data are lacking, some studies have demonstrated a relationship between LDL-C level and CKD. For instance, an analysis of check-up data in Japanese men found that serum levels of LDL-C were higher in participants with CKD compared with those who had normal kidney function.30 Further evidence of the association between cholesterol levels and kidney function has been provided from post hoc analyses of prospective studies of patients with CKD but without evident CVD.31,32 An analysis of data from the Physicians’ Health Study (a prospective analysis of men with mild or no renal insufficiency) reported an association between cholesterol levels and kidney function.31 Study participants with elevated non–high-density lipoprotein cholesterol (non– HDL-C) levels at baseline were at significantly greater risk of renal insufficiency.31 Likewise, a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study reported a relationship between LDL-C level and CKD.32 For this population of patients with T2DM and nephropathy, LDL-C lowering was 32
associated with a lower risk of developing ESRD.32 The correlation was most noted among patients with baseline LDL-C levels . 167 mg/dL. However, the authors suggested that lower risk of ESRD was largely due to a reduction in albuminuria.32 Additionally, in one study,33 the authors reported no association between LDL-C level and kidney function, and suggested that other lipid components are involved. This retrospective longitudinal study demonstrated an association between CKD and HDL-C or triglyceride levels but not LDL-C or total cholesterol levels.33
Reducing Cardiovascular Risk With Statins in Patients With CKD
As CKD is associated with a significant burden of CVD, control of other cardiovascular risk factors is important. Recent studies have shown that patients with early-stage CKD benefit from statin use to an equal or greater extent than patients with normal kidney function. Statins have been found to reduce cardiovascular risk in various patient populations with CKD.7–9, 12,16 An analysis of data from the Pravastatin Pooling Project found patients with CKD to be at increased risk of cardiovascular endpoints compared with participants with normal kidney function.7 Of 19 700 patients, 4491 (22.8%) had moderate CKD (eGFR 30–59.99 mL/min/1.73 m2), in whom treatment with pravastatin reduced mean LDL-C level from 151.6 mg/dL at baseline to 103.9 mg/dL by study end, and statin treatment was associated with a 23% decrease in risk of cardiovascular events compared with placebo (HR 0.77; 95% CI, 0.68–0.86). Similar reductions in LDL-C levels (163.7 mg/dL to 121.6 mg/dL) and risk of cardiovascular events compared with placebo (HR 0.78; 95% CI, 0.65–0.94) were recorded in patients with normal kidney function.7 In a meta-analysis including 51 099 participants from 80 trials,27 statin therapy significantly decreased mortality and CV events in patients with early stages of CKD; the benefit of lipid-lowering therapy has also been demonstrated by other meta-analyses.28,34,35
Primary Prevention
Several reports have demonstrated that statins reduce the risk of cardiovascular events in patients without a history of CVD. Sub-analyses of Pravastatin Pooling Project data have reported associations between pravastatin and reductions in cardiovascular events for patients with CKD7 or diabetes and CKD.36 More recently, a key meta-analysis that included 50 trials and a total of 30 144 patients with various stages of CKD found that statin treatment lowered LDL-C and total cholesterol levels, and these decreases were associated with
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Statins in Chronic Kidney Disease
significant reductions in fatal and nonfatal cardiovascular events, but not all-cause mortality.26 Recently, the SHARP study investigated the effect of lipid lowering with simvastatin/ezetimibe compared with placebo in patients with CKD. Patients treated with simvastatin/ ezetimibe experienced a significant reduction in major atherosclerotic events compared with those receiving placebo.25 Further support for the use of statins to prevent CVD in primary-prevention populations with CKD were provided by sub-analyses of landmark trials. One such analysis of patients with T2DM from the Collaborative Atorvastatin Diabetes Study (CARDS), reported that atorvastatin treatment was associated with a small increase in eGFR and was effective at decreasing CVD in patients with and without a moderately decreased eGFR.12 Further, in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, rosuvastatin therapy reduced the occurrence of first cardiovascular events and all-cause mortality in patients with an LDL-C level , 130 mg/dL, highsensitivity C-reactive protein (hsCRP) level $ 2.0 mg/L, and evidence of moderate CKD.16 Moreover, decline in kidney function was marginally slower in JUPITER participants receiving rosuvastatin than in those receiving placebo.37 Again, a subanalysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) reported that CVD events were reduced in patients with CKD receiving lovastatin 20 mg/day compared with placebo. However, no benefits in eGFR, kidney function, or incident CKD were evident in these patients.38
Secondary Prevention
The benefits of intensively lowering lipid levels in patients with CVD are well established and appear to be even greater in patients with renal insufficiency. The more recent evidence for renal and cardiovascular outcomes in secondary CVD prevention comes predominantly from sub-analyses of trials that compared aggressive atorvastatin therapy with more moderate statin doses or usual care. Some studies suggest that in populations of patients with CHD, the cardiovascular benefits of statin treatment may be even greater in patients with renal insufficiency.8,9 A post hoc analysis of renal outcomes in the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial reported that patients with CHD and CKD receiving a mean dose of atorvastatin 40.5 mg/day experienced a mean increase in eGFR, whereas the eGFR of patients allocated to usual care declined. In addition to improvement in renal function with atorvastatin treatment, patients with CKD experienced
greater cardiovascular risk reduction with atorvastatin compared with usual care than did patients without CKD.9 Dose-dependent improvements in eGFR with atorvastatin were reported in a post hoc analysis of the Treating to New Targets (TNT) trial, where overall atorvastatin treatment was associated with a rise in eGFR13: a 1-mL/min/1.73 m2 increase in eGFR was associated with a 2.7% decrease in major cardiovascular events. Another post hoc analysis of the TNT study found that compared with atorvastatin 10 mg/day, atorvastatin 80 mg/day reduced the relative risk of major cardiovascular events by 32% in patients with CKD, and by 15% in patients with normal eGFR.8 Similar results have been reported for TNT participants with diabetes,39 or T2DM and CKD.40 A sub-analysis of the Incremental Decrease in Endpoints Through Aggressive Lipid-Lowering (IDEAL) trial reported different treatment effects in patients with CKD and those without CKD. For patients with CKD, a significant benefit of high-dose atorvastatin compared with usual-dose simvastatin was found for any cardiovascular event, stroke, and peripheral artery disease, but not for major coronary events.41 In contrast, major coronary events and all other cardiovascular endpoints, except stroke and cardiovascular mortality, were reduced in patients without CKD.41 Finally, a recent subanalysis of the Scandinavian Simvastatin Survival Study (4S), where patients with CHD were randomized to simvastatin or placebo treatment and followed for a median of 5.4 years, revealed that statin treatment reduced the frequency of a $ 25% decline in kidney function compared with placebo (OR 0.68; 95% CI, 0.50–0.92; P = 0.01).17
Safety
Data of published clinical trials have demonstrated that s tatins are safe and well-tolerated, although for older patients, or patients with impaired liver or renal function, or patients receiving concomitant fibrates or cyclosporine treatment, the risk of statin-related muscle injury may increase.42 In recent years, various studies have shown comparable risk/benefit profiles of statins in patients with and without CKD.8,16,25 In the SHARP trial, among patients with CKD who were randomized to treatment with ezetimibe plus simvastatin, no excess risk for hepatitis, persistent increase of hepatic transaminases, gallstones, pancreatitis, cancer, or death from any non-vascular cause was found when compared with the placebo arm. Notably, the excess risk of myopathy was only about 2 per 10 000 patients per year of treatment with ezetimibe plus simvastatin.25
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Prakash C. Deedwania
Furthermore, several meta-analyses on the effect of statin therapy in patients with CKD have also reported that compared with controls, statins did not increase the rate of hepatic adverse events, muscular disorders including myopathy and rhabdomyolysis, cancer, or the incidence of withdrawal from treatment.26–28,34
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Suggested Mechanisms for the Benefits of Statins in CKD
The mechanism by which statins benefit the kidney is not fully understood; however, it is possible that a similar underlying pathology of both CVD and CKD may result in a protective effect of statin use in both conditions. One of the main uncertainties is whether the effect of statins on kidney function is derived from LDL-C level lowering or a pleiotropic effect. Despite CKD causing dyslipidemia, cholesterol levels may remain within normal ranges, or even be slightly reduced,43 suggesting that several effects of statins influence cardiovascular outcomes in patients with CKD. It has been hypothesized that oxidant stress and inflammation may provide the link between CVD and CKD.44 Hyperlipidemia may aggravate inflammation of the kidney.45 Lower LDL-C levels may moderate this effect, slowing the rate of decline in kidney function. However, LDL-C has several other roles in inflammation, and ascertaining whether each of these individual pathways is affected by either the lipid-lowering or pleiotropic properties of statins is challenging. Low-density lipoprotein cholesterol is implicated in both atherogenesis in vascular walls and mesangial cell proliferation in the kidney, both of which are associated with increased levels of inflammatory markers, which in turn are linked to an increased risk of CVD.46 Statins are known to increase the action of endothelial nitric oxide (NO) synthase and NO production.47 These effects are possibly due to inhibition of isoprenylation, as statins decrease the synthesis of isoprenoids in the mevalonic acid pathway,48 thereby resulting in decreased oxidant stress and reduced levels of inflammatory markers.49 On the other hand, endothelial NO synthase activity can also be suppressed by oxidized LDL-C. A reduction in serum LDL-C level due to statin use may result in a decreased oxidized LDL-C level, preventing down-regulation of endothelial NO synthase and decreasing oxidant stress. Another theory on the mechanism of renal protection by statins is prevention of glomerular damage by podocytes (glomerular visceral epithelial cells). Podocyte injury causes glomerulosclerosis and proteinuria, and leads to detection of podocytes in the urine of patients with glomerulonephritis.50 34
Before its withdrawal from the market, cerivastatin was shown to reduce levels of urinary podocytes in patients with glomerulonephritis compared with placebo.51
Summary
The underutilization of statins in patients with kidney disease may reflect safety concerns in CKD populations. Several trials have shown that statins are safe and reduce the risk of cardiovascular events among patients with CKD. However, data suggest that these benefits may not extend to patients with ESRD. The pathology of CVD in patients with latestage CKD may differ significantly from that in patients with early-stage CKD. Results from clinical studies imply that statins may be renoprotective and can moderate the decline in renal function. Trial data have suggested that some of these effects may be dose-dependent, with intensive lipid-lowering regimens offering greater benefit compared with more moderate lipidlowering regimens. Further investigation into dose-related outcomes and their implications for patients is needed. This review is limited because the studies mentioned were primarily focused on patients with existing CVD and analyses were predominantly post hoc. Whether the benefits of statins in the kidney extend beyond the secondary-prevention population is a question that warrants further investigation. What is clear is that the presence of CKD should not be considered a barrier to the use of statin treatment in patients at risk of cardiovascular events.
Acknowledgments
Editorial support was provided by Shirley Smith, PhD, and Shuang Li, PhD, at Engage Scientific Solutions and was funded by Pfizer.
Conflict of Interest Statement
Prakash C. Deedwania, MD, has worked as a consultant/ advisor for Pfizer, Amgen, and AstraZeneca, and is a member of the speakers bureau for Pfizer and AstraZeneca.
References 1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002; 39(2 Suppl 1):S1–S266. 2. Collins AJ, Foley RN, Chavers B, et al. United States Renal Data System 2011 Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Am J Kidney Dis. 2012;59(1 Suppl 1): A7, e1–e420. 3. Cowie CC, Rust KF, Ford ES, et al. Full accounting of diabetes and prediabetes in the U.S. population in 1988–1994 and 2005–2006. Diabetes Care. 2009;32(2):287–294.
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Statins in Chronic Kidney Disease 4. Hyre AD, Fox CS, Astor BC, Cohen AJ, Muntner P. The impact of reclassifying moderate CKD as a coronary heart disease risk equivalent on the number of US adults recommended lipid-lowering treatment. Am J Kidney Dis. 2007;49(1):37–45. 5. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–1305. 6. Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164(6):659–663. 7. Tonelli M, Isles C, Curhan GC, et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation. 2004;110(12):1557–1563. 8. Shepherd J, Kastelein JJ, Bittner V, et al; TNT (Treating to New Targets) Investigators. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am Coll Cardiol. 2008;51(15):1448–1454. 9. Koren MJ, Davidson MH, Wilson DJ, Fayyad RS, Zuckerman A, Reed DP; ALLIANCE Investigators. Focused atorvastatin therapy in managed-care patients with coronary heart disease and CKD. Am J Kidney Dis. 2009;53(5):741–750. 10. McCullough PA, Li S, Jurkovitz CT, et al; Kidney Early Evaluation Program Investigators. CKD and cardiovascular disease in screened high-risk volunteer and general populations: the Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Kidney Dis. 2008;51(4 Suppl 2):S38–S45. 11. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol. 2004;57(7):728–734. 12. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS Investigators. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis. 2009;54(5):810–819. 13. Shepherd J, Kastelein JJ, Bittner V, et al. Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study. Clin J Am Soc Nephrol. 2007;2(6):1131–1139. 14. Rahman M, Baimbridge C, Davis BR, et al; ALLHAT Collaborative Research Group. Progression of kidney disease in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Kidney Dis. 2008;52(3):412–424. 15. Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC; Cholesterol and Recurrent Events Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol. 2003;14(6):1605–1613. 16. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial. J Am Coll Cardiol. 2010;55(12):1266–1273. 17. Huskey J, Lindenfeld J, Cook T, et al. Effect of simvastatin on kidney function loss in patients with coronary heart disease: findings from the Scandinavian Simvastatin Survival Study (4S). Atherosclerosis. 2009;205(1):202–206. 18. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005–2016. 19. Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis. 2003;41(3):565–570.
20. Inoue T, Ikeda H, Nakamura T, et al. Potential benefit of statin therapy for dyslipidemia with chronic kidney disease: Fluvastatin Renal Evaluation Trial (FRET). Intern Med. 2011;50(12):1273–1278. 21. Fassett RG, Robertson IK, Ball MJ, Geraghty DP, Coombes JS. Effect of atorvastatin on kidney function in chronic kidney disease: a randomised double-blind placebo-controlled trial. Atherosclerosis. 2010;213(1):218–224. 22. Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol. 2006;17(7):2006–2016. 23. AstraZeneca. Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease (PLANET 1). Study Results. Available at: http://clinicaltrials.gov/ct2/show/results/NCT00296374. Accessed November 25, 2013. 24. AstraZeneca. Prospective Evaluation of Proteinuria and Renal Function in Non-diabetic Patients With Progressive Renal Disease (PLANET II). Study Results. Available at: http://clinicaltrials.gov/ct2/show/results/NCT00296400. Accessed November 25, 2013. 25. Baigent C, Landray MJ, Reith C, et al; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–2192. 26. Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ. 2008;336(7645):645–651. 27. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157(4):263–275. 28. Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipidlowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157(4):251–262. 29. Nikolic D, Banach M, Nikfar S, et al; Lipid and Blood Pressure MetaAnalysis Collaboration Group. A meta-analysis of the role of statins on renal outcomes in patients with chronic kidney disease. Is the duration of therapy important? Int J Cardiol. 2013;168(6):5437–5447. 30. Oda E, Kawai R. Low-density lipoprotein (LDL) cholesterol is crosssectionally associated with preclinical chronic kidney disease (CKD) in Japanese men. Intern Med. 2010;49(8):713–719. 31. Schaeffner ES, Kurth T, Curhan GC, et al. Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol. 2003; 14(8):2084–2091. 32. Tershakovec AM, Keane WF, Zhang Z, et al. Effect of LDL cholesterol and treatment with losartan on end-stage renal disease in the RENAAL study. Diabetes Care. 2008;31(3):445–447. 33. Tozawa M, Iseki K, Iseki C, Oshiro S, Ikemiya Y, Takishita S. Triglyceride, but not total cholesterol or low-density lipoprotein cholesterol levels, predict development of proteinuria. Kidney Int. 2002;62(5):1743–1749. 34. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart J. 2013;34(24):1807–1817. 35. Barylski M, Nikfar S, Mikhailidis DP, et al; Lipid and Blood Pressure Meta-Analysis Collaboration Group. Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy–a meta-analysis of 11 randomized controlled trials involving 21,295 participants. Pharmacol Res. 2013;72:35–44. 36. Tonelli M, Keech A, Shepherd J, et al. Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol. 2005;16(12):3748–3754. 37. Vidt DG, Ridker PM, Monyak JT, Schreiber MJ, Cressman MD. Longitudinal assessment of estimated glomerular filtration rate in apparently healthy adults: a post hoc analysis from the JUPITER study (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin). Clin Ther. 2011;33(6):717–725. 38. Kendrick J, Shlipak MG, Targher G, Cook T, Lindenfeld J, Chonchol M. Effect of lovastatin on primary prevention of cardiovascular events in mild CKD and kidney function loss: a post hoc analysis of the Air
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Prakash C. Deedwania Force/Texas Coronary Atherosclerosis Prevention Study. Am J Kidney Dis. 2010;55(1):42–49. 39. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care. 2006;29(6):1220–1226. 40. Shepherd J, Kastelein JP, Bittner VA, et al; Treating to New Targets Steering Committee and Investigators. Intensive lipid lowering with atorvastatin in patients with coronary artery disease, diabetes, and chronic kidney disease. Mayo Clin Proc. 2008;83(8):870–879. 41. Holme I, Fayyad R, Faergeman O, et al; Incremental Decrease in End Points through Aggressive Lipid Lowering Study Group. Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial. J Intern Med. 2010;267(6):567–575. 42. McKenney JM, Davidson MH, Jacobson TA, Guyton JR, National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97(8 A):89C–94C. 43. Tsimihodimos V, Dounousi E, Siamopoulos KC. Dyslipidemia in chronic kidney disease: an approach to pathogenesis and treatment. Am J Nephrol. 2008;28(6):958–973.
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44. Arici M, Walls J. End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int. 2001;59(2):407–414. 45. Rovin BH, Tan LC. LDL stimulates mesangial fibronectin production and chemoattractant expression. Kidney Int. 1993;43(1):218–225. 46. Coritsidis G, Rifici V, Gupta S, et al. Preferential binding of oxidized LDL to rat glomeruli in vivo and cultured mesangial cells in vitro. Kidney Int. 1991;39(5):858–866. 47. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998;97(12):1129–1135. 48. Kim SI, Kim HJ, Han DC, Lee HB. Effect of lovastatin on small GTP binding proteins and on TGF-beta1 and fibronectin expression. Kidney Int Suppl. 2000;77:S88–S92. 49. Vecchione C, Gentile MT, Aretini A, et al. A novel mechanism of action for statins against diabetes-induced oxidative stress. Diabetologia. 2007;50(4):874–880. 50. Mundel P. Urinary podocytes: lost and found alive. Kidney Int. 2003;64(4):1529–1530. 51. Nakamura T, Ushiyama C, Hirokawa K, et al. Effect of cerivastatin on proteinuria and urinary podocytes in patients with chronic glomerulonephritis. Nephrol Dial Transplant. 2002;17(5):798–802.
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Statins in Chronic Kidney Disease: Cardiovascular Risk and Kidney Function DOI: 10.3810/pgm.2014.01.2722
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Prakash C. Deedwania, MD University of California, San Francisco School of Medicine, Fresno, CA
Abstract: Chronic kidney disease (CKD) represents a serious public health concern. It has been associated with a significant burden of cardiovascular disease and studies have linked decreases in estimated glomerular filtration rate to higher incidences of cardiovascular events and mortality. Evidence from randomized clinical trials have shown that statins are a safe and effective treatment for improving cardiovascular outcomes in primary and secondary cardiovascular disease prevention in patients with CKD; despite this, statins are often underutilized in these patients. In addition to cardiovascular benefits, statin therapy may be associated with improvements in renal function in patients with kidney disease. Some statin treatment regimens have been shown to slow decline in kidney function, and some trials have found that intensive statin therapy improved kidney function. This review examines improved cardiovascular outcomes with statin treatment in patients with CKD (excluding end-stage renal disease) and investigates the effects of statin therapy on kidney function. Keywords: cardiovascular risk; statins; renal function; chronic kidney disease
Introduction
Correspondence: Prakash C. Deedwania, MD, Cardiology Division, Veterans Administration Central California Healthcare System, E224, 2615 E Clinton Ave, Fresno, CA 93703. Tel: 559-228-5325 Fax: 559-228-6961 E-mail: [email protected]
Chronic kidney disease (CKD) is defined by the National Kidney Foundation (NKF) clinical practice guidelines as the presence of kidney damage or reduced kidney function (estimated glomerular filtration rate [eGFR]) for $ 3 months.1 The guidelines stratify kidney disease into 5 clinical stages on the basis of pathologic abnormalities, markers of renal disease (such as proteinuria), measured GFR, or eGFR (Table 1). Chronic kidney disease represents a serious public health problem; the prevalence of any stage of CKD in the US population is estimated at 13% to 16%.2 The prevalence of CKD appears to be related to several patient risk factors, including age, diabetes mellitus, hypertension, and obesity. Kidney function declines naturally with age and prevalence of Stage 3 to 5 CKD has been estimated to be 26% in those aged $ 60 years.2 Type 2 diabetes mellitus (T2DM) is increasingly prevalent in the US population3 and # 40% of patients with T2DM may have concurrent CKD. As obesity and hypertension may be related to kidney disease, glycemic control and blood pressure reduction should be considered in the preservation of renal function. The presence of CKD is thought to be more prevalent among patients with established cardiovascular conditions, and CKD is considered a major risk factor for cardiovascular disease (CVD). Evidence has emerged highlighting the renoprotective effect of lipid management with statins. A recent study by the National Health and Nutrition Examination Survey (NHANES) III found that patients with CKD had higher levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) than those with normal renal function.4 Statins have been reported to slow or even reverse decline in renal function in patients with CKD, although the mechanism is not fully understood. Despite the NKF
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Prakash C. Deedwania
Table 1. NKF Kidney Disease Outcomes Quality Initiative Classification for Stages of CKD1 CKD Stage
eGFR (mL/min/1.73 m2)
1 (Early) 2 (Mild) 3 (Moderate) 4 (Severe) 5 (Kidney Failure)
$ 90 (plus kidney damage) 60–89 (plus kidney damage) 30–59 15–29 , 15
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Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NKF, National Kidney Foundation.
guidelines1 recommending their use, statins are underutilized in patients with CKD. This may, in part, be attributed to perceived safety and efficacy concerns associated with statin therapy in patients with CKD because many patients with CKD were excluded from early trials of statin therapy; additionally, trials in patients with end-stage renal disease (ESRD) failed to demonstrate cardiovascular benefit with statin therapy. Literature searches were performed using the PubMed MEDLINE database (www.ncbi.nlm.nih.gov) to identify English-language publications on: 1) risk of CVD in patients with CKD (excluding patients on dialysis); 2) the relation of LDL-C to risk of CKD; 3) the effect of statin therapy on renal function; and 4) CVD risk reduction with statins in patients with kidney disease. More than 1700 abstracts were reviewed for quantitative information on the relation between renal function and CVD or statin therapy, plus sufficient description of the population studied; however, no restrictions were made to the manner by which the relation was quantified. The full-length text of relevant abstracts was retrieved, and the references of these papers were reviewed. The link “Related citations in PubMed” was used to identify any additional publications. Additional references concerning the mechanisms of the effects of statins on the kidney were chosen based on the author’s knowledge on the subject.
Increased Risk of CVD in Patients With CKD
Patients with CKD are in the highest risk group for developing CVD, with cardiovascular mortality rates many times higher than in the general population.5 Studies have linked decreases in eGFR to increased risk of cardiovascular mortality.5 Indeed, the risk of CVD in patients with CKD is so great that these patients are even more likely to die from CVD than progress to ESRD.6 Traditional risk factors do not fully explain the increased cardiovascular risk; therefore CKD is now recognized as an independent risk factor for CVD.1 Investigations into the prevention of cardiovascular events have reported that the presence of CKD leads to an 30
increase in cardiovascular events.7–9 A longitudinal analysis of . 1 million adults in an integrated health care system reported an independent and graded association between patient eGFR and mortality, cardiovascular events, and hospitalization. The hazard ratio (HR) for cardiovascular events in patients with an eGFR of 45 to 59 mL/min/1.73 m2 was 1.40 (95% CI, 1.40–1.50) compared with patients who had an eGFR $ 60 mL/min/1.73 m2; rising to 3.40 (95% CI, 3.10–3.80) in patients with an eGFR , 15 mL/min/1.73 m2.5 Further, an analysis of the Kidney Early Evaluation Program (KEEP) and NHANES 1994–200410 reported that myocardial infarction (MI) and stroke were independently associated with CKD. The mortality rate in patients with CKD was higher than in participants without CKD (1.52 vs 0.33 deaths per 1000 patient-years, respectively), as was the risk of MI and stroke in KEEP (odds ratio [OR] 1.34; 95% CI, 1.25–1.43; P , 0.001) and NHANES 1999–2007 (OR 1.37; 95% CI, 1.10–1.70; P = 0.005).10
Effect of Statin Therapy on Markers of Renal Function
In addition to the potential to reduce LDL-C and cardiovascular events, statin therapy may have renal benefits in patients with kidney disease, independent of lipid lowering. Multiple landmark clinical trials have demonstrated modest renoprotection with statins (Table 2).7,9,11–18 Only a few prospective randomized studies have investigated the effect of a statin on kidney function; one of the studies demonstrated that addition of atorvastatin 10–40 mg/day to a regimen of antihypertensive medication slowed progression of kidney disease in patients with existing CKD and hypercholesterolemia.19 Likewise, a study investigating whether fluvastatin has renoprotective effects in patients with both hyperlipidemia and CKD, reported improvements in markers of renal function among patients treated with fluvastatin.20 A recent randomized controlled trial conducted in northern Tasmania investigated the effect of atorvastatin on kidney function in patients with Stage 2 to 4 CKD with all levels of proteinuria and serum cholesterol. The study reported a non-significant trend towards slower eGFR decline with atorvastatin 10 mg/ day compared with placebo.21 A key meta-analysis assessing how statins improve renal outcomes was conducted by Sandhu et al22 on 27 trials that were published before March 2005, which included a total of 39 704 patients. This meta-analysis detected a 1.22-mL/min/ 1.73 m2/year weighted mean difference in eGFR in patients receiving a statin compared with patients given placebo (95% CI, 0.44–2.00). The difference was equivalent to a 76%
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Statins in Chronic Kidney Disease
Table 2. Effect of Statin Use on Markers of Kidney Function in Clinical Trials Trial
Patients
Intervention
Follow-Up (Y)
Study N
Effect of Statin on Kidney Functiona
CHD
A10–80 vs UC
3
1600
ALLIANCE9 CARDS12 TNT13
CHD DM CHD
A10–80 vs UC A10 vs pbo A80 vs A10
4.5 3.9 4.9
2442 2838 10 001
ALLHAT-LLT14
HTN + $ 1 CHD RF
P40 vs UC
4.8
10 355
CARE15 PPP7 JUPITER16 4S17 HPS18
Previous MI CHD (or high risk) hsCRP $ 2.0 mg/L CHD CHD/OAD/DM
P40 vs pbo P40 vs pbo R20 vs pbo S20 vs pbo S40 vs pbo
∼5 ∼5 1.9 5.5 4.6
4159 19 768 17 802 4444 20 536
Increased by 12% with A10–80 and SC Increased by 4.9% with any statin and UC Increased by 0.8 mL/min/1.73 m2 with A10–80 Increased by 0.18 mL/min/1.73 m2/y with A10 Increased by 5.2 mL/min/1.73 m2 with A80 Increased by 3.5 mL/min/1.73 m2 with A10 No significant difference between P40 and UC (similar decline in both treatment arms) Slower decline by 2.5 mL/min/1.73 m2/y with P40b Slower decline by 0.1 mL/min/1.73 m2/y with P40 Slower decline by ∼0.5 mL/min/1.73 m2 with R20 Slower decline by 0.07 mL/min/1.73 m2/y with S20 Slower decline by 0.8 mL/min/1.73 m2 with S40
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GREACE
11
Marker of kidney function assessed in all trials except GREACE was eGFR; marker of kidney function assessed in GREACE was estimated CrCl. In patients with eGFR , 40 mL/min/1.73 m2. Abbreviations: 4S, Scandinavian Simvastatin Survival Study; A, atorvastatin; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial– Lipid-Lowering Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; CARDS, Collaborative Atorvastatin Diabetes Study; CARE, Cholesterol and Recurrent Events; CHD, coronary heart disease; CKD, chronic kidney disease; CrCl, creatinine clearance; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HPS, Heart Protection Study; hsCRP, high-sensitivity C-reactive protein; HTN, hypertension; JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin; MI, myocardial infarction; OAD, occlusive arterial disease; P, pravastatin; pbo, placebo; R, rosuvastatin; RFs, risk factors; S, simvastatin; SC, structured care; TNT, Treating to New Targets; UC, usual care. a
b
reduction in rate of loss of kidney function in patients treated with a statin. A subpopulation of statin-treated patients with CVD also recorded a significantly slower decrease in eGFR, 0.93 mL/min/1.73 m2/year (95% CI, 0.10–1.76) compared with placebo. Much of the heterogeneity observed in this meta-analysis was ascribed to the benefit of atorvastatin treatment with respect to kidney function loss.22 However, in this meta-analysis the reduction in the rate of loss of kidney function in patients receiving statin versus placebo did not extend to the subpopulation of patients with diabetes.22 Although moderate statin regimes may slow decline in patient kidney function, such as in the Heart Protection Study (HPS), the eGFR of patients receiving simvastatin 40 mg/day decreased significantly less (by a mean of 0.8 mL/ min/1.73 m2) than that of patients allocated to placebo during 4.6 years.18 Other trials have found intensive statin therapy to improve kidney function.11,15 In the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, 1600 participants with coronary heart disease (CHD) were randomized to either usual care or structured care with atorvastatin (dose range 10–80 mg/day). Over 36 months, creatinine clearance (CrCl) in patients who were not treated with a statin (including those who discontinued atorvastatin in the structured-care group) fell by 5.2%. Patients treated with any statin in the usual-care arm achieved an average CrCl increase of 4.9%, whereas CrCl in the structured-care arm improved by 12%. The greatest improvement in CrCl during the course of the study was observed in patients with the lowest CrCl values at baseline.11 The findings were similar
to the trend observed with pravastatin use in the Cholesterol and Recurrent Events (CARE) study, where MI survivors with a baseline eGFR , 40 mL/min/1.73 m2 experienced eGFR decrease at a slower rate when treated with a statin compared with placebo.15 Recent clinical trials indicate that rosuvastatin and atorvastatin may have different effects on the kidney in patients with and without diabetes. In the Prospective Evaluation of Proteinuria and Renal Function in Diabetic/Nondiabetic Patients with Progressive Renal Disease Trial (PLANET) I/II trials, hyperlipidemic patients treated with atorvastatin 80 mg/day had significant reductions in proteinuria of 12.6% for those with diabetes, and 24.1% for non-diabetic patients. In contrast, rosuvastatin 10 and 40 mg/day had no significant effect on proteinuria in patients with or without diabetes. Additionally, substantial declines in renal function were found in patients treated with rosuvastatin 40 mg/day, but not in their counterparts treated with atorvastatin 80 mg/day.23,24 It should also be noted that some studies did not demonstrate renal benefits of statin treatment. For example, in a post hoc analysis of the lipid-lowering arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), during a mean follow-up of 4.8 years, pravastatin was not found to be superior to usual care in preventing the onset of ESRD or the composite endpoints of ESRD and 25% or 50% reductions in kidney function. This was consistent across eGFR strata; however, a considerable number of patients from the usual care arm received statin therapy, which may partially explain some
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Prakash C. Deedwania
of the observations.14 In the prospective Study of Heart and Renal Protection (SHARP) trial, no difference was found in the progression to ESRD between patients assigned to treatment with simvastatin plus ezetimibe or placebo.25 Although effects of statin therapy on CrCl or GFR have not been confirmed by earlier meta-analyses,26–28 in a metaanalysis published in August 2013, Nikolic et al29 reported that significant renoprotective effects of statins in patients with CKD may depend on treatment duration. The authors analyzed data from 6452 patients with CKD from 20 trials who were randomized to statin therapy or placebo. Significant effects of statin treatment on serum creatinine were only found for long-term (3-year) therapy (−0.65 mg/dL, 95% CI, −1.00 to −0.30; P = 0.0003). The summary of standardized effect size of mean differences of eGFR was 0.29 mL/min/ 1.73 m2 (95% CI, 0.01–0.58; P = 0.04), which was dependent on the treatment duration—for patients with CKD treated with statins for 1 to 3 years, the increase in eGFR was significant (0.50 mL/min/1.73 m2; 95% CI, 0.40–0.60; P , 0.0001), whereas for patients with CKD who received statin treatment for either shorter (# 1 year) or longer (. 3 years) periods, no significant increase was observed.29
Relationship Between Cholesterol and CKD
Whether or not a causal relationship exists between cholesterol and kidney disease, lipid control is of increased importance for patients with CKD as they are at increased risk of cardiovascular events. Although prospective data are lacking, some studies have demonstrated a relationship between LDL-C level and CKD. For instance, an analysis of check-up data in Japanese men found that serum levels of LDL-C were higher in participants with CKD compared with those who had normal kidney function.30 Further evidence of the association between cholesterol levels and kidney function has been provided from post hoc analyses of prospective studies of patients with CKD but without evident CVD.31,32 An analysis of data from the Physicians’ Health Study (a prospective analysis of men with mild or no renal insufficiency) reported an association between cholesterol levels and kidney function.31 Study participants with elevated non–high-density lipoprotein cholesterol (non– HDL-C) levels at baseline were at significantly greater risk of renal insufficiency.31 Likewise, a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study reported a relationship between LDL-C level and CKD.32 For this population of patients with T2DM and nephropathy, LDL-C lowering was 32
associated with a lower risk of developing ESRD.32 The correlation was most noted among patients with baseline LDL-C levels . 167 mg/dL. However, the authors suggested that lower risk of ESRD was largely due to a reduction in albuminuria.32 Additionally, in one study,33 the authors reported no association between LDL-C level and kidney function, and suggested that other lipid components are involved. This retrospective longitudinal study demonstrated an association between CKD and HDL-C or triglyceride levels but not LDL-C or total cholesterol levels.33
Reducing Cardiovascular Risk With Statins in Patients With CKD
As CKD is associated with a significant burden of CVD, control of other cardiovascular risk factors is important. Recent studies have shown that patients with early-stage CKD benefit from statin use to an equal or greater extent than patients with normal kidney function. Statins have been found to reduce cardiovascular risk in various patient populations with CKD.7–9, 12,16 An analysis of data from the Pravastatin Pooling Project found patients with CKD to be at increased risk of cardiovascular endpoints compared with participants with normal kidney function.7 Of 19 700 patients, 4491 (22.8%) had moderate CKD (eGFR 30–59.99 mL/min/1.73 m2), in whom treatment with pravastatin reduced mean LDL-C level from 151.6 mg/dL at baseline to 103.9 mg/dL by study end, and statin treatment was associated with a 23% decrease in risk of cardiovascular events compared with placebo (HR 0.77; 95% CI, 0.68–0.86). Similar reductions in LDL-C levels (163.7 mg/dL to 121.6 mg/dL) and risk of cardiovascular events compared with placebo (HR 0.78; 95% CI, 0.65–0.94) were recorded in patients with normal kidney function.7 In a meta-analysis including 51 099 participants from 80 trials,27 statin therapy significantly decreased mortality and CV events in patients with early stages of CKD; the benefit of lipid-lowering therapy has also been demonstrated by other meta-analyses.28,34,35
Primary Prevention
Several reports have demonstrated that statins reduce the risk of cardiovascular events in patients without a history of CVD. Sub-analyses of Pravastatin Pooling Project data have reported associations between pravastatin and reductions in cardiovascular events for patients with CKD7 or diabetes and CKD.36 More recently, a key meta-analysis that included 50 trials and a total of 30 144 patients with various stages of CKD found that statin treatment lowered LDL-C and total cholesterol levels, and these decreases were associated with
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Statins in Chronic Kidney Disease
significant reductions in fatal and nonfatal cardiovascular events, but not all-cause mortality.26 Recently, the SHARP study investigated the effect of lipid lowering with simvastatin/ezetimibe compared with placebo in patients with CKD. Patients treated with simvastatin/ ezetimibe experienced a significant reduction in major atherosclerotic events compared with those receiving placebo.25 Further support for the use of statins to prevent CVD in primary-prevention populations with CKD were provided by sub-analyses of landmark trials. One such analysis of patients with T2DM from the Collaborative Atorvastatin Diabetes Study (CARDS), reported that atorvastatin treatment was associated with a small increase in eGFR and was effective at decreasing CVD in patients with and without a moderately decreased eGFR.12 Further, in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study, rosuvastatin therapy reduced the occurrence of first cardiovascular events and all-cause mortality in patients with an LDL-C level , 130 mg/dL, highsensitivity C-reactive protein (hsCRP) level $ 2.0 mg/L, and evidence of moderate CKD.16 Moreover, decline in kidney function was marginally slower in JUPITER participants receiving rosuvastatin than in those receiving placebo.37 Again, a subanalysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) reported that CVD events were reduced in patients with CKD receiving lovastatin 20 mg/day compared with placebo. However, no benefits in eGFR, kidney function, or incident CKD were evident in these patients.38
Secondary Prevention
The benefits of intensively lowering lipid levels in patients with CVD are well established and appear to be even greater in patients with renal insufficiency. The more recent evidence for renal and cardiovascular outcomes in secondary CVD prevention comes predominantly from sub-analyses of trials that compared aggressive atorvastatin therapy with more moderate statin doses or usual care. Some studies suggest that in populations of patients with CHD, the cardiovascular benefits of statin treatment may be even greater in patients with renal insufficiency.8,9 A post hoc analysis of renal outcomes in the Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial reported that patients with CHD and CKD receiving a mean dose of atorvastatin 40.5 mg/day experienced a mean increase in eGFR, whereas the eGFR of patients allocated to usual care declined. In addition to improvement in renal function with atorvastatin treatment, patients with CKD experienced
greater cardiovascular risk reduction with atorvastatin compared with usual care than did patients without CKD.9 Dose-dependent improvements in eGFR with atorvastatin were reported in a post hoc analysis of the Treating to New Targets (TNT) trial, where overall atorvastatin treatment was associated with a rise in eGFR13: a 1-mL/min/1.73 m2 increase in eGFR was associated with a 2.7% decrease in major cardiovascular events. Another post hoc analysis of the TNT study found that compared with atorvastatin 10 mg/day, atorvastatin 80 mg/day reduced the relative risk of major cardiovascular events by 32% in patients with CKD, and by 15% in patients with normal eGFR.8 Similar results have been reported for TNT participants with diabetes,39 or T2DM and CKD.40 A sub-analysis of the Incremental Decrease in Endpoints Through Aggressive Lipid-Lowering (IDEAL) trial reported different treatment effects in patients with CKD and those without CKD. For patients with CKD, a significant benefit of high-dose atorvastatin compared with usual-dose simvastatin was found for any cardiovascular event, stroke, and peripheral artery disease, but not for major coronary events.41 In contrast, major coronary events and all other cardiovascular endpoints, except stroke and cardiovascular mortality, were reduced in patients without CKD.41 Finally, a recent subanalysis of the Scandinavian Simvastatin Survival Study (4S), where patients with CHD were randomized to simvastatin or placebo treatment and followed for a median of 5.4 years, revealed that statin treatment reduced the frequency of a $ 25% decline in kidney function compared with placebo (OR 0.68; 95% CI, 0.50–0.92; P = 0.01).17
Safety
Data of published clinical trials have demonstrated that s tatins are safe and well-tolerated, although for older patients, or patients with impaired liver or renal function, or patients receiving concomitant fibrates or cyclosporine treatment, the risk of statin-related muscle injury may increase.42 In recent years, various studies have shown comparable risk/benefit profiles of statins in patients with and without CKD.8,16,25 In the SHARP trial, among patients with CKD who were randomized to treatment with ezetimibe plus simvastatin, no excess risk for hepatitis, persistent increase of hepatic transaminases, gallstones, pancreatitis, cancer, or death from any non-vascular cause was found when compared with the placebo arm. Notably, the excess risk of myopathy was only about 2 per 10 000 patients per year of treatment with ezetimibe plus simvastatin.25
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Prakash C. Deedwania
Furthermore, several meta-analyses on the effect of statin therapy in patients with CKD have also reported that compared with controls, statins did not increase the rate of hepatic adverse events, muscular disorders including myopathy and rhabdomyolysis, cancer, or the incidence of withdrawal from treatment.26–28,34
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Suggested Mechanisms for the Benefits of Statins in CKD
The mechanism by which statins benefit the kidney is not fully understood; however, it is possible that a similar underlying pathology of both CVD and CKD may result in a protective effect of statin use in both conditions. One of the main uncertainties is whether the effect of statins on kidney function is derived from LDL-C level lowering or a pleiotropic effect. Despite CKD causing dyslipidemia, cholesterol levels may remain within normal ranges, or even be slightly reduced,43 suggesting that several effects of statins influence cardiovascular outcomes in patients with CKD. It has been hypothesized that oxidant stress and inflammation may provide the link between CVD and CKD.44 Hyperlipidemia may aggravate inflammation of the kidney.45 Lower LDL-C levels may moderate this effect, slowing the rate of decline in kidney function. However, LDL-C has several other roles in inflammation, and ascertaining whether each of these individual pathways is affected by either the lipid-lowering or pleiotropic properties of statins is challenging. Low-density lipoprotein cholesterol is implicated in both atherogenesis in vascular walls and mesangial cell proliferation in the kidney, both of which are associated with increased levels of inflammatory markers, which in turn are linked to an increased risk of CVD.46 Statins are known to increase the action of endothelial nitric oxide (NO) synthase and NO production.47 These effects are possibly due to inhibition of isoprenylation, as statins decrease the synthesis of isoprenoids in the mevalonic acid pathway,48 thereby resulting in decreased oxidant stress and reduced levels of inflammatory markers.49 On the other hand, endothelial NO synthase activity can also be suppressed by oxidized LDL-C. A reduction in serum LDL-C level due to statin use may result in a decreased oxidized LDL-C level, preventing down-regulation of endothelial NO synthase and decreasing oxidant stress. Another theory on the mechanism of renal protection by statins is prevention of glomerular damage by podocytes (glomerular visceral epithelial cells). Podocyte injury causes glomerulosclerosis and proteinuria, and leads to detection of podocytes in the urine of patients with glomerulonephritis.50 34
Before its withdrawal from the market, cerivastatin was shown to reduce levels of urinary podocytes in patients with glomerulonephritis compared with placebo.51
Summary
The underutilization of statins in patients with kidney disease may reflect safety concerns in CKD populations. Several trials have shown that statins are safe and reduce the risk of cardiovascular events among patients with CKD. However, data suggest that these benefits may not extend to patients with ESRD. The pathology of CVD in patients with latestage CKD may differ significantly from that in patients with early-stage CKD. Results from clinical studies imply that statins may be renoprotective and can moderate the decline in renal function. Trial data have suggested that some of these effects may be dose-dependent, with intensive lipid-lowering regimens offering greater benefit compared with more moderate lipidlowering regimens. Further investigation into dose-related outcomes and their implications for patients is needed. This review is limited because the studies mentioned were primarily focused on patients with existing CVD and analyses were predominantly post hoc. Whether the benefits of statins in the kidney extend beyond the secondary-prevention population is a question that warrants further investigation. What is clear is that the presence of CKD should not be considered a barrier to the use of statin treatment in patients at risk of cardiovascular events.
Acknowledgments
Editorial support was provided by Shirley Smith, PhD, and Shuang Li, PhD, at Engage Scientific Solutions and was funded by Pfizer.
Conflict of Interest Statement
Prakash C. Deedwania, MD, has worked as a consultant/ advisor for Pfizer, Amgen, and AstraZeneca, and is a member of the speakers bureau for Pfizer and AstraZeneca.
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