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Clinical Nephrology |
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* Medicine; Critical Care; Public Health Sciences, University of Alberta; || Institute of Health Economics, Edmonton, Alberta, Canada; and Veterans Affairs Pittsburgh Healthcare System and Renal-Electrolyte Division, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
Address correspondence to: Dr. Marcello Tonelli, University of Alberta, Division of Nephrology & Immunology, 7-129 Clinical Science Building, 8440 112 Street, Edmonton, Alberta T6B 2B7, Canada. Phone: 780-407-8716; Fax: 780-407-7878; mtonelli{at}ualberta.ca
Received for publication January 6, 2006. Accepted for publication April 20, 2006.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionReferences |
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Animal models of hyperlipidemia that is produced by cholesterol-rich diets show evidence of renal injury on biopsy (9), and epidemiologic studies suggest that elevated cholesterol and triglyceride levels are associated with more rapid kidney function loss (10–12). Possible mechanisms include accelerated atherosclerosis of arteries within the kidney and damaging effects of lipids on mesangial cells (13). Studies in animal models show that treatment of dyslipidemia reduces renal injury by decreasing urine albumin excretion and reducing histologic damage, such as mesangial matrix expansion and hypercellularity (14–16). A previous systematic review pooled the literature from all human studies that were conducted before 2000 (17) (n = 404 participants) and suggested that pharmacologic lipid modification may slow the progression of CKD. Studies that were included in this review evaluated multiple classes of medications, including statins, fibric acid derivatives, and probucol.
More recently, results from several studies (18–20) addressed the potential renal benefits of statins in particular. Statins inhibit 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in the production of mevalonic acid, which is essential for cholesterol synthesis. Given the increasing use of statins for prevention of CVD, a summary of their effects on renal function loss would be of interest to clinicians and may help to inform recommendations for management of CKD. We conducted a systematic review and meta-analysis to determine the effect of statins on the rate of kidney function loss and proteinuria.
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Materials and Methods |
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Search Strategy
A comprehensive search strategy was formulated to identify all relevant studies regardless of language or publication status, including published, unpublished, in press, and in progress. Two reviewers searched Medline (1969 to March 2005), EMBASE (1988 to March 2005), and the Cochrane Central Register of Controlled Trials (CENTRAL) databases. The search strategies are included in the Appendix. The search terms were identified to include all studies that evaluated statin therapy on the effect of renal function or proteinuria. The citations of existing reviews and of trials that were identified by the above methods were reviewed by two reviewers to include pertinent studies. Abstracts from major nephrology conference proceedings (American Society of Nephrology; Canadian Society of Nephrology), the metaRegistry of controlled trials (www.controlled-trials.com/mrct/), and the personal files of the review authors also were searched. Any study that was considered relevant by one or both reviewers was retrieved for further review.
Study Selection
All studies that were identified by the search strategy were screened independently by two reviewers. The full text of the potentially relevant articles subsequently was obtained. Each study was assessed independently by two reviewers for inclusion in the review using predetermined eligibility criteria. Studies were eligible for inclusion when they were randomized, controlled trials or randomized, crossover trials; included participants who were older than 18 yr; measured or estimated kidney function (GFR, creatinine clearance, or proteinuria); and randomly assigned therapy with a statin. We excluded studies that did not have a control group for direct comparison with the statin group and those that included participants with ESRD. Disagreements were resolved by discussion and/or consultation with a third party.
Validity Assessment and Data Extraction
The qualitative details were assessed to evaluate impact on internal validity. A standard data extraction method was used to record the following properties of each trial in a database: Study characteristics (design, method of randomization, and withdrawals/dropouts), participants (age, gender, renal function at the time statin therapy was initiated, fasting serum lipid profile, and cause of renal disease), therapeutic intervention (type of statin, dose of statin, duration of therapy, and co-interventions), outcomes (types of outcome measures, timing of outcomes, and adverse effects), results, whether the studies used an intention-to-treat analysis, and funding source. Study quality was assessed using a previously validated index (22,23). A second reviewer checked the extracted data for accuracy. In cases in which necessary data were missing from the studies, additional information was requested from the authors.
Outcome Measures
The primary outcome was rate of change in estimated GFR (eGFR) in milliliters per minute per year. Although creatinine clearance is conceptually different from GFR, it commonly is used as an estimate of GFR (24); therefore, creatinine clearance was used interchangeably with GFR to assess the primary outcome. Similarly, estimates of GFR and/or creatinine clearance that were normalized to body surface area were pooled with those that were not. Because the focus of this analysis was on change in kidney function and because the index of kidney function was constant for both groups within a particular study, these decisions were considered unlikely to introduce bias. Positive differences in per-year rates of change indicate slower decline in renal function in the statin group, as compared with the placebo group.
As a secondary outcome, we considered change in urinary protein excretion from baseline to end of follow-up. Results from timed urine specimens for proteinuria and albuminuria were converted to grams per 24 h. Results from spot urine specimens (protein to creatinine or albumin to creatinine ratio) were converted to milligrams per gram of creatinine. Negative differences in changes from baseline indicate greater decreases in proteinuria or albuminuria in the statin group as compared with the placebo group.
Clinical Subpopulations
The primary analysis pooled the results from all studies. However, we presented results separately for trials that studied participants who were selected on the basis of CVD, glomerulonephritis (GN), diabetes, or HTN. Because of the large size of the CVD group, we also presented results from the GN, diabetes, and HTN groups combined.
Statistical Analyses
SD were imputed using interquartile ranges (dividing the range by 1.35 [25]) and full ranges (dividing the range by values from Pearson’s table [26]). Change-from-baseline SD were calculated using correlations that were estimated from other included studies (27). GFR means and SD were extrapolated to per-year estimates, assuming a linear rate of change and holding the coefficient of variation fixed (28). Standardized mean difference (SMD) was used to pool results from all studies that reported untransformed change in urinary protein excretion (i.e., those that were not reported solely as geometric means or logged values). Weighted mean differences (WMD) were used to pool change-from-baseline per-year GFR estimates. Percentage of prevented loss was calculated using the difference in change-from-baseline GFR means divided by the control change-from-baseline GFR mean. An overall pooled percentage of prevented loss was calculated using the same weights as those used in the WMD calculation. WMD was used to pool results separately for timed collections of urinary protein or albumin.
We used Review Manager 4.2.7 (29) to pool data and calculate mean differences. Because of the differences expected between studies (particularly in clinical populations), we decided a priori to combine results using a random-effects model. Statistical heterogeneity was quantified using the I2 statistic (30). A priori we planned to use meta-regression (31) to examine the association between certain variables (mean age, mean total serum cholesterol, baseline mean GFR, baseline mean proteinuria, type of statin, and quality criteria) and the effect of statins on the outcomes. In sensitivity analyses, we assessed the likelihood that our findings were influenced by the assumptions that we made about the SD of the effect sizes. Results were robust to increasing and decreasing this SD by a factor of 1.5, suggesting that these estimates were unlikely to have influenced our findings. Additional sensitivity analyses included only trials with 
1 yr of follow-up. Publication bias was assessed using weighted regression (32). Statistical significance was set at P < 0.05 for all analyses.
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Results |
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4, and 16 (59%) of 27 had a Jadad score of 
2. The characteristics of the included studies are shown in Table 1.
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Effect of Statins on Rate of Change in eGFR
The effect of statins on rate of change in eGFR was favorable in 18 of 22 cohorts (38,867 participants). Overall, the change in the WMD for eGFR was statistically significant (1.22 ml/min per yr; 95% confidence interval [CI] 0.44 to 2.00), corresponding to a 76% reduction in the overall rate of loss. There was substantial heterogeneity in the estimate of statin effect on renal function loss (I2 = 96%; Figure 2A). The benefit of statin therapy was statistically significant in the CVD subpopulation (0.93 ml/min per yr; 95% CI 0.10 to 1.76; I2 = 99%, six cohorts, 38,311 participants; Figure 2A). The effect of statins was NS in the other individual subpopulations (diabetes: 3.24 ml/min per yr, 95% CI –0.46 to 6.95, I2 = 0%, five cohorts, 122 participants; GN: 1.4, 95% CI –6.7 to 9.5, I2 = 69%, seven studies, 222 participants; and HTN: 6.1, 95% CI –2.3 to 14.4, I2 = 56%, four cohorts, 212 participants). When these three subpopulations were combined, the pooled effect of statins remained nonsignificant (3.1 ml/min per yr; 95% CI –0.2 to 6.4; I2 = 46%; 16 cohorts, 556 participants).
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1 yr of follow-up. Specifically, the overall benefit of statin therapy was 1.24 ml/min per 1.73 m2/yr (95% CI 0.47 to 2.02), and substantial heterogeneity remained (I2 = 98%). Little change was apparent in the diabetes, HTN, and CVD subgroups when trials with <1 yr of follow-up were excluded. However, in the GN subgroup, the overall beneficial effect of statins on GFR increased from 1.40 (95% CI –6.69 to 9.49) to 5.35 ml/min per 1.73 m2/yr (95% CI 2.19 to 8.51), and the heterogeneity disappeared (from 69% to 0%).
Factors Associated with the Effect of Statins on eGFR
Mean age, mean baseline serum cholesterol, mean change in baseline serum cholesterol in the statin therapy group, mean eGFR at baseline, and clinical population (CVD versus non-CVD) were explored in univariable meta-regression. None was found to be significantly associated with the effect of statins on rate of change in eGFR (all P > 0.1). However, three trials that used atorvastatin were associated with an additional beneficial effect on kidney function loss (
= 2.5 ml/min per yr slower; 95% CI 1.8 to 3.2; P < 0.001), compared with trials that studied other statins (Figure 2B). Adjustment for atorvastatin (versus other statins) reduced I2 from 96% to 46%, suggesting that this characteristic accounted for a substantial proportion of the observed heterogeneity in the effect of statin therapy. One atorvastatin study (36) was particularly influential; removing this study reduced the pooled rate of change in eGFR to 0.42 ml/min per yr (95% CI 0.13 to 0.71; I2 reduced to 62%).
Three of six quality items were significantly associated with treatment effect in meta-regression. Open-label trials and trials that reported withdrawals explicitly were associated with larger treatment effects ( = 2.4 ml/min per yr, 95% CI 1.7 to 3.2, P < 0.001, I2 reduced to 49%; and 2.5 ml/min per yr, 95% CI 1.9 to 3.2, P < 0.001, I2 reduced to 45%). Trials with an industrial sponsor were associated with smaller treatment effects in univariable meta-regression ( = –2.5 ml/min per yr; 95% CI –3.5 to –1.6; P < 0.001; I2 reduced to 58%). Restricting the meta-analysis to high-quality trials (Jadad score 3) maintained the statistical significance of the overall change in GFR but reduced the estimate from 1.22 (95% CI 0.44 to 2.00) to 0.22 ml/min per yr (0.07 to 0.38; I2 = 42%; nine cohorts, 34,453 participants).
Effect of Statins on Proteinuria and Albuminuria
The point estimate for the effect of statins on rate of change in proteinuria was favorable in seven of nine studies (350 participants) that performed timed urine collections. Overall, the change in proteinuria WMD was statistically NS (reduction of 0.37 g/24 h; 95% CI –0.75 to 0.02) and had large heterogeneity (I2 = 83%; Figure 3A). One trial assessed proteinuria in terms of urinary protein:creatinine ratio and found a significant reduction as a result of statin therapy (reduction 4400 mg/g; 95% CI 2806 to 5994).
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When reductions in albuminuria and proteinuria were considered together, the number of studies that were available for analysis increased to 18. The SMD for the effect of proteinuria on albuminuria or proteinuria was statistically significant (–0.58 units of SD; 95% CI –0.98 to –0.17; I2 = 89%; Figure 3B). Results were similar when only trials with at least 1 yr of follow-up were included (–0.47 units of SD; 95% CI –0.90 to –0.05; I2 = 76%). Meta-regression was repeated using the same list of covariates considered in analyses of eGFR; none was found to be significantly associated with the effect of statins on rate of change in combined albuminuria and proteinuria (all P > 0.1). Of note, the effect of statins on proteinuria was not significantly more pronounced in any of the four clinical subpopulations.
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Discussion |
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When specific subgroups of participants were considered, statin treatment did not significantly reduce the rate of kidney function loss in participants with GN, diabetes, or HTN. However, a significant benefit of statin therapy was observed in the much larger subgroup of participants with CVD (n = 38,311). Even within this subgroup, we observed statistically significant heterogeneity, which seemed to be due to the large treatment effect observed in the two trials that studied atorvastatin. Meta-regression found that atorvastatin use was associated with a significantly larger beneficial effect on the rate of kidney function loss than other statins (P < 0.001), and excluding the more influential of the two reduced the pooled benefit of statin therapy on eGFR from 1.2 to 0.4 ml/min per yr. Whether the seemingly larger benefit of atorvastatin was due to its relatively more potent lipid-lowering effect as compared with other statins, resulted from pleiotropic (non–lipid-mediated) effects, or was confounded by other between-study differences will require further study. However, the magnitude of cholesterol reduction from baseline was not significantly associated with the seeming renal benefit of statins in meta-regression.
Other study characteristics that were associated with larger treatment effects included open-label design, explicit reporting of loss to follow-up, and lack of industrial sponsorship. We were unable to identify any clinical characteristics that were responsible for significant heterogeneity of effect, which by extension might have suggested populations that would derive particular renal benefit from statins.
Statin treatment also seemed to reduce modestly urinary protein excretion. Studies that reported urinary protein excretion were conducted in participants with GN, diabetes, or HTN and used a variety of indices for protein excretion. The overall estimate pooled data from 18 studies of 1323 participants and indicated that statin therapy reduced protein excretion by 0.6 SD (P = 0.005). It is difficult to convert SMD to absolute treatment effects, but Figure 3A suggests that statin therapy reduced 24-h protein excretion by approximately 0.4 g in the populations studied. Although NS, this point estimate may provide some guidance as to the absolute magnitude of the reduction in protein excretion observed when results from all studies were pooled. Whether the absolute magnitude of this seeming reduction would be larger in the presence of heavier proteinuria will require further study.
Hyperlipidemia is associated with more rapid kidney function loss, and individuals with renal impairment are more likely to have hyperlipidemia, although not all patients with elevated lipid levels have kidney disease (62). It has been speculated that hyperlipidemia may exacerbate preexisting renal impairment by direct injury to the glomerular basement membrane (63). A second possibility is that statins improve GFR by improving endothelial function, leading to increased renal perfusion (64). Finally, the putative benefits of statins on kidney function may be attributable to their effects on proteinuria, which is a powerful predictor of kidney function loss. Experimental data suggest that statins reduce proteinuria at least in part by reducing inflammation and fibrosis in the renal interstitium, seemingly through actions on monocyte chemotactic protein-1 and TGF- (65,66). Like others (58), Zoja et al. (65,66) found that the effects of statins were markedly enhanced by concomitant use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Although we were not able to confirm this hypothesis in our study, therapy of progressive renal disease in humans typically includes these agents, especially in the presence of proteinuria.
To our knowledge, this is the largest systematic review to evaluate the renal effects of statins. Our findings generally are consistent with an earlier meta-analysis that identified a total of 13 studies (404 participants) and included multiple classes of lipid-lowering agent (17). Although our analysis was performed and reported as recommended by published guidelines, it has several limitations that should be considered. First, there was considerable variation in study populations, intervention (type and dose of statin), outcomes (estimates of GFR and proteinuria), and duration. Although we attempted to control for some of these differences using stratification and meta-regression, it is likely that these differences contributed to the between-study heterogeneity alluded to above. Second, we acknowledge that pooled analyses potentially are problematic in the face of substantial heterogeneity. Although we attempted to address this through the use of random-effects models, it is possible that this heterogeneity affected our results. Third, 12 (44%) of 27 included studies were <1 yr in duration, and all studied surrogates for the clinically relevant outcome of interest: Progression to ESRD. Whether the modest reduction in the rate of kidney function loss suggested in this review will result in a clinically relevant renal benefit remains unclear. Fourth, although we included unpublished studies when possible, the possibility of publication bias remains. Fifth, although it has been suggested that the renal effects of statins may be most pronounced in individuals with lower levels of kidney function (36,67), most studies did not stratify by baseline kidney function; therefore, we could not confirm this possibility. However, baseline kidney function was not significantly associated with the effect of statins on rate of change in GFR in univariable meta-regression. Finally, although useful for summarizing the current state of knowledge, systematic review and meta-analysis have widely known limitations (68).
Despite our findings, these methodologic limitations (especially those that are attributable to the existing literature on this topic) make it clear that additional large randomized trials will be required to show that statins are associated with renal benefit. Participants should have progressive loss of kidney function, and specific populations of interest would include those with lower GFR at baseline, as well as people with heavy proteinuria. A clinically relevant outcome such as the composite of ESRD, doubling of serum creatinine, or death should be studied, and duration of follow-up should be at least 4 yr and possibly longer. These studies will need to be conducted at multiple centers, because the known cardiovascular benefit of statins in people with mild to moderate CKD will pose an additional ethical challenge to recruitment. The ongoing Study of Heart and Renal Protection (SHARP) (69) is an example of such a trial, but other studies are needed, especially in patients with GN.
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Conclusion |
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Acknowledgments |
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We thank the following authors for sending us additional data: The Pravastatin Pooling Project investigators, Brian Rayner, Tsung-Ming Lee, and Gen Yasuda. We also thank Janice Varney for additional librarian support and Alex Stewart and Julie Paterson for text retrieval.
M.T. has received research grants from Bristol-Myers-Squibb and honoraria for continuing medical education events from Pfizer and previously served on a Pfizer advisory board. L.F.F. serves on the Pfizer speakers bureau and has served as a consultant to Pfizer.
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Footnotes |
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References |
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H. H.H. Feringa, S. E. Karagiannis, M. Chonchol, R. Vidakovic, P. G. Noordzij, A. Elhendy, R. T. van Domburg, G. Welten, O. Schouten, J. J. Bax, et al. Lower Progression Rate of End-Stage Renal Disease in Patients with Peripheral Arterial Disease Using Statins or Angiotensin-Converting Enzyme Inhibitors J. Am. Soc. Nephrol., June 1, 2007; 18(6): 1872 - 1879. [Abstract] [Full Text] [PDF]
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E. Ritz and C. Wanner Lipid Changes and Statins in Chronic Renal Insufficiency J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S226 - S230. [Abstract] [Full Text] [PDF]
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M. Tonelli Do statins protect the kidney as well as the heart? Nephrol. Dial. Transplant., November 1, 2006; 21(11): 3005 - 3006. [Full Text] [PDF]
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L. J. Appel A Primer on the Design, Conduct, and Interpretation of Clinical Trials Clin. J. Am. Soc. Nephrol., November 1, 2006; 1(6): 1360 - 1367. [Abstract] [Full Text] [PDF]
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