NDT Advance Access originally published online on September 12, 2006
Nephrology Dialysis Transplantation 2006 21(11):3005-3006; doi:10.1093/ndt/gfl505
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Do statins protect the kidney as well as the heart?
Department of Medicine, University of Alberta, Department of Critical Care, University of Alberta, Institute of Health Economics and Department of Public Health Sciences, University of Alberta, Edmonton, Canada
Correspondence and offprint requests to: Dr Tonelli, 7-129 Clinical Sciences Building, 8440-112 Street, Edmonton, Alberta T6G 2G3, Canada. Email: mtonelli{at}ualberta.ca
Keywords: statins; CKD; PREVEND study
Statins are widely prescribed for the prevention of vascular disease, based on a large body of evidence showing that they reduce mortality and the risk of vascular events [1]. The idea that dyslipidaemia might promote progressive kidney disease was first advanced more than 100 years ago [2], and is supported by experimental and clinical evidence [3]. It has been suggested that lipid-modifying treatment reduces proteinuria and prevents kidney function loss—especially statins that have been the most extensively studied class of agent for this indication.
A recent systematic review of 27 randomized trials (with a total of 39 704 participants) suggested that statins reduce the rate of kidney function loss by 1.2 ml/min/year (95% CI 0.4, 2.0) or 
76% [4]. A second systematic review of 15 randomized studies (1384 participants) found that statins reduce albuminuria by 47 (95% CI 26, 67) and 48% (95% CI 25, 71) in people with >300 mg/24 h and 30–300 mg/24 h of albumin excretion at baseline, respectively. However, statins did not significantly influence urinary albumin excretion when baseline levels were <30 mg/24 h [5].
An article from the PREVEND group, in this issue of NDT, seeks to evaluate the effects of statins on the rate of change in estimated glomerular filtration rate (eGFR) and urinary albumin excretion. Atthobari et al. take the unconventional approach of presenting results from both an observational cohort study and a nested randomized controlled trial in the same paper. The randomized trial (PREVEND-IT) used a 2 x 2 factorial design to evaluate the effects of pravastatin 40 mg and/or fosinopril 20 mg daily compared with placebo in 864 normotensive people with microalbuminuria (but not overt proteinuria), who were identified by a screening program in the general population. The main results of this trial have been previously reported [7] and the current article focuses on the 392 subjects who did not receive fosinopril, among whom the rate of change in albumin excretion and eGFR were similar in pravastatin and placebo recipients.
At first glance, the findings of PREVEND-IT appear to conflict with the meta-analyses described above. The discrepancy cannot be accounted for by disparaging the quality of the carefully conducted PREVEND-IT study, which was relatively large and had good internal validity, apart from a high frequency (25%) of loss to follow-up. Instead, differences in population characteristics may be responsible for the different findings compared with previous work.
PREVEND-IT participants who received neither fosinopril nor statin had relatively preserved kidney function at baseline (mean eGFR 76 ± 12 ml/min). These people were at low renal risk, since the average loss of eGFR was only 0.7 ml/min decline over 4 years, and few had clinically relevant declines in kidney function during the study period. This low event rate reduces statistical power to show an effect of statin on kidney function loss. No benefit of statins was noted in PREVEND-IT for urinary albumin excretion, which is interesting and worthy of publication. However, mean baseline albumin excretion was also very low in both groups. In addition to reducing statistical power, this characteristic may have selected for a population which derives less renal benefit from statins, as suggested by the meta-analysis above, other human studies [8] and experimental data [9]. Thus, the current paper is consistent with previous work suggesting that the putative renal benefits of statins are attenuated or absent in people without overt proteinuria, or with higher levels of kidney function.
The PREVEND cohort study compares the rate of change in eGFR among statin users and non-users among a subgroup (3440/8592; 40.0%) of adult participants in a population-based cohort that was enriched for microalbuminuria. After adjustment for certain potential confounders (including use of a propensity score), urine albumin excretion increased in both groups but slightly more among statin users. Similar results were obtained with respect to eGFR, which declined equally among statin users and non-users.
Although carefully conducted, the cohort study may not extend the findings from PREVEND-IT because of confounding by indication—an inherent limitation of this type of analysis which is no fault of Atthobari et al. Specifically, the characteristics of statin users and non-users are so different that it seems unlikely that multivariate adjustment is sufficient, especially for the limited variables in the data set. For example, statin users were 17 years older on average, had substantially higher blood pressure and were 13 times as likely to have prior myocardial infarction. Unfortunately, when measured comorbidities are very different in two groups of study participants, unmeasured characteristics (which cannot be controlled for) often vary as well, introducing bias.
There is no question that participants in observational and randomized trials are often different, and that including a wider spectrum of participants can improve generalizability. However, if the factors that differ between participants in randomized controlled trials (RCTs) and observational studies (including motivation, adherence, intelligence, specific exclusion criteria) are relevant for external validity, they are probably also relevant for internal validity. Sadly, these factors are usually not measured in observational studies and, therefore, cannot be adjusted for. Despite the best efforts of the authors, the use of large sample sizes and sophisticated statistical techniques cannot correct for bias introduced by non-randomized designs—a lesson which the nephrology community has been slow to learn, despite several well-publicized examples [10–12].
These caveats notwithstanding, the paper by Atthobari et al. is important, since many of the available (positive) studies in this area have significant weaknesses. Specifically, many trials are small, or do not study clinically relevant outcomes. In addition, many are post hoc analyses that have their own well-documented limitations. Of course, these limitations also potentially affect the reliability of the meta-analyses referred to above. Therefore, although the weight of evidence suggests that statins may improve renal outcomes in certain populations (especially when significant proteinuria is present), additional well- designed randomized trials are required to confirm this hypothesis.
An ideal trial would evaluate whether a statin (as an add-on to conventional therapy) reduces time to doubling of serum creatinine or end-stage renal disease, especially in a high-risk population with heavy proteinuria. The Study of Heart and Renal Protection (which evaluates the benefit of combined simvastatin/ezetimibe therapy vs placebo in people, and will include >4000 participants with non-dialysis dependent kidney disease) offers the best opportunity so far to test this hypothesis [13].
At present, existing data do not support the prescription of statin therapy solely to achieve renal benefit. Doctors should decide whether to prescribe these agents to patients with proteinuria and/or impaired kidney function based on their risk/benefit ratio for prevention of atherosclerosis [14].
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Acknowledgments |
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M.T. was supported by salary awards from the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research.
Conflict of interest statement. M.T. received a research grant (>$10 000) from Bristol–Myers Squibb in 2003, served on a Pfizer advisory board in 2004, received honoraria (<$10 000) from Pfizer for continuing medical education lectures in 2004-2005 and received a research grant from Astra Zeneca (<$10 000) in 2005. Honoraria (<$10 000) provided by Merck and Astra Zeneca for academic grand rounds given in 2006 were donated directly to charity.
(See related article by Jarir Atthobari et al. The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study. Nephrol Dial Transplant 2006; 21: 3106–3114.)
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[Abstract/Free Full Text]
Accepted in revised form: 31. 7.06
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Related articles in NDT:
- The effect of statins on urinary albumin excretion and glomerular filtration rate: results from both a randomized clinical trial and an observational cohort study
- Jarir Atthobari, Auke H. Brantsma, Ron T. Gansevoort, Sipke T. Visser, Folkert W. Asselbergs, Wiek H. van Gilst, Paul E. de Jong, Lolkje T. W. de Jong-van den Berg, and on behalf of PREVEND study group
NDT 2006 21: 3106-3114.[Abstract] [FREE Full Text]
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