doi: 10.1161/CIRCULATIONAHA.105.576926
(Circulation. 2006;113:e59-e60.)
© 2006 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Tonelli et al, "Effect of Pravastatin on Rate of Kidney Function Loss in People With or at Risk for Coronary Disease"
University Hospitals of Cleveland, Case Western Reserve University, Division of Nephrology, Cleveland, Ohio
We read with interest the article by Tonelli et al1 in which the authors showed that pravastatin decreases the rate of kidney function loss in patients with moderate chronic kidney disease (CKD), ie, glomerular filtration rate between 30 and 60 mL/min per 1.73 m2. This effect was not shown in patients with normal kidney function or in patients with mild CKD.
The authors do not discuss the possible mechanisms of the beneficial effect provided by pravastatin therapy. A closer look at the studied population shows that in this study, at baseline, patients with normal kidney function and mild CKD have higher levels of low-density lipoprotein and total cholesterol than patients with moderate CKD. Data on the lipid profile after treatment with pravastatin have not been presented. Considering that the treated subjects in all groups received the same dose of pravastatin, it is expected that the drops in cholesterol and low-density lipoprotein levels would be almost the same. In this case, one might argue that the protective effect of pravastatin on glomerular filtration rate is independent of its lipid-lowering effect and perhaps related to its anti-inflammatory effects. CKD is associated with higher levels of inflammatory biomarkers,2 and inflammation may mediate progressive renal injury.3,4 The antiinflammatory effects of statins are well known.5 It is possible that the beneficial effects of pravastatin demonstrated in this study relate to its anti-inflammatory effects. The presence of higher inflammatory markers in patients with moderate CKD than in patients with mild CKD may explain better protective effects of pravastatin on glomerular filtration rate in patients with moderate CKD. Analyses of levels of inflammatory biomarkers, if available, before and after pravastatin therapy may be valuable in exploring this issue further.
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1. Tonelli M, Isles C, Craven T, Tonkin A, Pfeffer MA, Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J, West M, Packard C, Curhan GC. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation. 2005; 112: 171–178.
2. Tonelli M, Sacks F, Pfeffer M, Jhangri GS, Curhan G. Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int. 2005; 68: 237–245.[CrossRef][Medline] [Order article via Infotrieve]
3. Shlipak MG, Fried LF, Crump C, Bleyer AJ, Manolio TA, Tracy RP, Furberg CD, Psaty BM. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation. 2003; 107: 87–92.
4. Panichi V, Migliori M, De Pietro S, Taccola D, Bianchi AM, Norpoth M, Metelli MR, Giovannini L, Tetta C, Palla R. C reactive protein in patients with chronic renal diseases. Ren Fail. 2001; 23: 551–562.[CrossRef][Medline] [Order article via Infotrieve]
5. Albert MA, Danielson E, Rifai N, Ridker PM Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001; 286: 64–70.
Division of Nephrology, Division of Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada
Department of Medicine, Dumfries and Galloway Royal Infirmary, Dumfries, Scotland, UK
Wake Forest University School of Medicine, Winston-Salem, NC
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass
University of Glasgow, Glasgow, Scotland, UK
Department of Nutrition, Harvard School of Public Health, Boston, Mass
University of Sydney, Sydney, Australia
Department of Medicine, University of Queensland, Brisbane, Australia
Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, Scotland, UK
Department of Epidemiology, Harvard School of Public Health, Boston, Mass
We thank Drs Rashidi and Rahman for their interest in our article and agree that the mechanism by which pravastatin might preserve kidney function is of major scientific interest. The putative renal benefits of statins might be mediated through improved endothelial or cardiac function (improved renal perfusion),1 reduction in proteinuria,2 improved serum lipid profile, or some other mechanism such as systemic or intrarenal antiinflammatory actions.3 Unfortunately, our data do not permit us to conclude which, if any, of these mechanisms are responsible. We agree that data on inflammatory biomarkers after randomization would have been very interesting, especially because baseline markers of inflammation appear to predict renal benefit from pravastatin.4 However, these measurements have not been done on most of the participants in our analysis.
Drs Rashidi and Rahman correctly point out that baseline low-density lipoprotein cholesterol levels were lower among those with moderate chronic kidney disease. However, as reported in our previous analysis from this data set,5 the reductions in low-density lipoprotein and total cholesterol caused by pravastatin use were significantly greater among those with estimated glomerular filtration rate <60 mL/min per 1.73m2 compared with those with normal renal function. It is thus difficult to conclude that lipid-lowering effects per se were not responsible for the apparent renal benefits of pravastatin, and we agree that further studies are required.
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Disclosures
Dr Tonelli has received a research grant from Bristol-Myers Squibb and has received honoraria from and served on the advisory board of Pfizer. Dr Craven has served as a consultant to Bristol- Myers Squibb. Dr Tonkin has received a research grant as cochairman of the management committee of study of rosuvastatin (AstraZeneca) and has received honoraria for speaking at symposia sponsored by AstraZeneca, Pfizer, and Sankyo. Dr Pfeffer has received honoraria from and has served as a consultant to Bristol-Myers Squibb. Dr Shepherd has received research funding and has served as a consultant to Bristol-Myers Squibb. Dr Sacks has served on the speakers bureaus of and/or received honoraria from Bristol-Myers Squibb and Sankyo and has served as a consultant to Bristol-Myers Squibb. Dr Furberg has received research grants from GlaxoSmithKline. Dr Curhan has received a research grant from NIDDK. Dr Cobbe has received research grants from Bristol-Myers Squibb and AstraZeneca and has served on the speakers bureau of and/or received honoraria from AstraZeneca.
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1. O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation. 1997; 95: 1126–1131.
2. Lee TM, Su SF, Tsai CH. Effect of pravastatin on proteinuria in patients with well-controlled hypertension. Hypertension. 2002; 40: 67–73.
3. Zoja C, Corna D, Camozzi D, Cattaneo D, Rottoli D, Batani C, Zanchi C, Abbate M, Remuzzi G. How to fully protect the kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol. 2002; 13: 2898–2908.
4. Tonelli M, Sacks F, Pfeffer M, Jhangri GS, Curhan G. Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int. 2005; 68: 237–245.[CrossRef][Medline] [Order article via Infotrieve]
5. Tonelli M, Isles C, Curhan GC, Tonkin A, Pfeffer MA, Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J, Craven T, West M. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation. 2004; 110: 1557–1563.
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