Statins and chronic kidney disease
- Behdad Afzali, MRCP, PhD, PGDip, FHEA, MAcadMEd
Behdad Afzali, MRCP, PhD, PGDip, FHEA, MAcadMEd
- Wellcome Trust Intermediate Research Fellow, King's College
- Honorary Consultant Nephrologist, Guy's and St Thomas's Hospitals NHS Trust
- Guest Researcher, National Institutes of Health
- David JA Goldsmith, MA, FRCP
David JA Goldsmith, MA, FRCP
- Department of Nephrology and Transplantation
- Guy's Hospital, London
Normal individuals demonstrate a decline in renal function over time. Above the age of 30, this amounts to an average decrease of 0.7 to 0.9 mL/min in the glomerular filtration rate (GFR) per year . Once renal injury has occurred, independent of etiology, the decline in GFR can be accelerated by hypertension, proteinuria, and possibly by dyslipidemia [2-4].
The rate of decline in GFR in established chronic kidney disease (CKD) can be decelerated with early intervention. Perhaps the most successful intervention is the reduction of elevated blood pressure , and there may be an added benefit to using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), particularly in those with significant proteinuria. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
In animals, dyslipidemia is causally associated with glomerular injury, leading to the development of glomerulosclerosis [6-8]. However, this does not correlate with human studies in which lipid-rich conditions, such as familial hyperlipidemia, do not seem to lead to clinically relevant renal injury. Perhaps this is due to earlier development of significant cardiovascular disease or targeted interventional therapy. On the other hand, once CKD has been established, small series have demonstrated an association between progression of renal disease and hyperlipidemia .
Secondary analyses of data on subsets of patients with decreased kidney function recruited into several trials of hypertensive and/or dyslipidemic cohorts have helped to clarify some of these issues. However, in interpreting these post-hoc analyses, it is important to exercise considerable caution as renal dysfunction was not the primary objective of the studies and significant inaccuracies may accrue as a result of subanalysis, with increased risk of type I errors. In addition, the evaluation of renal function in these post-hoc analyses typically is done using formulaic manipulation of plasma creatinine levels, with all of the obvious shortcomings of this methodology.
The evidence linking dyslipidemia management with statins to the decline in renal function will be presented in this topic review. Additional reasons for the use of statins in those with renal disease, including an overview of its possible benefits in decreasing the risk of adverse cardiovascular outcomes, will also be presented briefly. Overviews of the use of statins in patients without renal failure are presented separately. (See "Statins: Actions, side effects, and administration" and "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".)
- Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985; 33:278.
- Mogensen CE. Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scand J Clin Lab Invest 1976; 36:383.
- Parving HH, Smidt UM, Friisberg B, et al. A prospective study of glomerular filtration rate and arterial blood pressure in insulin-dependent diabetics with diabetic nephropathy. Diabetologia 1981; 20:457.
- Viberti GC, Bilous RW, Mackintosh D, Keen H. Monitoring glomerular function in diabetic nephropathy. A prospective study. Am J Med 1983; 74:256.
- Taal MW, Brenner BM. Evolving strategies for renoprotection: non-diabetic chronic renal disease. Curr Opin Nephrol Hypertens 2001; 10:523.
- Keane WF, Kasiske BL, O'Donnell MP. Lipids and progressive glomerulosclerosis. A model analogous to atherosclerosis. Am J Nephrol 1988; 8:261.
- Lambert G, Sakai N, Vaisman BL, et al. Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice. J Biol Chem 2001; 276:15090.
- Mühlfeld AS, Spencer MW, Hudkins KL, et al. Hyperlipidemia aggravates renal disease in B6.ROP Os/+ mice. Kidney Int 2004; 66:1393.
- Samuelsson O, Mulec H, Knight-Gibson C, et al. Lipoprotein abnormalities are associated with increased rate of progression of human chronic renal insufficiency. Nephrol Dial Transplant 1997; 12:1908.
- Konstadinidou I, Boletis JN, Perrea D, et al. Beneficial effects of fluvastatin on progressive renal allograft dysfunction. Transplant Proc 2003; 35:1364.
- Barenbrock M, Kosch M, Jöster E, et al. Reduced arterial distensibility is a predictor of cardiovascular disease in patients after renal transplantation. J Hypertens 2002; 20:79.
- Goldsmith D, MacGinley R, Smith A, Covic A. How important and how treatable is vascular stiffness as a cardiovascular risk factor in renal failure? Nephrol Dial Transplant 2002; 17:965.
- Blacher J, Safar ME, Pannier B, et al. Prognostic significance of arterial stiffness measurements in end-stage renal disease patients. Curr Opin Nephrol Hypertens 2002; 11:629.
- Kosch M, Barenbrock M, Suwelack B, et al. Effect of a 3-year therapy with the 3-hydroxy-3-methylglutaryl coenzyme a reductase-inhibitor fluvastatin on endothelial function and distensibility of large arteries in hypercholesterolemic renal transplant recipient. Am J Kidney Dis 2003; 41:1088.
- Ichihara A, Hayashi M, Ryuzaki M, et al. Fluvastatin prevents development of arterial stiffness in haemodialysis patients with type 2 diabetes mellitus. Nephrol Dial Transplant 2002; 17:1513.
- Nakamura T, Ushiyama C, Hirokawa K, et al. Effect of cerivastatin on urinary albumin excretion and plasma endothelin-1 concentrations in type 2 diabetes patients with microalbuminuria and dyslipidemia. Am J Nephrol 2001; 21:449.
- Dogra G, Irish A, Chan D, Watts G. A randomized trial of the effect of statin and fibrate therapy on arterial function in CKD. Am J Kidney Dis 2007; 49:776.
- Epstein M, Campese VM. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on renal function. Am J Kidney Dis 2005; 45:2.
- Chang JW, Yang WS, Min WK, et al. Effects of simvastatin on high-sensitivity C-reactive protein and serum albumin in hemodialysis patients. Am J Kidney Dis 2002; 39:1213.
- Panichi V, Paoletti S, Mantuano E, et al. In vivo and in vitro effects of simvastatin on inflammatory markers in pre-dialysis patients. Nephrol Dial Transplant 2006; 21:337.
- McCarty MF. Reduction of serum C-reactive protein by statin therapy may reflect decreased isoprenylation of Rac-1, a mediator of the IL-6 signal transduction pathway. Med Hypotheses 2003; 60:634.
- Mänttäri M, Tiula E, Alikoski T, Manninen V. Effects of hypertension and dyslipidemia on the decline in renal function. Hypertension 1995; 26:670.
- Schaeffner ES, Kurth T, Curhan GC, et al. Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 2003; 14:2084.
- Chawla V, Greene T, Beck GJ, et al. Hyperlipidemia and long-term outcomes in nondiabetic chronic kidney disease. Clin J Am Soc Nephrol 2010; 5:1582.
- Rahman M, Yang W, Akkina S, et al. Relation of serum lipids and lipoproteins with progression of CKD: The CRIC study. Clin J Am Soc Nephrol 2014; 9:1190.
- Muntner P, Coresh J, Smith JC, et al. Plasma lipids and risk of developing renal dysfunction: the atherosclerosis risk in communities study. Kidney Int 2000; 58:293.
- Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation 2005; 111:3051.
- Ozsoy RC, Koopman MG, Kastelein JJ, Arisz L. The acute effect of atorvastatin on proteinuria in patients with chronic glomerulonephritis. Clin Nephrol 2005; 63:245.
- Lee TM, Lin MS, Tsai CH, Chang NC. Add-on and withdrawal effect of pravastatin on proteinuria in hypertensive patients treated with AT receptor blockers. Kidney Int 2005; 68:779.
- Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006; 145:117.
- Atthobari J, Brantsma AH, Gansevoort RT, 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.
- Ruggenenti P, Perna A, Tonelli M, et al. Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial. Clin J Am Soc Nephrol 2010; 5:1928.
- 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; 336:645.
- Tonelli M, Moyé L, Sacks FM, et al. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med 2003; 138:98.
- Tonelli M, Moyé L, Sacks FM, et al. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003; 14:1605.
- Tonelli M, Sacks F, Pfeffer M, et al. Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int 2005; 68:237.
- Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7.
- Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361:2005.
- Athyros VG, Papageorgiou AA, Mercouris BR, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 2002; 18:220.
- 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; 57:728.
- Tonelli M, Isles C, Craven T, et al. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation 2005; 112:171.
- 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; 41:565.
- Sandhu S, Wiebe N, Fried LF, Tonelli M. Statins for improving renal outcomes: a meta-analysis. J Am Soc Nephrol 2006; 17:2006.
- Ozsoy RC, van der Steeg WA, Kastelein JJ, et al. Dyslipidaemia as predictor of progressive renal failure and the impact of treatment with atorvastatin. Nephrol Dial Transplant 2007; 22:1578.
- Rahman M, Baimbridge C, Davis BR, et al. 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; 52:412.
- Fink HA, Ishani A, Taylor BC, et al. Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 2012; 156:570.
- 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; 2:1131.
- Campese VM, Park J. HMG-CoA reductase inhibitors and renal function. Clin J Am Soc Nephrol 2007; 2:1100.
- Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2009; :CD007784.
- Baigent C, Landray MJ, Reith C, et al. 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; 377:2181.
- Haynes R, Lewis D, Emberson J, et al. Effects of lowering LDL cholesterol on progression of kidney disease. J Am Soc Nephrol 2014; 25:1825.
- Gupta R, Plantinga LC, Fink NE, et al. Statin use and sepsis events [corrected] in patients with chronic kidney disease. JAMA 2007; 297:1455.
- Harris KP, Wheeler DC, Chong CC, Atorvastatin in CAPD Study Investigators. Continuous ambulatory peritoneal dialysis. A placebo-controlled trial examining atorvastatin in dyslipidemic patients undergoing CAPD. Kidney Int 2002; 61:1469.
- Holdaas H, Fellström B, Jardine AG, et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361:2024.
- Baigent C, Landray M, Leaper C, et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis 2005; 45:473.
- PHYSIOLOGIC EFFECTS
- Vascular stiffness and endothelial dysfunction
- Inflammation and end-stage renal disease
- EFFECT OF DYSLIPIDEMIA ON KIDNEY FUNCTION
- STATINS AND KIDNEY FUNCTION
- Effect on protein excretion
- Effect on chronic kidney disease progression
- STATINS AND CARDIOVASCULAR OUTCOMES IN CHRONIC KIDNEY DISEASE
- Patients on dialysis
- Patients not on dialysis
- STATINS AND SEPSIS
- ADVERSE EFFECTS OF STATINS IN CHRONIC KIDNEY DISEASE
- SUMMARY AND RECOMMENDATIONS