Revisão Revisado por pares

Effects of Statins on Renal Function

2007; Elsevier BV; Volume: 82; Issue: 11 Linguagem: Inglês

10.4065/82.11.1381

ISSN

1942-5546

Autores

Rajiv Agarwal,

Tópico(s)

Pharmaceutical Economics and Policy

Resumo

Patients with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease than end-stage renal disease. Dyslipidemia is highly prevalent in patients with CKD and may contribute to the elevated cardiovascular risk as well as CKD progression. Statins are lipid-lowering drugs that appear to protect the kidneys via cholesterol reduction as well as noncholesterol-mediated mechanisms. Subgroup analyses of major clinical studies and meta-analyses of smaller trials indicate that statin therapy slows the decline of the glomerular filtration rate. Additionally, statins appear to reduce proteinuria in patients with CKD. Statins are well recognized to reduce cardiovascular morbidity and mortality in patients with and without documented cardiovascular disease and in certain high-risk populations, such as persons with diabetes mellitus. However, conclusive evidence for improved cardiovascular outcomes with statin therapy for CKD is not yet available. Several ongoing studies are evaluating the effect of statins on cardiovascular end points in patients with CKD and may provide data needed to support adjunctive use of these agents in this high-risk population. Patients with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease than end-stage renal disease. Dyslipidemia is highly prevalent in patients with CKD and may contribute to the elevated cardiovascular risk as well as CKD progression. Statins are lipid-lowering drugs that appear to protect the kidneys via cholesterol reduction as well as noncholesterol-mediated mechanisms. Subgroup analyses of major clinical studies and meta-analyses of smaller trials indicate that statin therapy slows the decline of the glomerular filtration rate. Additionally, statins appear to reduce proteinuria in patients with CKD. Statins are well recognized to reduce cardiovascular morbidity and mortality in patients with and without documented cardiovascular disease and in certain high-risk populations, such as persons with diabetes mellitus. However, conclusive evidence for improved cardiovascular outcomes with statin therapy for CKD is not yet available. Several ongoing studies are evaluating the effect of statins on cardiovascular end points in patients with CKD and may provide data needed to support adjunctive use of these agents in this high-risk population. Chronic kidney disease (CKD) affects an estimated 19 million people in the United States, representing 11% of the total adult population.1Coresh J Astor BC Greene T Eknoyan G Levey AS Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.Am J Kidney Dis. 2003; 41: 1-12Abstract Full Text Full Text PDF PubMed Scopus (2306) Google Scholar, 2Coresh J Byrd-Holt D Astor BC et al.Chronic kidney disease awareness, prevalence, and trends among US adults, 1999 to 2000.J Am Soc Nephrol. 2005 Jan; 16 (Epub 2004 Nov 24.): 180-188Crossref PubMed Scopus (691) Google Scholar Chronic kidney disease may be divided into 5 stages on the basis of glomerular filtration rate (GFR) and evidence of structural or functional renal abnormalities, such as persistent albuminuria or proteinuria.3National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar Stages 1 and 2 are characterized by evidence of kidney damage with normal or mildly reduced GFR, respectively, whereas stages 3 to 5 indicate progressively greater reductions in GFR below 60 mL/min per 1.73 m2 with or without known etiology of kidney damage. When both kidneys are involved, any GFR less than 60 mL/min per 1.73 m2 should be considered to be due to renal injury and therefore pathological. Rates of progression of CKD may differ; rarely, patients may even improve. In general, however, the condition of persons with CKD will deteriorate. The progressive course of CKD is a function of many factors, including the presence of concomitant disease, such as diabetes mellitus or proteinuric glomerular disease. Most patients with CKD have stage 1 to 3 disease; an estimated 7.6 million people have stage 3 disease.1Coresh J Astor BC Greene T Eknoyan G Levey AS Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey.Am J Kidney Dis. 2003; 41: 1-12Abstract Full Text Full Text PDF PubMed Scopus (2306) Google Scholar However, nearly 500,000 people in the United States are in the most advanced stage of CKD, also known as end-stage renal disease (ESRD), and require regular dialysis treatment.4US Renal Data System USRDS 2006 Annual data report, part 2: incidence and prevalence.Available at: www.usrds.org/adr_2006.htmGoogle Scholar Although the progressive course of CKD is well recognized, patients with CKD are likely to die of cardiovascular disease before they reach ESRD.5Sarnak MJ Levey AS Schoolwerth AC et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2881) Google Scholar In fact, CKD is an independent risk factor for cardiovascular disease, particularly in higher-risk populations.5Sarnak MJ Levey AS Schoolwerth AC et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2881) Google Scholar This point is illustrated in a post hoc analysis of pooled data from 4 major longitudinal, community-based studies: of 26,912 subjects, 4278 had preexisting cardiovascular disease.6Weiner DE Tighiouart H Stark PC et al.Kidney disease as a risk factor for recurrent cardiovascular disease and mortality.Am J Kidney Dis. 2004; 44: 198-206Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar After adjusting for potential confounders, the risk for the composite outcome of myocardial infarction (MI), fatal coronary artery disease (CAD), stroke, and all-cause mortality was significantly higher in persons with than without CKD (hazard ratio, 1.35; 95% confidence interval [CI], 1.21-1.52). Notably, the increased risk associated with CKD was comparable to the risk associated with diabetes mellitus, hypertension, or left ventricular hypertrophy, each of which is well documented as a cardiovascular risk factor. Similar findings were obtained in a post hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) study, which enrolled 9297 patients with vascular disease or diabetes mellitus.7Mann JFE Gerstein HC Pogue J Bosch J Yusuf S HOPE Investigators Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial.Ann Intern Med. 2001; 134: 629-636Crossref PubMed Scopus (1254) Google Scholar The subset of patients with mild renal dysfunction had nearly twice the risk of cardiovascular mortality and all-cause mortality (both P<.001) as those with normal renal function. On the basis of a large body of evidence from these and other studies, the American Heart Association recommends that patients with CKD be placed in the highest risk group for subsequent cardiovascular events. Current treatment recommendations should take into account the high-risk status of this group of patients.5Sarnak MJ Levey AS Schoolwerth AC et al.Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention.Circulation. 2003; 108: 2154-2169Crossref PubMed Scopus (2881) Google Scholar Many traditional and nontraditional cardiovascular risk factors are highly prevalent in CKD.8Parikh NI Hwang SJ Larson MG Meigs JB Levy D Fox CS Cardiovascular disease risk factors in chronic kidney disease: overall burden and rates of treatment and control.Arch Intern Med. 2006; 166: 1884-1891Crossref PubMed Scopus (176) Google Scholar In the Framingham Offspring Cohort, patients with CKD were significantly more likely to have low levels of high-density lipoprotein cholesterol (45% vs 29%; P<.001) and elevated triglycerides (40% vs 30%; P<.001) and tended to be more likely to have elevated low-density lipoprotein (LDL) cholesterol (61% vs 45%; P=.06) than those without CKD.8Parikh NI Hwang SJ Larson MG Meigs JB Levy D Fox CS Cardiovascular disease risk factors in chronic kidney disease: overall burden and rates of treatment and control.Arch Intern Med. 2006; 166: 1884-1891Crossref PubMed Scopus (176) Google Scholar In the Third National Health and Nutrition Examination Survey (NHANES III), participants with CKD (GFR <60 mL/min per 1.73 m2) had higher levels of apolipoprotein B and lower levels of apolipoprotein A than those with normal renal function (P=.003 and P=.021, respectively).9Muntner P Hamm LL Kusek JW Chen J Whelton PK He J The prevalence of nontraditional risk factors for coronary heart disease in patents with chronic kidney disease.Ann Intern Med. 2004; 140: 9-17Crossref PubMed Scopus (355) Google Scholar Dyslipidemia is not only highly prevalent in CKD, but it also increases the risk of renal dysfunction in otherwise healthy individuals. The Physicians' Health Study followed 4483 initially healthy men for a mean of 14.2 years.10Schaeffner ES Kurth T Curhan GC et al.Cholesterol and the risk of renal dysfunction in apparently healthy men.J Am Soc Nephrol. 2003; 14: 2084-2091PubMed Google Scholar After adjustment for potential confounding factors (cardiovascular risk factors and development of hypertension and cardiovascular disease), men in the highest quartile of total cholesterol/high-density lipoprotein cholesterol ratio had a 92% higher risk (95% CI, 22%-204%) of developing CKD than those in the lowest quartile. The role of dyslipidemia in promoting kidney damage has been shown in experimental models. Rats fed a diet rich in cholesterol and fat exhibited increased numbers of glomeruli with sclerotic foci vs those on a low-fat, cholesterol-free diet.11Grone HJ Walli A Grone E et al.Induction of glomerulosclerosis by dietary lipids: a functional and morphological study in the rat.Lab Invest. 1989; 60: 433-436PubMed Google Scholar When administered to rats with kidney disease caused by unilateral nephrectomy, the cholesterol- and fat-rich diet augmented the glomerular lesions in the remaining kidney.11Grone HJ Walli A Grone E et al.Induction of glomerulosclerosis by dietary lipids: a functional and morphological study in the rat.Lab Invest. 1989; 60: 433-436PubMed Google Scholar In rats fed a high-cholesterol diet, the severity of the hypercholesterolemia correlated with proteinuria (r=0.672) and was accompanied by increased numbers of glomeruli with lipid deposits.12Rayner HC Ross-Gilbertson VL Walls J The role of lipids in the pathogenesis of glomerulosclerosis in the rat following subtotal nephrectomy.Eur J Clin Invest. 1990; 20: 97-104Crossref PubMed Scopus (21) Google Scholar Lipid deposition can directly damage the glomerular basement membrane. It can also stimulate mesangial cell activation and proliferation, a process similar to smooth muscle cell proliferation in the evolution of atherosclerotic plaque13Kasiske BL O'Donnell MP Schmitz PG Kim Y Keane WF Renal injury of diet-induced hypercholesterolemia in rats.Kidney Int. 1990; 37: 880-891Crossref PubMed Scopus (277) Google Scholar, 14Agarwal R Curley TM The role of statins in chronic kidney disease.Am J Med Sci. 2005; 330: 69-81Crossref PubMed Scopus (24) Google Scholar (Figure 1). Mesangial cells then release chemokines that recruit monocytes to the mesangium, where they are transformed into resident macrophages that secrete proinflammatory and profibrotic mediators capable of augmenting the proliferative process.15Rovin BH Tan LC LDL stimulates mesangial fibronectin production and chemoattractant expression.Kidney Int. 1993; 43: 218-225Crossref PubMed Scopus (158) Google Scholar, 16Pai R Kirschenbaum MA Kamanna VS Low-density lipoprotein stimulates the expression of macrophage colony-stimulating factor in glomerular mesangial cells.Kidney Int. 1995; 48: 1254-1262Crossref PubMed Scopus (47) Google Scholar, 17Guijarro C Kasiske BL Kim Y O'Donnel MP Lee HS Keane WF Early glomerular changes in rats with dietary-induced hypercholesterolemia.Am J Kidney Dis. 1995; 26: 152-161Abstract Full Text PDF PubMed Scopus (90) Google Scholar The macrophages also ingest lipids to become foam cells, which are commonly detected at early stages of glomerulonephritis.18Magil AB Interstitial foam cells and oxidized lipoprotein in human glomerular disease.Mod Pathol. 1999; 12: 33-40PubMed Google Scholar Each of these cell types is capable of producing reactive oxygen species that oxidize LDL. Oxidized LDL, in turn, can cause further monocyte recruitment, endothelial dysfunction, and mesangial cell cytotoxicity.17Guijarro C Kasiske BL Kim Y O'Donnel MP Lee HS Keane WF Early glomerular changes in rats with dietary-induced hypercholesterolemia.Am J Kidney Dis. 1995; 26: 152-161Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 19Kamanna VS Pai R Roh DD Kirschenbaum MA Oxidative modification of low-density lipoprotein enhances the murine mesangial cell cytokines associated with monocyte migration, differentiation, and proliferation.Lab Invest. 1996; 74: 1067-1079PubMed Google Scholar, 20Tashiro K Makita Y Shike T et al.Detection of cell death of cultured mouse mesangial cells induced by oxidized low-density lipoprotein.Nephron. 1999; 82: 51-58Crossref PubMed Scopus (18) Google Scholar The endothelin system is also upregulated in hypercholesterolemia. Therefore, endothelin-A receptor blockade might protect the kidney from injury to the renal microvessels. In fact, in a porcine model, endothelin-A receptor blockade improved microvascular endothelial function in the hypercholesterolemic kidney as well as microvascular remodeling and function.21Chade AR Krier JD Textor SC Lerman A Lerman LO Endothelin-a receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia.J Am Soc Nephrol. 2006 Dec; 17 (Epub 2006 Nov 2.): 3394-3403Crossref PubMed Scopus (36) Google Scholar If dyslipidemia promotes renal injury, then reducing dyslipidemia should slow or prevent the progression of CKD. Indeed, experimental models show that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, decrease the severity of glomerular damage and preserve renal function.22O'Donnell MP Kasiske BL Katz SA Schmitz PG Keane WF Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats.Hypertension. 1992; 20: 651-658Crossref PubMed Scopus (104) Google Scholar, 23Rubin R Silbiger S Sablay L Neugarten J Combined antihypertensive and lipid-lowering therapy in experimental glomerulonephritis.Hypertension. 1994; 23: 92-95Crossref PubMed Scopus (22) Google Scholar, 24Vázquez-Pérez S Aragoncillo P de Las Heras N et al.Atorvastatin prevents glomerulosclerosis and renal endothelial dysfunction in hypercholesterolaemic rabbits.Nephrol Dial Transplant. 2001; 16: 40-44Crossref PubMed Scopus (49) Google Scholar For example, New Zealand rabbits fed a diet rich in cholesterol became hypercholesterolemic, with evidence of endothelial dysfunction in renal segmental arteries as well as glomerular hypertrophy and diffuse glomerulosclerosis.24Vázquez-Pérez S Aragoncillo P de Las Heras N et al.Atorvastatin prevents glomerulosclerosis and renal endothelial dysfunction in hypercholesterolaemic rabbits.Nephrol Dial Transplant. 2001; 16: 40-44Crossref PubMed Scopus (49) Google Scholar In this model, atorvastatin attenuated the increase in plasma cholesterol and prevented renal artery endothelial dysfunction, glomerular hypertrophy, and most of the glomerulosclerosis. Statins lower serum cholesterol levels and may therefore be expected to reduce lipid deposits in the kidney. Nevertheless, the exact mechanism by which statins protect against renal damage is unclear. Statins inhibit the rate-limiting enzyme (HMG-CoA reductase) in cholesterol synthesis, but inhibition of this enzyme also leads to downstream inhibition of the synthesis of the isoprenoids farnesyl pyrophosphate and geranyl pyrophosphate.25Epstein M Campese VM Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on renal function.Am J Kidney Dis. 2005; 45: 2-14Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 26Blanco-Colio LM Tuñón J Martín-Ventura JL Egido J Anti-inflammatory and immunomodulatory effects of statins.Kidney Int. 2003; 63: 12-23Crossref PubMed Scopus (274) Google Scholar These isoprenoids normally attach to intracellular signaling proteins to facilitate a variety of cellular responses, including gene expression, membrane trafficking, cell proliferation and migration, and programmed cell death. By blocking isoprenoid synthesis, statins produce an array of anti-inflammatory and vascular effects that are independent of cholesterol reduction. For example, stem cells govern numerous ischemic and degenerative disorders, and recent investigations have shown that statins may play a role in modulating stem cell functions.27Romagnani P Lasagni L Mazzinghi B Lazzeri E Romagnani S Pharmacological modulation of stem cell function.Curr Med Chem. 2007; 14: 1129-1139Crossref PubMed Scopus (43) Google Scholar Similarly, impaired endothelial progenitor cell function is characteristic of vascular injury, and statin therapy may improve the regenerative capacity of progenitor cells.28Walter DH Dimmeler S Zeiher AM Effects of statins on endothelium and endothelial progenitor cell recruitment.Semin Vasc Med. 2004; 4: 385-393Crossref PubMed Scopus (61) Google Scholar Levels of advanced glycation end products (the result of increasing oxidative stress) appear to increase as GFR decreases. In addition, renal insufficiency is associated with increased levels of inflammatory and procoagulant biomarkers, even in patients without cardiovascular disease.29Shlipak MG Fried LF Crump C et al.Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency.Circulation. 2003; 107: 87-92Crossref PubMed Scopus (665) Google Scholar Attenuation of the inflammatory response to renal injury is considered another possible explanation for the renoprotective actions of statin therapy. In an open-label trial in which 91 patients with CKD were randomly assigned to treatment with 10 mg/d of rosuvastatin or no lipid-lowering treatment for 20 weeks, a 47% reduction in median high-sensitivity C-reactive protein in treated patients was accompaniedby a statistically significant improvement in GFR.30Verma A Ranganna KM Reddy RS Verma M Cordon NF Effect of rosuvastatin on C-reactive protein and renal function in patients with chronic kidney disease.Am J Cardiol. 2005 Nov 1; 96 (Epub 2005 Sep 8.): 1290-1292Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar The efficacy of statin therapy in reducing major cardiovascular events and mortality has been established in a series of large long-term outcome studies that enrolled patients with or without evidence of cardiovascular disease and a wide range of baseline cholesterol levels.31Shepherd J Cobbe SM Ford I West of Scotland Coronary Prevention Study Group et al.Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.N Engl J Med. 1995; 333: 1301-1307Crossref PubMed Scopus (7473) Google Scholar, 32Sacks FM Pfeffer MA Moye LA Cholesterol and Recurrent Events Trial Investigators et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N Engl J Med. 1996; 335: 1001-1009Crossref PubMed Scopus (7197) Google Scholar, 33The Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.N Engl J Med. 1998; 339: 1349-1357Crossref PubMed Scopus (5572) Google Scholar, 34Heart 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: 7-22Abstract Full Text Full Text PDF PubMed Scopus (7649) Google Scholar, 35Koren MJ Hunninghake DB ALLIANCE Investigators Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study.J Am Coll Cardiol. 2004; 44: 1772-1779PubMed Google Scholar Patients with renal dysfunction were excluded from early statin trials, limiting the availability of data on the efficacy of statin therapy in these patients. However, some secondary-prevention studies have reported the impact of statin therapy on renal function as part of a secondary or post hoc analysis (Table 1).36Tonelli M Moyé L Sacks FM Cole T Curhan GC Cholesterol and Recurrent Events (CARE) 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: 1605-1613Crossref PubMed Scopus (296) Google Scholar, 37Athyros 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: 728-734Crossref PubMed Scopus (392) Google Scholar, 38Koren MJ Davidson MH ALLIANCE Investigators Impact of aggressive treatment with atorvastatin in renal function in managed care patients with coronary heart disease: the ALLIANCE study [abstract 1070-123].J Am Coll Cardiol. 2005; 45: 391APubMed Google Scholar, 39Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial.Lancet. 2003; 361: 2005-2016Abstract Full Text Full Text PDF PubMed Scopus (2601) Google Scholar, 40Tonelli M Isles C Curhan GC et al.Effect of pravastatin on cardiovascular events in people with chronic kidney disease.Circulation. 2004 Sep 21; 110 (Epub 2004 Sep 13.): 1557-1563Crossref PubMed Scopus (348) Google Scholar, 41Baigent 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: 473-484Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 42Holdaas H Fellstrom B Jardine AG Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (801) Google Scholar, 43Wanner C Krane V März W et al.German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.N Engl J Med. 2005; 353: 238-248Crossref PubMed Scopus (2208) Google Scholar, 44Asselbergs FW Diercks GF Hillege HL Prevention of Renal and Vascular Endstage Disease Intervention Trial Investigators et al.Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria.Circulation. 2004 Nov 2; 110 (Epub 2004 Oct 18.): 2809-2816Crossref PubMed Scopus (480) Google ScholarTABLE 1Overview of Renal Outcomes in Major Statin Trials*ALERT = Assessment of Lescol in Renal Transplantation; ALLIANCE = Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; CAD = coronary artery disease; CARE = Cholesterol and Recurrent Events; CHF = chronic heart failure; CKD = chronic kidney disease; CrCl = creatinine clearance; CV = cardiovascular; DM = diabetes mellitus; GFR = glomerular filtration rate; GREACE = GREek Atorvastatin and Coronary–heart-disease Evaluation; LDL-C = low-density lipoprotein cholesterol; LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease; MI = myocardial infarction; PCR = percutaneous coronary revascularization; PREVEND-IT = Prevention of Renal and Vascular Endstage Disease Intervention Trial; TC = total cholesterol; TG = triglyceride; UA = unstable angina; UK-HARP-I = First United Kingdom Heart and Renal Protection study; WOSCOPS = West of Scotland Coronary Prevention Study; 4D Study = Die Deutsche Diabetes Dialyse Studie.TrialPatient populationNo. of patientsStatin/dosePrimary outcomeResultsSecondary and post hoc analyses of renal outcomes in major statin trialsCARE36Tonelli M Moyé L Sacks FM Cole T Curhan GC Cholesterol and Recurrent Events (CARE) 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: 1605-1613Crossref PubMed Scopus (296) Google ScholarPatients with CAD and moderate CKD (GFR <60 mL/min/1.73 m2) to severe CKD (GFR <40 mL/min/1.73 m2) (TC <240 mg/dL)690Pravastatin (40 mg/d) vs placebo for ≥3 yRate of change in GFRStatin was significantly superior to placebo in slowing rate of decline of GFR (by 2.5 mL/min/1.73 m2 per year; P=.0001) in patients with severe CKD, but was not superior in patients with mild CKDGREACE37Athyros 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: 728-734Crossref PubMed Scopus (392) Google ScholarPreviously untreated dyslipidemic patients with CAD1600Dose-titrated atorvastatin (10-80 mg/d) vs usual care for 3 y (mean)All-cause and coronary mortality, coronary morbidity (nonfatal MI, revascularization, UA, and CHF), strokeCrCl increased by 12% in atorvastatin group (P<.0001) and by 4.9% in the usual care group that also took statins (P=.003), but declined by 5.3% (P=.0001) in usual care patients who did not take statinsALLIANCE 38Koren MJ Davidson MH ALLIANCE Investigators Impact of aggressive treatment with atorvastatin in renal function in managed care patients with coronary heart disease: the ALLIANCE study [abstract 1070-123].J Am Coll Cardiol. 2005; 45: 391APubMed Google ScholarDyslipidemic patients with CAD and CrCl of 88.6 mL/min and 87.2 mL/min at baseline for participants receiving atorvastatin therapy and usual care, respectively2442Atorvastatin (titrated to 80 mg/d) vs usual care for 4 yDeterioration in renal function in CAD patientsMean decline of 4.4% in the usual care group (P=.0001 vs baseline). CrCl did not change in the atorvastatin group vs baseline. Highly significant difference between the statin and usual care groups in mean change from baseline (P=.0001)Heart Protection Study39Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial.Lancet. 2003; 361: 2005-2016Abstract Full Text Full Text PDF PubMed Scopus (2601) Google ScholarPatients ≤80 y with occlusive arterial disease or DM5963Simvastatin (40 mg/d) vs placebo for 4-8 y (mean)Major coronary event, stroke, or revascularizationSmaller increase in plasma creatinine and smaller reduction in estimated GFR with statin therapy vs placebo (P<.0001 and P=.0003, respectively)Pravastatin Pooling Project (WOSCOPS, CARE, LIPID)40Tonelli M Isles C Curhan GC et al.Effect of pravastatin on cardiovascular events in people with chronic kidney disease.Circulation. 2004 Sep 21; 110 (Epub 2004 Sep 13.): 1557-1563Crossref PubMed Scopus (348) Google ScholarPatients with and without CAD and with moderate CKD (GFR, 30-60 mL/min/1.73 m2)4491†Of whom 3310 (74%) had CAD.PravastatinTime to MI, coronary death, or PCRSignificant reduction in primary outcome in statin-treated patients with moderate CKD (hazard ratio, 0.77; 95% confidence interval, 0.68-0.86); reduction in total mortality in treated patients. Benefit seen in patients with and without CADStudies conducted in patients with kidney diseaseUK-HARP-I 41Baigent 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: 473-484Abstract Full Text Full Text PDF PubMed Scopus (172) Google ScholarPredialysis (n=242), dialysis (n=73), and renal transplant (n=133) patients448Simvastatin (20 mg/d) vs placebo + aspirin vs placebo (2 × 2 factorial design) for 1 yEfficacy and safetyStatin treatment lowered LDL-C by approximately 24%; no evidence of toxicityALERT42Holdaas H Fellstrom B Jardine AG Assessment of LEscol in Renal Transplantation (ALERT) Study Investigators et al.Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomized, placebo-controlled trial.Lancet. 2003; 361: 2024-2031Abstract Full Text Full Text PDF PubMed Scopus (801) Google ScholarRenal transplant patients, with and without CAD (TC, 154-346 mg/dL)2102Fluvastatin vs placebo for 5.1 y (mean)Cardiac death, nonfatal MI, or coronary interventionNo significant risk reduction in statin-treated patients4D Study43Wanner C Krane V März

Referência(s)