• Min Jun, Vinod Venkataraman, Mona Razavian, Bruce Cooper, Sophia Zoungas, Toshiharu Ninomiya, Angela C Webster, and Vlado Perkovic.
• Renal and Metabolic Division, The George Institute for Global Health, Camperdown, Australia.
• Cochrane Db Syst Rev. 2012 Oct 17; 10 (10): CD008176CD008176.

BackgroundChronic kidney disease (CKD) is a significant risk factor for premature cardiovascular disease and death. Increased oxidative stress in people with CKD has been implicated as a potential causative factor for some cardiovascular diseases. Antioxidant therapy may reduce cardiovascular mortality and morbidity in people with CKD.ObjectivesTo examine the benefits and harms of antioxidant therapy on mortality and cardiovascular events in people with CKD stages 3 to 5; dialysis, and kidney transplantation patients.Search MethodsWe searched the Cochrane Renal Group's specialised register (July 2011), CENTRAL (Issue 6, 2011), MEDLINE (from 1966) and EMBASE (from 1980).Selection CriteriaWe included all randomised controlled trials (RCTs) investigating the use of antioxidants for people with CKD, or subsets of RCTs reporting outcomes for participants with CKD.Data Collection And AnalysisTitles and abstracts were screened independently by two authors who also performed data extraction using standardised forms. Results were pooled using the random effects model and expressed as either risk ratios (RR) or mean difference (MD) with 95% confidence intervals (CI).Main ResultsWe identified 10 studies (1979 participants) that assessed antioxidant therapy in haemodialysis patients (two studies); kidney transplant recipients (four studies); dialysis and non-dialysis CKD patients (one study); and patients requiring surgery (one study). Two additional studies reported the effect of an oral antioxidant inflammation modulator in patients with CKD (estimated glomerular filtration rate (eGFR) 20 to 45 mL/min/1.73 m²), and post-hoc findings from a subgroup of people with mild-to-moderate renal insufficiency (serum creatinine ≥125 μmol/L) respectively. Interventions included different doses of vitamin E (two studies); multiple antioxidant therapy (three studies); co-enzyme Q (one study); acetylcysteine (one study); bardoxolone methyl (one study); and human recombinant superoxide dismutase (two studies).Compared with placebo, antioxidant therapy showed no clear overall effect on cardiovascular mortality (RR 0.95, 95% CI 0.70 to 1.27; P = 0.71); all-cause mortality (RR 0.93, 95% CI 0.76 to 1.14; P = 0.48); cardiovascular disease (RR 0.78, 95% CI 0.52 to 1.18; P = 0.24); coronary heart disease (RR 0.71, 95% CI 0.42 to 1.23; P = 0.22); cerebrovascular disease (RR 0.91, 95% CI 0.63 to 1.32; P = 0.63); or peripheral vascular disease (RR 0.54, 95% CI 0.26 to 1.12; P = 0.10). Subgroup analyses found no evidence of significant heterogeneity based on proportions of males (P = 0.99) or diabetes (P = 0.87) for cardiovascular disease. There was significant heterogeneity for cardiovascular disease when studies were analysed by CKD stage (P = 0.003). Significant benefit was conferred by antioxidant therapy for cardiovascular disease prevention in dialysis patients (RR 0.57, 95% CI 0.41 to 0.80; P = 0.001), although no effect was observed in CKD patients (RR 1.06, 95% CI 0.84 to 1.32; P = 0.63).Antioxidant therapy was found to significantly reduce development of end-stage of kidney disease (ESKD) (RR 0.50, 95% CI 0.25 to 1.00; P = 0.05); lowered serum creatinine levels (MD 1.10 mg/dL, 95% CI 0.39 to 1.81; P = 0.003); and improved creatinine clearance (MD 14.53 mL/min, 95% CI 1.20 to 27.86; P = 0.03). Serious adverse events were not significantly increased by antioxidants (RR 2.26, 95% CI 0.74 to 6.95; P = 0.15).Risk of bias was assessed for all studies. Studies that were classified as unclear for random sequence generation or allocation concealment reported significant benefits from antioxidant therapy (RR 0.57, 95% CI 0.41 to 0.80; P = 0.001) compared with studies at low risk of bias (RR 1.06, 95% CI 0.84 to 1.32; P = 0.63).Authors' ConclusionsAlthough antioxidant therapy does not reduce the risk of cardiovascular and all-cause death or major cardiovascular events in people with CKD, it is possible that some benefit may be present, particularly in those on dialysis. However, the small size and generally suboptimal quality of the included studies highlighted the need for sufficiently powered studies to confirm this possibility. Current evidence suggests that antioxidant therapy in predialysis CKD patients may prevent progression to ESKD; this finding was however based on a very small number of events. Further studies with longer follow-up are needed for confirmation. Appropriately powered studies are needed to reliably assess the effects of antioxidant therapy in people with CKD.

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