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Meta-Analysis
. 2012 Oct 17;10(10):CD008176.
doi: 10.1002/14651858.CD008176.pub2.

Antioxidants for chronic kidney disease

Min Jun  1 , Vinod Venkataraman, Mona Razavian, Bruce Cooper, Sophia Zoungas, Toshiharu Ninomiya, Angela C Webster, Vlado Perkovic
Affiliations
Meta-Analysis

Antioxidants for chronic kidney disease

Min Jun et al. Cochrane Database Syst Rev. .

Update in

  • Antioxidants for adults with chronic kidney disease.
    Colombijn JM, Hooft L, Jun M, Webster AC, Bots ML, Verhaar MC, Vernooij RW. Colombijn JM, et al. Cochrane Database Syst Rev. 2023 Nov 2;11(11):CD008176. doi: 10.1002/14651858.CD008176.pub3. Cochrane Database Syst Rev. 2023. PMID: 37916745 Free PMC article.

Abstract

Background: Chronic 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.

Objectives: To 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 methods: We searched the Cochrane Renal Group's specialised register (July 2011), CENTRAL (Issue 6, 2011), MEDLINE (from 1966) and EMBASE (from 1980).

Selection criteria: We 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 analysis: Titles 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 results: We 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' conclusions: Although 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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Conflict of interest statement

  1. Min Jun: none known

  2. Vinod Venkataraman: none known

  3. Mona Razavian: none known

  4. Bruce Cooper: none known

  5. Sophia Zoungas has previously received speaker honoria from Servier, MSD, Novartis, Novo Nordisk, Sanofi Aventis, Boehringer Ingelheim, GSK, Pfizer, and Astra Zeneca/BMS and has previously served on external advisory boards for MSD, Novo Nordisk, Boehringer Ingleheim, Sanofi Aventis and Astra Zeneca/BMS.

  6. Toshiharu Ninomiya: none known

  7. Angela C Webster: none known

  8. Vlado Perkovic is supported by a fellowship from the Heart Foundation of Australia and a various grants from the Australian National Health and Medical Research Council. He has received speakers fees from Roche, Servier and Astra Zeneca, funding for a clinical trial from Baxter, and serves on Steering Committees for trials funded by Johnson and Johnson, Boehringer Ingelheim, Vitae and Abbott. His employer conducts clinical trials funded by Servier, Johnson and Johnson, Roche and Merck.

Figures

1
1
Flowchart indicating the process of study identification and selection for this review
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 1 Cardiovascular mortality.
1.2
1.2. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 2 All‐cause mortality.
1.3
1.3. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 3 Cardiovascular disease.
1.4
1.4. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 4 Coronary heart disease.
1.5
1.5. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 5 Cerebrovascular disease.
1.6
1.6. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 6 Peripheral vascular disease.
1.7
1.7. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 7 Serum creatinine.
1.8
1.8. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 8 Mean change in GFR.
1.9
1.9. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 9 ESKD.
1.10
1.10. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 10 Adverse events.
1.11
1.11. Analysis
Comparison 1 Antioxidants versus placebo/standard therapy, Outcome 11 Cancer.
2.1
2.1. Analysis
Comparison 2 Subgroup analysis: Gender and outcomes, Outcome 1 Cardiovascular disease by gender.
2.2
2.2. Analysis
Comparison 2 Subgroup analysis: Gender and outcomes, Outcome 2 Cardiovascular death by gender.
2.3
2.3. Analysis
Comparison 2 Subgroup analysis: Gender and outcomes, Outcome 3 All‐cause mortality by gender.
3.1
3.1. Analysis
Comparison 3 Subgroup analysis: Clinical outcomes by diabetes, Outcome 1 Cardiovascular disease by diabetes.
3.2
3.2. Analysis
Comparison 3 Subgroup analysis: Clinical outcomes by diabetes, Outcome 2 Cardiovascular death by diabetes.
4.1
4.1. Analysis
Comparison 4 Subgroup analysis: Clinical outcomes by CKD stage, Outcome 1 Cardiovascular disease by CKD stage.
4.2
4.2. Analysis
Comparison 4 Subgroup analysis: Clinical outcomes by CKD stage, Outcome 2 Cardiovascular death by CKD stage.
4.3
4.3. Analysis
Comparison 4 Subgroup analysis: Clinical outcomes by CKD stage, Outcome 3 Mortality by CKD stage.
4.4
4.4. Analysis
Comparison 4 Subgroup analysis: Clinical outcomes by CKD stage, Outcome 4 Cerebrovascular events by CKD stage.
4.5
4.5. Analysis
Comparison 4 Subgroup analysis: Clinical outcomes by CKD stage, Outcome 5 Coronary disease by CKD stage.
5.1
5.1. Analysis
Comparison 5 Cardiovascular disease by CKD stage by stage, Outcome 1 CVD by CKD.
See this image and copyright information in PMC

References

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References to other published versions of this review

Perkovic 2009
    1. Perkovic V, Venkataraman V, Cooper B, Zoungas S, Webster AC. Antioxidants for chronic kidney disease. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD008176] - DOI - PMC - PubMed

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