A Meta-Analysis of the Effects of Homocysteine-Lowering Therapy on Chronic Kidney Disease

Abstract Hyperhomocysteinemia is common in chronic kidney disease; however, whether homocysteine-lowering therapy slows chronic kidney disease progression remains uncertain. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guideline, we systematically searched PubMed and Web of Science (inception to January 2025) for randomized controlled trials evaluating folic acid alone or combined with vitamin B versus placebo/usual care/low-dose regimens in populations across the chronic kidney disease spectrum. The primary end point was composite kidney outcomes (all-cause mortality, cardiovascular events, and kidney disease progression). Relative risks with 95% confidence intervals were pooled using fixed- or random-effect models according to heterogeneity. Nine trials comprising 23,638 participants met inclusion criteria. Overall heterogeneity for the primary outcome was low (I²=27%), and homocysteine-lowering therapy was associated with a marginal reduction in composite kidney outcomes (relative risk=0.96 and 95% confidence interval=0.92–1.00; p = 0.04). Subgroup analyses suggested a greater benefit in participants with normal to moderate chronic kidney disease (relative risk=0.89 and 95% confidence interval=0.81–0.97; p=0.008) and in non-White populations (relative risk=0.89 and 95% confidence interval=0.81–0.97; p=0.008). No significant effects were observed for cardiovascular events (relative risk=0.94 and 95% confidence interval=0.84–1.06) or all-cause mortality (relative risk=0.99 and 95% confidence interval 0.87–1.11). In conclusion, homocysteine-lowering therapy yields, at most, a small reduction in composite kidney outcomes with limited clinical significance and provides no detectable benefits for cardiovascular events or mortality.