The Homocysteine Paradox in Diabetic Nephropathy: A Comprehensive Meta-Analysis Reveals Strong Biomarker Association but No Therapeutic Benefit from B-Vitamin Supplementation

Background The role of homocysteine (Hcy) in diabetic nephropathy (DN) remains paradoxical: while epidemiological studies consistently associate hyperhomocysteinemia with DN risk, interventional trials with B-vitamins have yielded conflicting results. This meta-analysis comprehensively integrates observational and interventional evidence to resolve this discrepancy and clarify the clinical utility of Hcy monitoring and B-vitamin therapy in DN. Methods We systematically searched PubMed, Scopus, and Web of Science through May 2024 for studies comparing Hcy, folate, and vitamin B12 levels between DN patients and diabetic controls, and randomized controlled trials (RCTs) evaluating B-vitamin supplementation. Random-effects models were used for meta-analysis, with subgroup analyses to explore heterogeneity. Results Across 45 studies (29 observational, 16 interventional), DN patients exhibited significantly higher Hcy levels (+ 2.81 µmol/L; 95% CI: 1.95–3.66) and lower folate levels (-2.09 nmol/L; 95% CI: -3.80 to -0.38) compared to diabetic controls without nephropathy. A clear dose-response relationship emerged: Hcy levels increased progressively from normoalbuminuria to microalbuminuria (+ 1.32 µmol/L) to macroalbuminuria (+ 3.58 µmol/L). Elevated Hcy was associated with 22% increased odds of DN (OR: 1.22; 95% CI: 1.13–1.32). Crucially, while B-vitamin supplementation effectively reduced Hcy levels (-3.35 µmol/L with folic acid), it conferred no renal benefit—showing no significant effects on eGFR (-1.91 mL/min/1.73m²) or creatinine levels. Conclusion This study establishes Hcy as a robust biomarker of DN severity but demonstrates that B-vitamin supplementation, despite effectively lowering Hcy, does not improve renal outcomes. These findings resolve the Hcy paradox in DN, suggesting that hyperhomocysteinemia may be a consequence rather than cause of renal impairment, and argue against routine B-vitamin supplementation for renal protection in DN patients. Further research is needed to explore potential benefits in specific patient subgroups. Systematic review registration: PROSPERO, CRD420251069868