Ascorbic acid as an adjunct therapy for anemia in erythropoietin-treated hemodialysis patients: a systematic review and meta-analysis

ABSTRACT Background Anemia is a common complication in chronic kidney disease (CKD), especially in hemodialysis patients, causing fatigue and reduced quality of life. Standard treatments involve iron and erythropoietin (EPO). Ascorbic acid (vitamin C) supports iron metabolism by converting ferric to ferrous iron and enhancing absorption and mobilization. This systematic review and meta-analysis evaluated the effectiveness of ascorbic acid in improving hematologic and iron parameters in adult anemic patients undergoing maintenance hemodialysis. Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was performed in PubMed, EMBASE, Cochrane, Scopus, Web of Science, CINAHL and Google Scholar through May 2025. Only randomized controlled trials and crossover studies assessing ascorbic acid in adult anemic hemodialysis patients were included. The protocol was registered in the International Prospective Register of Systematic Review (PROSPERO) (CRD420251056337). Primary outcomes were hemoglobin (Hb), ferritin, serum iron, transferrin saturation (TSAT) and total iron-binding capacity (TIBC). Meta-analyses used DerSimonian-Laird random-effects models. Results Of 479 screened articles, 14 studies were included. Ascorbic acid supplementation was associated with a modest but significant increase in Hb [mean difference (MD) 0.94 g/dL; 95% confidence interval (CI) 0.57 to 1.31; P < .01; I² = 87.2%] and TSAT (MD 6.86%; 95% CI 1.93 to 11.78; P < .01; I² = 96.7%). Ferritin levels showed a slight but significant reduction (MD −65.00 ng/mL; 95% CI −117.20 to −12.80; P = .01; I² = 57.2%), along with a decrease in TIBC (MD −22.54 µg/dL; 95% CI −42.37 to −2.72; P = .03; I² = 76.1%). EPO requirements expressed as units/kg/week were significantly reduced (MD −21.29; 95% CI −27.73 to −14.84; P < .01; I² = 0.0%). No significant changes were observed in serum iron levels or EPO dosage expressed as IU/week. Conclusion Ascorbic acid supplementation may confer modest hematologic benefits in hemodialysis patients with improvements in Hb, TSAT and iron utilization, and a small reduction in weight-adjusted erythropoiesis-stimulating agent dose. However, the certainty of evidence is low, and long-term safety and patient-centered outcomes remain unestablished.