Randomized Controlled Trial of the Effect of Short-term Coadministration of Methylcobalamin and Folate on Serum ADMA Concentration in Patients Receiving Long-term Hemodialysis

Background: Serum asymmetric dimethylarginine (ADMA) levels are increased in maintenance hemodialysis patients, and this abnormality may increase cardiovascular risk. We investigated whether combined administration of oral folate and intravenous methylcobalamin in such patients is more beneficial than oral folate alone at decreasing circulating ADMA levels. Study Design: Randomized controlled trial. Setting & Participants: Patients undergoing hemodialysis. Intervention: 40 patients were randomly assigned to 1 of 2 groups. For 3 weeks, they received supplementation with either folate alone (15 mg/d; n = 20; folate group) or coadministered folate (15 mg/d) and methylcobalamin (500 mu g after each hemodialysis treatment 3 times weekly; n = 20; methylcobalamin group). Outcomes: Primary outcomes: normalization of plasma homocysteine levels (<15 mu mol/L), decrease in serum ADMA levels. Secondary outcomes: change in augmentation index in the carotid artery and ratios of S-adenosylmethionine to S-adenosylhomocysteine (as a transmethylation indicator) and dimethylamine to ADMA (as an indicator of ADMA hydrolysis). Measurements: Blood samples were collected under fasting conditions during the prehemodialysis procedure. Results: The proportion showing normalization of plasma homocysteine levels was much greater in the methylcobalamin group (18 of 20 patients; 90%) than in the folate group (6 of 20; 30%; P < 0.001). The percentage of decrease in ADMA levels was greater in the methylcobalamin than folate group (25.4% +/- 10.2% vs 13.2% +/- 11.2%; P < 0.001). The increase in ratio of S-adenosylmethionine to S-adenosylhomocysteine was not different between the 2 groups; however, the ratio of dimethylamine to ADMA was increased in only the methylcobalamin group (P = 0.04). Augmentation index was decreased in only the methylcobalamin group (P = 0.03). Limitations: This study had an open-label nature and did not examine long-term effects of homocysteine-normalizing therapy (no clinical end points). Conclusion: Coadministration of intravenous methylcobalamin and oral folate in hemodialysis patients normalized hyperhomocysteinemia and decreased ADMA levels and arterial stiffness. We suggest that this regimen may have greater potential than folate alone to decrease cardiovascular risk in such patients. Am J Kidney Dis 55: 1069-1078. (C) 2010 by the National Kidney Foundation, Inc.