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(Circulation. 2000;101:2829.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Controlled Comparison of L-5-Methyltetrahydrofolate Versus Folic Acid for the Treatment of Hyperhomocysteinemia in Hemodialysis Patients

Andrew G. Bostom, MD, MS; Douglas Shemin, MD; Pamela Bagley, PhD; Ziad A. Massy, MD; Abdul Zanabli, MD; Kenneth Christopher, MD; Paul Spiegel, MD; Paul F. Jacques, ScD; Lance Dworkin, MD; Jacob Selhub, PhD

From the Division of General Internal Medicine, Memorial Hospital of Rhode Island, Pawtucket (A.G.B.); the Division of Renal Diseases, Rhode Island Hospital, Providence (A.G.B., D.S., A.Z., K.C., P.S., L.D.); the Vitamin Bioavailability Laboratory, Jean Mayer Human Nutrition Research Center, Boston, Mass (A.G.B., P.B., P.F.J., J.S.); and the Division of Nephrology, INSERM U507, Necker Hospital, Paris, France (Z.A.M.).

Correspondence to Andrew G. Bostom, MD, MS, Division of General Internal Medicine, Memorial Hospital of Rhode Island, 111 Brewster St, Pawtucket, RI 02860. E-mail abostom{at}loa.com

Background—The hyperhomocysteinemia regularly found in hemodialysis patients is largely refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid. We evaluated whether a high-dose L-5-methyltetrahydrofolate–based regimen provided improved total homocysteine (tHcy)–lowering efficacy in chronic hemodialysis patients.

Methods and Results—We block-randomized 50 chronic, stable hemodialysis patients on the basis of their screening predialysis tHcy levels, sex, and dialysis center into 2 groups of 25 subjects treated for 12 weeks with oral folic acid at 15 mg/d (FA group) or an equimolar amount (17 mg/d) of oral L-5-methyltetrahydrofolate (MTHF group). All 50 subjects also received 50 mg/d of oral vitamin B₆ and 1.0 mg/d of oral vitamin B₁₂. The mean percent reductions (±95% CIs) in predialysis tHcy were not significantly different: MTHF, 17.0% (12.0% to 22.0%); FA, 14.8% (9.6% to 20.1%); P=0.444 by matched ANCOVA adjusted for pretreatment tHcy. Final on-treatment values (mean with 95% CI) were MTHF, 20.0 µmol/L (18.8 to 21.2 µmol/L); FA, 19.5 µmol/L (18.3 to 20.7 µmol/L). Moreover, neither treatment resulted in "normalization" of tHcy levels (ie, final on-treatment values <12 µmol/L) among a significantly different or clinically meaningful number of patients: MTHF, 2 of 25 (8%); FA, 0 of 25 (0%); Fisher’s exact test of between-groups difference, P=0.490.

Conclusions—Relative to high-dose folic acid, high-dose oral L-5-methyltetrahydrofolate–based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients. The preponderance of hemodialysis patients (ie, >90%) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen. This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution.

Key Words: homocysteine • kidney • trials

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