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Effect of High Dose Folic Acid Therapy on Hyperhomocysteinemia in Hemodialysis Patients

Results of the Vienna Multicenter Study

GERE SUNDER-PLASSMANN^*, MANUELA FÖDINGER, HEIDI BUCHMAYER, MENELAOS PAPAGIANNOPOULOS, JADWIGA WOJCIK, JOSEF KLETZMAYR^*, BRIGITTE ENZENBERGER, OSKAR JANATA^§, WOLFGANG C. WINKELMAYER^||, GERNOT PAUL^§, MARTIN AUINGER, URSULA BARNAS^§ and WALTER H. HÖRL^*

^* Klinische Abteilung für Nephrologie und Dialyse, Universitätsklinik für Innere Medizin III, Vienna, Austria
Klinisches Institut für Medizinische und Chemische Labordiagnostik, University of Vienna, Vienna, Austria
3. Medizinische Abteilung, Krankenhaus Lainz, Vienna, Austria
^§ 1. Medizinische Abteilung, Donauspital, Vienna, Austria
^|| 1. Medizinische Abteilung, Kaiser Franz Josef Spital, Vienna, Austria.

Correspondence to Dr. Gere Sunder-Plassmann, Klinische Abteilung für Nephrologie und Dialyse, Universitätsklinik für Innere Medizin III, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: +43 1 40400 4391; Fax: +43 1 40400 4392; E-mail: Gere.Sunder-Plassmann{at}akh-wien.ac.at

Abstract. Homocysteine is associated with atherosclerosis and enhanced cardiovascular risk. In previous studies, treatment with folic acid up to 15 mg/d failed to correct hyperhomocysteinemia in the majority of end-stage renal disease patients. A dose of 30 or 60 mg of folic acid per day was compared with 15 mg/d in an attempt to normalize hyperhomocysteinemia in 150 hemodialysis patients. In a randomized, double-blind, multicenter study, 144 patients completed the 4-wk treatment period and 121 patients completed the 6-mo follow-up. Total homocysteine plasma levels were reduced by 32.1% (15 mg/d), 29.9% (30 mg/d), or 37.8% (60 mg/d) with no significant differences found between the three treatment groups. Baseline total homocysteine plasma concentration was an independent predictor of the response to folic acid therapy (P = 0.0001), whereas the 5,10-methylenetetrahydrofolate reductase polymorphisms (MTHFR 677C T and 1298A C) had no influence. Nevertheless, patients with the MTHFR 677TT genotype more frequently attained normal total homocysteine plasma levels than patients with the CC or CT genotype (P = 0.025). In response to 60 mg of folic acid per day, TT genotype patients had lower folate plasma levels compared to CC or CT genotype patients (P = 0.016). After completion of the 4-wk treatment period with 30 or 60 mg of folic acid per day, there was a marked rebound of total homocysteine plasma levels at the end of the follow-up in patients with the MTHFR 677TT genotype, which even exceeded baseline values in several patients (P = 0.0001). This study clearly demonstrates that doses of 30 or 60 mg of folic acid per day are not more effective than 15 mg/d in reducing hyperhomocysteinemia in regular hemodialysis patients. Patients with the MTHFR 677TT genotype are more likely to realize normal total homocysteine plasma levels. Folic acid at 30 or 60 mg/d but not 15 mg/d results in a rebound of total homocysteine plasma concentrations when treatment is stopped.

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