Treatment of hyperhomocysteinemia in hemodialysis patients and renal transplant recipients

Background. Hyperhomocysteinemia, a putative atherothrombotic risk factor, is observed in at least 85% of patients undergoing maintenance hemodialysis (HD). as well as 65 to 70% of renal transplant recipients (RTRs). The hype rhomocysteinemia regularly found in HD patients is largely refractory to co mbined oral vitamin B supplementation featuring supraphysiological doses of folic acid (FA). Relative to their HD counterparts. the hyperhomocysteinem ia of RTRs appears to be considerably less refractory to treatment with hig h-dose FA-based vitamin B supplementation regimens, although controlled com parison data are lacking. We evaluated whether improved total homocysteine (tHcy)-lowering efficacy could be achieved in chronic HD patients with a hi gh-dose L-5-methyltetrahydrofolate (MTHF)-based regimen, as suggested by re cent uncontrolled findings, and compared the relative responsiveness of RT Rs and HD patients with equivalent baseline tHcy levels, to 12 weeks of tHc y lowering with combined fulate-based vitamin B treatment. Methods. First, we blocked randomized 50 chronic, stable HD patients based on their screening predialysis tHcy levels, sex, and dialysis center into t wo groups of 25 subjects treated for 12 weeks with oral FA at 15 mg/day, or an equimolar amount (17 mg/day) of oral MTHF. All 50 subjects also receive d 50 mg/day of oral vitamin B-o and 1.0 mg/day of oral vitamin B-12. Results. The mean percentage (%) reductions(+/- 95% confidence intervals) i n 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 analysis of covariance adjusted for pretreatment tHcy]. Final on-treatment values (mean with 95% confidence interval) were. MTHF, 20.0 mu mol/L (18.8 to 21.2); and FA, 19.5 mu mol/L (18.3 to 20.7). Moreover, neither treatment resulted in "normaliz ation" of tHcy levels (that is, final on-treatment values <12 <mu>mol/L) am ong a significantly different or clinically meaningful number of patients [ MTHF, 2 out of 25 (8%); FA, 0 out of 25 (0%); Fisher's exact lest of betwee n groups difference, P = 0.490]. Second, we compared the relative responsiv eness of (N = 10) RTRs and (N = 39) HD patients with equivalent baseline tH cy levels (RTR range of 14.2 to 23.6 mu mol/L, and HD range of 14.4 to 24.9 mu mol/L) to 12 weeks of tHcy-lowering treatment. The RTRs received 2.4 mg /day of FA, 50.0 mg/day of vitamin B-o, and 0.4 mg/day of vitamin B-12 whil e the HD patients received 15 mg/day of FA or an equimolar amount (17 mg/da y) of the reduced folate, MTHF, in addition to 50.0 mg/day of vitamin B-o a nd 1.0 mg/day of vitamin B-12. The mean percentage (%) reductions (+/- 95% confidence interval) in tHcy were as follows: RTR 28.1% (16.2 to 40.0%); F- ID 12.1% (6.6 to 17.7%, P = 0.027 for comparison of between groups differen ces by analysis of covariance adjusted for baseline tHcy levels). Moreover, 5 out of 18 (50.0%) of the RTR versus only 2 out of 39 (5.1%) of the HD pa tients had final on-treatment tHcy levels <12 <mu>mol/L (P = 0.002 for comp arison of between groups differences by Fisher's exact test). Conclusions. First, in comparison to high-dose FA, high-dose oral MTHF-base d supplementation does not afford improved tHcy-lowering efficacy among HD patients. The preponderance of HD patients (that is, >90%) exhibits mild hy perhomocysteinemia refractory to treatment with either regimen. This treatm ent refractoriness is not related to defects in folate absorption or circul ating plasma and tissue distribution. Secund, relative to RTR with comparab le baseline tHcy levels, the mild hyperhomocysteinemia of maintenance HD pa tients is much more refractory to tHcy-lowering vitamin B treatment regimen s featuring supraphysiological amounts of FA or the reduced folate MTHF. Ac cordingly, RTRs are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering vitamin B intervention may reduce arteriosclerotic cardiovascular disease event rates in patients wit h chronic renal disease.