Pharmacologic B-vitamin therapy for hyperhomocysteinemia in dialysis patients: has the time come?

Hyperhomocysteinemia, the state of elevated plasma homocysteine levels, is an independent risk factor for atherothrombosis and arteriosclerosis. For incompletely understood reasons, renal disease appears to predispose to hyperhomocysteinemia. In fact, as renal function declines, plasma homocysteine levels rise. Mild to moderate hyperhomocysteinemia is almost universal among end-stage renal disease (ESRD) patients, who have negligible functioning renal mass. This tendency towards a hyperhomocysteinemic state may partially explain the dramatically high rate of cardiovascular morbidity and death seen in this population. Hyperhomocysteinemic subjects with normal kidney function can usually reduce or normalize homocysteine levels with modest B-vitamin (folic acid, vitamin B6, vitamin B12) supplementation. However, subjects with reduced renal function require much higher ("pharmacologic") B-vitamin doses to achieve equivalent reductions, while ESRD subjects are resistant to even massive doses. Study design flaws and the inclusion of potentially B-vitamin-deficient subjects in homocysteine-lowering trials has made interpretation of this literature difficult. Nonetheless, it appears that the modest standard daily dialysis vitamin supplements are equivalent to pharmacologic B-vitamin therapy in lowering homocysteine levels in ESRD patients and should be the recommended method of treatment in this population at the present time.