Erythropoietin, folic acid deficiency and hyperhomocysteinemia: is there apossible relationship in chronically hemodialyzed patients?

Aims: To examine the possible relationships between recombinant human eryth ropoietin (rhEPO) therapy, serum folic acid and homocysteine levels in a co hort of stable, chronically hemodialyzed patients. Material and methods: Th e study was cross-sectional in its first phase and consisted of 3 groups of subjects (group 1: 6 healthy controls; group 2: 7 dialyzed patients not re ceiving rhEPO; group 3: 14 patients on rhEPO therapy). Hematological and bi ochemical parameters were taken after an overnight fast in all subjects. Th e second phase of the study was prospective, and included 8 dialyzed patien ts, and investigated the effects of a 6-month period of folic acid suppleme ntation (10 mg, 3 times a week) on the same parameters examined in the firs t phase of the study. Results: In the first part of the study hemoglobin le vels were near-normal, or normal, in all patients. No differences in hemogl obin or hematocrit values were observed in the 3 groups. 80% of all hemodia lyzed patients had low serum folic acid levels, irrespective of whether the y were receiving rhEPO. Serum erythropoietin level was elevated in group 3 (23.3 +/- 10.4 mIU/ml). In group 2, serum erythropoietin level was not diff erent from that of the healthy controls (13.5 +/- 11.2 vs. 8.0 +/- 5.4 mIU/ ml, p = n.s.). Total serum homocysteine levels were elevated in all dialyze d patients (group 2: 24.7 +/- 9.2 mu mol/l; group 3: 31.6 +/- 14.4 mu mol/l ), with a significant difference seen when comparing controls and those dia lyzed patients on rhEPO therapy (8.7 +/- 2.2 vs. 31.6 +/- 14.4 mu mol/l; p < 0.05). Significant correlations (ANOVA) were observed between serum eryth ropoietin and folic acid levels (r = -0.382; p = 0.049), and between folic acid and homocysteine levels (r = -0.560; p = 0.002). In the second part of the study folic acid supplementation led to a highly significant reduction in homocysteine levels (20.9+/-4.9 vs. 11.9 +/- 2.5 mu mol/l; p < 0.0005). Two of 3 patients receiving rhEPO therapy, had rhEPO discontinued after co mmencing folic acid, as hemoglobin levels remained adequate, even without r hEPO. Conclusions: In hemodialyzed patients, the presence of a near-normal hemoglobin level, irrespective of rhEPO therapy, implies efficient erythrop oiesis. Without adequate folic acid reserves, folic acid deficiency may dev elop in these patients and this will aggravate already high homocysteine le vels. Therefore, folic acid supplementation is warranted in hemodialyzed pa tients, especially in those patients with hemoglobin levels approaching nor mal. This treatment is safe and effective in reducing homocysteine levels, especially when given in high doses for prolonged periods of time.