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

AIMS: To examine the possible relationships between recombinant human erythropoietin (rhEPO) therapy, serum folic acid and homocysteine levels in a cohort of stable, chronically hemodialyzed patients. MATERIAL AND METHODS: The 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 receiving rhEPO; group 3: 14 patients on rhEPO therapy). Hematological and biochemical parameters were taken after an overnight fast in all subjects. The second phase of the study was prospective, and included 8 dialyzed patients, and investigated the effects of a 6-month period of folic acid supplementation (10 mg, 3 times a week) on the same parameters examined in the first phase of the study. RESULTS: In the first part of the study hemoglobin levels were near-normal, or normal, in all patients. No differences in hemoglobin or hematocrit values were observed in the 3 groups. 80% of all hemodialyzed patients had low serum folic acid levels, irrespective of whether they 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 different 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 dialyzed patients (group 2: 24.7+/-9.2 micromol/l; group 3: 31.6+/-14.4 micromol/l), with a significant difference seen when comparing controls and those dialyzed patients on rhEPO therapy (8.7+/-2.2 vs. 31.6+/-14.4 micromol/l; p<0.05). Significant correlations (ANOVA) were observed between serum erythropoietin 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 micromol/l; p<0.0005). Two of 3 patients receiving rhEPO therapy, had rhEPO discontinued after commencing folic acid, as hemoglobin levels remained adequate, even without rhEPO. CONCLUSIONS: In hemodialyzed patients, the presence of a near-normal hemoglobin level, irrespective of rhEPO therapy, implies efficient erythropoiesis. Without adequate folic acid reserves, folic acid deficiency may develop in these patients and this will aggravate already high homocysteine levels. Therefore, folic acid supplementation is warranted in hemodialyzed patients, especially in those patients with hemoglobin levels approaching normal. This treatment is safe and effective in reducing homocysteine levels, especially when given in high doses for prolonged periods of time.

Calcium balance during pulse alfacalcidol therapy for secondary hyperparathyroidism in CAPD patients treated with 1.0 and 1.25 mmol/L dialysate calcium.

Hypercalcemia frequently occurs in continuous ambulatory peritoneal dialysis (CAPD) patients treated with calcium carbonate and vitamin D metabolites. To reduce the incidence of this complication, it has been proposed to use dialysate solutions with a low calcium concentration. However, there is concern that these solutions may lead to a negative calcium balance. We measured calcium balance in 13 CAPD patients with secondary hyperparathyroidism who were treated with calcium carbonate and alfacalcidol, 2 microg twice weekly, while using 1.0- (1.0 group) and 1.25-mmol/L (1.25 group) dialysate calcium solutions. Calcium absorption was measured after the administration of Ca47. Results for the 1.0 (n = 6) and 1.25 (n = 7) groups included fractional calcium absorptions of 0.14 (range, 0.09 to 0.27) and 0.08 (range, 0.03 to 0.40; P = not significant [NS]) and calcium absorptions of 380 +/- 92 and 331 +/- 83 mg/d (P = NS). Dialysate calcium losses were 93 +/- 20 and 91 +/- 26 mg/d, and total calcium losses (dialysate and urine) were 106 +/- 16 and 108 +/- 40 mg/d (P = NS). Calcium balance was positive in all patients (274 +/- 92 and 223 +/- 65 mg/d; P = NS). These data suggest that the use of 1.0- and 1.25-mmol/L calcium solutions in conjunction with calcium carbonate and pulse alfacalcidol therapy is associated with a positive calcium balance in CAPD patients.

Effect of nifedipine on the renal functional reserve in cyclosporine-treated renal-transplant recipients.

Cyclosporine decreases renal perfusion and impairs the renal hemodynamic response to a protein load. High-dose nifedipine has been shown to elevate renal plasma flow (RPF). We measured the renal functional reserve of 6 cyclosporine-treated renal-transplant recipients following intravenous administration of an amino acid solution, before and 2 weeks after therapy with high-dose nifedipine (up to 120 mg/day). Pretreatment renal functional reserve was nil Following administration of nifedipine, RPF increased by 22% (p < 0.01), filtration fraction decreased by 14% (p < 0.005) and renal vascular resistance declined by 39% (p < 0.005). Renal functional reserve remained unchanged. High-dose nifedipine increases renal perfusion but does not restore renal functional reserve in cyclosporine-treated renal-transplant recipients.

Effect of verapamil on bone resorption and formation in uremic rats.

It has been shown in vitro that verapamil inhibits parathyroid hormone-induced bone resorption. To determine the effect of verapamil administration on bone histology in rats with chronic renal failure, male Wistar rats were divided into three groups: subtotally nephrectomized (SNX), SNX treated with verapamil, 8 mg/kg/day p.o. (SNX-V) and control (C). Thirteen weeks later, the mandibular condyle bone was studied by histomorphometry. When compared to C rats, SNX rats had active bone disease, with increased resorption parameters (resorption surface, active resorption surface, osteoclast number) and accelerated mineral appositional rate. These parameters improved with verapamil administration. When compared to C rats, SNX-V rats had decreased osteoid seam width and mineral appositional rate. Serum parathyroid hormone was similarly elevated in both uremic groups. These data suggest that verapamil administration improves active bone disease in rats with chronic renal failure and decreases bone formation.

Therapy with nifedipine in asthma: a randomized double-blind crossover trial.

A randomized double-blind crossover trial with nifedipine (10 mg orally four times a day for 2 weeks) was carried out in 11 asthmatic patients. The analysis of the differences between the periods of running-in, placebo and nifedipine administration showed a mild improvement in symptom scores during the nifedipine period (2.8 +/- 1.5, 2.8 +/- 1.8 and 2.1 +/- 1.6, respectively; P less than 0.05). Drug intake and peak expiratory flow rates remained unchanged. This suggests that the drug did not influence the baseline bronchial tone, but might have attenuated some superimposed exacerbations due to unavoidable exposure to cold, effort or allergens. We conclude that the benefit of orally administered nifedipine in low doses has little value in the treatment of asthma.

Combined tubular dysfunction in medullary cystic disease.

A patient with medullary cystic disease presented with a combined tubular dysfunction, including severe salt wasting, renal tubular acidosis types I and IV, and marked aldosterone resistance. High-dose mineralocorticoid treatment partially corrected the defect in potassium excretion and did not affect natriuresis. Plasma aldosterone level was more than 30 times the upper normal level and was decreased but not normalized by captopril administration and volume expansion. The severe hemodynamic and metabolic consequences of these defects were corrected by renal transplantation.