Calcitriol Increases Burst-Forming Unit-Erythroid Proliferation in Chronic Renal Failure

Abstract

Background: Calcitriol (C) improves anemia in chronic renal failure. This effect may be related to the suppression of iPTH release, or to a direct effect on erythropoiesis. Methods: Thirty-three patients with chronic renal failure were enrolled; among them, 24 were on chronic hemodialysis and 9 on conservative management. None had other chronic or hematological disease, aluminum levels were below 20 µg/l and DFO testing was negative. The iPTH range was 250–480 pg/l. None were treated with C or r-HuEpo. In vitro study: Samples were drawn for a basal erythroid precursor (burst forming unit-erythroid BFU-E) study: Mononuclear cells were incubated for 14 days with r-HuEpo 3U/ml (A), r-HuEpo 3U/l + C 30 pg (B), r-HuEpo 3U/ml + C 300 pg (C), or r-HuEpo 30 U/ml + C 300 pg (D). In vivo study: After the basal evaluation, 10 patients on chronic dialysis were treated with C (Calcijex-Abbott) 1 µg three times a week, and 4 patients served as controls. BFU-E studies were performed after 1, 2 and 4 months. Results: In vitro, culture B showed increased BFU-E proliferation vs. A (41 ± 23 vs. 27 ± 15, p < 0.02); in cultures C and D, proliferation was 61 ± 31 and 78 ± 42, respectively, p < 0.01 vs. A. There was no difference among patients with predialysis renal failure and those on dialysis. BFU-E proliferation was inversely related to basal Hb (p < 0.04) and CRP levels (p < 0.05). During the in vivo study, all cultures showed a progressive increase in proliferation without a plateau level (basal, after 1, 2 and 4 months, respectively) In A: 17 ± 8, 22 ± 13, 30.9 ± 14.9, 41.4 ± 20; in B: 27.3 ± 15, 35.6 ± 20, 45.5 ± 21, 57 ± 26; in C: 48.2 ± 20.6, 63.7 ± 32, 75.7 ± 37, 83 ± 40; in D: 72 ± 24, 91 ± 42, 106 ± 42, 110 ± 42.3 (all p < 0.001). Hb and Hct showed a significant increase (p < 0.03) in the treatment group. The decrease in iPTH was not related to BFU-E proliferation. Conclusions: In chronic uremia, C has a direct effect on erythroid precursors proliferation, as demonstrated both in vitro and in vivo, with a synergistic effect with r-HuEpo. C may be a useful adjuvant therapy to r-HuEpo treatment.

Cholecalciferol Supplementation in Hemodialysis Patients

“…The role of vitamin D metabolism has also been involved in the improvement of erythropoiesis by a direct effect on erythroid precursor proliferation (31) and/or, marginally, by controlling secondary hyperparathyroidism (32). In our study, the dosage of the erythroid-stimulating agent was reduced, with no modification of hemoglobin values.…”

Ergocalciferol Supplementation in Hemodialysis Patients With Vitamin D Deficiency: A Randomized Clinical Trial

“…Only one prior RCT reported on ESA dose; it found a reduction in ESA but was a very small (n=22) and unblinded study. 24 Reduced expression of proinflammatory cytokines is the proposed mechanism by which nutritional vitamin D is hypothesized to affect erythropoiesis, 13 although convincing evidence of a role for nutritional vitamin D in mediating inflammation in a manner that impacts on clinical outcomes remains to be demonstrated. 28,29 Prior RCTs that have measured inflammation in patients on hemodialysis after vitamin D supplementation have not found reductions in cytokines or T-cell or monocyte mediators.…”

“…6 A reduction in ESA dose has been found in nonrandomized trials of nutritional vitamin D supplementation in patients on hemodialysis, [6][7][8] and cross-sectional studies show an inverse relationship between serum 25(OH)D and hemoglobin and ESA dose. [9][10][11][12] In vitro and in vivo studies under conditions of vitamin D deficiency have demonstrated increased erythropoeisis with addition of vitamin D. 13,14 The postulated mechanism for nutritional vitamin D's effect is via the suppression of cytokines inhibitory to erythroid progenitors. 14 Increased availability of iron through suppression of hepcidin may also play a role.…”

Prevalence of Vitamin D Deficiency and the Safety and Effectiveness of Monthly Ergocalciferol in Hemodialysis Patients

“…Calcitriol has been shown to have a direct proliferative effect on erythroid burst-forming units, and this effect is synergistic with epoetin [31]. Calcitriol also augments cultured stem cell proliferation alone and in the presence of supraphysiologic doses of epoetin [32].…”