Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure. A synergistic effect with r-HuEpo.
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 microg/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 microg 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.
Aucella
Filippo
F
Department of Nephrology and Dialysis, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. faucel@tin.it
Scalzulli
Rosario Potito
RP
Gatta
Giuseppe
G
Vigilante
Mimmo
M
Carella
Angelo Michele
AM
Stallone
Carmine
C
D000740:Anemia / Q000188:drug therapy; D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D004357:Drug Synergism; D041905:Erythroid Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
D011994:Recombinant Proteins; D004921:Erythropoietin; D002117:Calcitriol