[Increased in vitro and ex vivo proliferation of erythroid precursors induced by calcitriol in chronic renal failure. Synergistic effect with rHuEPO].
BACKGROUND
Calcitriol (C) improves anemia in chronic renal failure. This improvement may be related to the suppression of iPTH release, but also to a direct effect on erythropoiesis.


METHODS
In order to verify this hypothesis, 33 patients with chronic renal failure were enrolled: 24 were undergoing hemodialysis, 9 managed conservatively. All patients were free from other chronic or hematological disease, had a negative DFO test and aluminum levels below 20 mcg/l. iPTH range was 250-480 pg/l. None had yet been treated with C. In vitro study- Samples were drawn for a basal erythroid precursors (Burst Forming Unit-Erythroid BFU-E) study. After mononuclear cells were isolated by centrifugation with Ficoll-Hypaque, they were incubated for 15 days with rHuEPO 3U/ml (A), rHuEPO 3U/l + C 30 pg (B), rHuEPO 3U/ml + C 300 pg (C), rHuEPO 30 U/ml + C 300 pg (D) was performed. Ex vivo study- After the basal evaluation, 10 pts on dialysis were treated with C (Calcijex-Abbott) 1  g three times a week. BFU-E studies were performed after 1,2 and 4 months.


RESULTS
In vitro, culture B showed an increased BFU-E proliferation vs A (41+/- 23 vs 27+/-15, p less than 0.02); in C and D cultures proliferation was 61+/-31 and 78+/- 42 respectively, p less than 0.01 vs A. There was no difference among pts with renal failure and pts treated conservatively. During the in vivo study all cultures showed a progressive proliferation increase, without a plateau level (basal, after 1, 2, 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 (always p less than 0.001). The hematocrit and hemoglobin increase was constant but not significant. The iPTH decrease was not related to BFU-E proliferation.


CONCLUSIONS
In chronic uremia C has a direct effect on erythroid precursor proliferation, both in vitro and ex vivo, with a sinergystic effect with rHuEPO. This effect is not related to iPTH suppression. C may be a useful adjuvant therapy for rHuEPO treatment.
Aucella
F
F
Divisione di Nefrologia e Dialisi, Ospedale "Casa Sollievo della Sofferenza" - IRCCS, San Giovanni Rotondo (FG), Italy. faucel@tin.it
Gatta
G
G
Vigilante
M
M
Scalzulli
R P
RP
Mantuano
S
S
Carotenuto
M
M
Stallone
C
C
D000328:Adult; D000368:Aged; D000740:Anemia / Q000188:drug therapy / Q000209:etiology; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004357:Drug Synergism; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010281:Parathyroid Hormone / Q000097:blood; D011994:Recombinant Proteins; D006435:Renal Dialysis
D010281:Parathyroid Hormone; D011994:Recombinant Proteins; D004921:Erythropoietin; D002117:Calcitriol