Synergistic effect of desferrioxamine and recombinant erythropoietin on erythroid precursor proliferation in chronic renal failure.
BACKGROUND
Desferrioxamine (DFO) has been suggested to improve erythropoiesis in end-stage renal failure independently of its aluminium (Al)-chelating effect. A possible synergistic effect of DFO and recombinant human erythropoietin (r-HuEpo) could be very useful in treating anaemia of chronic renal failure.


METHODS
In order to verify whether a synergistic action of DFO and r-HuEpo exists, we enrolled 11 patients undergoing chronic haemodialysis and r-HuEpo treatment. All had a negative DFO test, very low serum Al levels (< 20 microg/l), ferritin > 100 ng% and iPTH < 200 pg/l. Samples were drawn for a basal erythroid precursor (burst-forming unit-Erythroid, BFU-E) evaluation. After isolation by Ficoll Hypaque, a 14 day incubation was carried out with: (i) r-HuEpo 3 U/ml; (ii) r-HuEpo 30 U/ml; and (iii) r-HuEpo 30 U/ml + DFO 167 microg/ml. Patients then received 5 mg/kg DFO infused during the last hour of each dialysis session for 12 weeks. New BFU-E evaluations were performed after 2, 6 and 12 weeks of treatment. BFU-E colonies were counted in duplicate with an inverted microscope after 14 days. Haemoglobin (Hb), ferritin, transferrin, reticulocytes, hypochromic erythrocytes, soluble transferrin receptor and serum erythropoietin were also evaluated at the same time.


RESULTS
High dose r-HuEpo achieved greater proliferation than low dose r-HuEpo cultures during all phases of the study. At baseline, r-HuEpo and DFO culture had a greater number of colony units than high dose r-HuEpo culture ( 103.7 +/- 50.2 vs 95.1 +/- 50.5, NS). This increase became significant after 2 weeks (145 +/- 59.3 vs 122.9 +/- 59.6, P < 0.02), and remained so at 6 (167.4 +/- 60.3 vs 149 +/- 55.6, P < 0.01) and 12 weeks (191 +/- 64.5 vs 155.1 +/- 56.3, P < 0.01). An increased proliferation was observed after DFO therapy in all culture studies: low dose r-HuEpo culture increased from 69.4 +/- 38.2 to 86.6 +/- 48.5, 115 +/- 39 and 123 +/- 46; high dose r-HuEpo culture increased from 95.1 +/- 50.5 to 122.9 +/- 59, 149 +/- 55.6 and 155.1 +/- 56.3 and r-HuEpo plus DFO culture from 103.7 +/- 50.2 to 145 +/- 59.3, 167 +/- 60.3 and 191 +/- 64.5 at 2, 6 and 12 weeks, respectively (all P < 0.01 by ANOVA). Haemoglobin, reticulocytes and soluble transferrin receptor were slightly increased, while ferritin decreased. Hypochromic erytrocytes were variable.


CONCLUSIONS
DFO increases erythroid precursor proliferation and has a synergistic in vivo effect with r-HuEpo in patients with chronic renal failure. Further investigations are needed to evaluate whether such an effect may have clinical application.
Aucella
F
F
Department of Nephrology and Dialysis, Scientific Institute Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy.
Vigilante
M
M
Scalzulli
P
P
Musto
P
P
Prencipe
M
M
Valente
G L
GL
Carotenuto
M
M
Stallone
C
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology; D003114:Colony-Forming Units Assay; D003676:Deferoxamine / Q000008:administration & dosage*; D004357:Drug Synergism; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D004921:Erythropoietin; D003676:Deferoxamine