A B S T R A C T Fetal mouse liver and normal human bone marrow cell cultures were used for studies on the inhibition of erythroid colony formation (CFU-E) by sera from anemic patients with end-stage renal failure and the polyamine spermine. Sera from each of eight predialysis uremic anemic patients with end-stage renal failure produced a significant (P < 0.001) inhibition of erythroid colony formation in the fetal mouse liver cell cultures when compared to sera from normal human volunteers. In vivo or in vitro dialysis of the uremic sera with a 3,500-dalton exclusion limit membrane removed the inhibitor from uremic sera. The uremic serum dialysate provided by the membrane fractionation was significantly inhibitory in the erythroid cell cultures. When this dialysate was applied to gel filtration chromatography (Bio-Gel P-2) the inhibitor was found to be in the same molecular weight range as [14C]spermine. The polyamine spermine produced a dose-related inhibition of erythroid colony formation (CFU-E) in fetal mouse liver and normal human bone marrow cultures. Thus, the following evidence is provided that the in vitro inhibitor of erythropoiesis found in chronic renal failure patients' sera is identical with the polyamine spermine: (a) the inhibitor and radiolabeled spermine appeared in identical Bio-Gel P-2 effluent fractions; (b) when spermine was added to normal human sera at concentrations reported in sera of uremic patients, and studied in both the fetal mouse liver cell culture and normal human bone marrow cultures, a dose-related inhibition of erythroid colony Heiz W. Radtke was a Postdoctoral Fellow in the Depart-

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Anemia of endstage renal failure improves shortly after kidney transplantation. However, in about 10% of transplanted patients polycythemia occurs. By use of a sensitive in vitro bioassay the pathogenetic role of erythropoietin (Ep) was investigated in 12 patients with post-transplant erythrocytosis (PTE), and compared to 12 non-PTE patients. The mean Ep of 160 mU/ml was significantly elevated in patients with PTE as compared to 25 mU/ml of 36 healthy controls, whereas, the mean Ep of 24 mU/ml in non-PTE patients did not differ significantly from healthy controls. To further elucidate the mechanism of inappropriate Ep production, selective venous catheterization of native and transplanted kidneys was performed in six patients. In four PTE patients the mean Ep in native kidney veins of 110 mU/ml was significantly higher than the peripheral Ep of 66 mU/ml, whereas, mean Ep in kidney graft veins was 51 mU/ml. In contrast, in two non-PTE patients no significant difference between mean Ep from native and transplanted kidney veins was observed. We conclude that some patients escape from normal feedback regulation either due to autonomous Ep production or due to feedback regulation at an elevated level of hematocrit and that inappropriate Ep production originates from the diseased native kidneys.

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By use of the fetal mouse liver cell assay, serum erythropoietin (SEp) concentration was measured in 135 patients at various stages of chronic renal failure and in 59 healthy subjects. In patients with creatinine clearances (CCr) ranging from 2 to 40 ml/min/1.73 sq m, endocrine renal function was found to deteriorate in parallel to excretory renal function. The known negative correlation between SEp and hematocrit (Hct) was not apparent, probably because of the loss of renal mass accompanying progress of anemia and renal insufficiency. In contrast, in patients with minimal variation of residual excretory renal function, as in individual patients investigated repeatedly within a short period of time, changes of Hct were always accompanied by opposite changes of corresponding SEp concentrations. Thus, patients with chronic renal failure have a sustained regulatory feedback mechanism between Hct and SEp, which probably works at a lower level.