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Erythrokinetic studies were performed in subjects on continuous ambulatory peritoneal dialysis, during a trial examining the effectiveness of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) in correcting the anaemia associated with end stage renal disease. 15 subjects (mean haemoglobin concentration 6.9 g/dl, SD 1.1) entered the study, and during treatment 9 were restudied at a haemoglobin concentration of 11-11.5 g/dl and six underwent a third study at haemoglobin 13-13.5 g/dl. By adjusting the dose of r-HuEPO, a stepwise increase in haemoglobin concentration was achieved, and this was accompanied by increases in total red cell volume and erythron transferrin uptake. Plasma volume decreased as red cell volume increased, leaving total blood volume essentially unchanged. Red cell survival, modestly reduced before treatment (mean 64, range 44-96 d, n = 6) tended to increase during treatment and when subjects were retested at a haemoglobin concentration of 13-13.5 g/dl (after 38-62 weeks treatment), the mean increase in red cell survival was 20 d (95% confidence interval 1-39 d). Thus subcutaneous r-HuEPO is effective in correcting the anaemia of end stage renal disease when administered thrice weekly to subjects on continuous ambulatory peritoneal dialysis. It produces an increase in haemoglobin concentration primarily by expanding the erythron, and may have a secondary effect, seen after several months of treatment, of increasing red cell survival.

Studies were directed to characterization of the anaemia of renal failure of 11 patients on haemodialysis and determination of the way in which it is corrected by human erythropoietin derived from recombinant DNA expressed in Chinese hamster ovary cells (r-HuEPO) administered intravenously. Erythrokinetics before treatment showed that total red cell mass was below normal and that both erythron transferrin uptake and red cell survival were modestly reduced; treatment increased both total red cell mass and erythron transferrin uptake but did not change red cell survival in previously untransfused patients. When BFU-e and CFU-e from patient bone marrow were cultured in autologous serum we found no evidence for inhibitors of erythroid progenitor maturation in patient serum compared with normal. Erythroid expansion in response to r-HuEPO was not limited by the availability of iron, iron requirements for new red cell formation being met from stores (if adequate) or from oral iron supplements. In pharmacokinetic studies the plasma clearance of r-HuEPO could be expressed by a three-parameter exponential curve with T1/2 range of 2.3 to 7.3 h. T1/2 after the first dose of r-HuEPO was not significantly different from that after 14 to 54 weeks treatment when the erythron had expanded to a new steady state. Erythron transferrin uptake before treatment was related to endogenous production of erythropoietin estimated from the plasma clearance of the first dose of r-HuEPO administered intravenously. This finding suggested that the availability of erythropoietin was the main factor limiting expansion of the erythron. This conclusion was supported by the continuity of the relationship during the response to treatment.

We studied 20 patients with chronic airflow obstruction, 10 patients without polycythaemia and 10 patients with compensatory polycythaemia having respectively mean red cell mass 24.7 (SD 4.2) and 47.8 (SD 7.5) ml/kg, mean daytime PaO2 7.6 and 6.9 kPa, mean FEV1 0.85 and 0.821. Groups were matched for severity of daytime arterial hypoxaemia but nocturnal arterial oxygen desaturation was more severe in the patients with polycythaemia than in those without. We also studied six additional patients with chronic airflow obstruction and polycythaemia and 19 normal controls. Estimates of serum immunoreactive erythropoietin (siEp) in those without polycythaemia were 19 m-i.u./ml (geometric mean) with 95% confidence range 11-35 m-i.u./ml and stable during 3 months. In those with polycythaemia they were similar and consistent in five and, in the other five, higher on at least one occasion. There was no significant difference between siEp in daytime (12.00 hours to 16.00 hours) and morning (07.00 hours) samples but geometric mean estimates of erythropoietin in paired daytime and morning samples were higher and more variable in patients with polycythaemia than in those without. The geometric mean estimate of siEp in all patients with chronic airflow obstruction and polycythaemia was greater than in normal subjects but, despite secondary polycythaemia, siEp could be in the range for normal subjects. In the patients with polycythaemia we were unable to predict the finding of normal or elevated siEp. Changes in siEp after erythrapheresis (10-26% reduction in packed cell volume) were observed in the 10 patients with polycythaemia and in one without. One month after erythrapheresis, packed cell volume remained below and siEp was above initial pretreatment levels, implying an erythropoietin secretory response and that the development of secondary polycythaemia had induced a fall in siEp.