HISTORICAL REVIEW ON THE USE OF RECOMBINANT-HUMAN-ERYTHROPOIETIN IN CHRONIC-RENAL-FAILURE

The success of maintenance haemodialysis in the 1960s was blighted by the problem of anaemia. Treatment with iron, folic acid, androgens and transfusions did no more than minimize its effects. The need for a re newable source of erythropoietin was appreciated very early but the ho pe took 25 years to realize. Cloning and expression of the human gene was achieved in 1984 and clinical trials planned even before the descr iptions of the recombinant hormone were published. The Amgen material was tested in parallel studies in Seattle and England and by the end o f 1986 the efficacy of recombinant human erythropoietin (r-HuEPO) give n in large intravenous bolus doses in reversing the anaemia of uraemia was established. The benefits were immediately obvious: relief from t ransfusion dependence was the unequivocal evidence but the effect on ' wellbeing' though subjective was remarkable. Large clinical trials wer e completed in Europe and the USA so that r-HuEPO was licensed as a th erapeutic drug less than two years later. The pilot studies flagged a number of key issues: hypertension, sometimes with encephalopathy, occ urred in patients whose blood pressure was labile before treatment; va scular access failure seemed more frequent and hyperkalaemia was thoug ht to reflect less efficient dialysis. Failure to respond focused atte ntion on iron balance as well as on factors such as infection, alumini um, and hyperparathyroidism. A more clear understanding of the pathoge nesis of the anaemia of uraemia was made possible by dissection of the specific effects of the exogenous erythropoietin on erythroid functio n. Knowledge of pharmacokinetics immediately suggested that subcutaneo us administration would be more physiological and effective. This has proved to be correct in some but not all studies. The discomfort assoc iated with subcutaneous injection of one preparation is an unresolved issue. The price of erythropoietin drew attention to the overall cost of renal replacement treatment and to the quality of life of dialysis- dependent patients. Persuasive evidence of the benefits has emerged fr om randomized trials but these are associated with a significant cost that can only in part be offset against blood transfusions and admissi ons. The effect on patient survival remains to be determined.