Stimulation of Tumour Necrosis Factor-alpha Production by Recombinant Human Erythropoietin may Contribute to Failure of Therapy

Although the mechanism of unresponsiveness to recombinant human erythropoietin therapy in dialysis patients has been studied extensively in recent years, many aspects remain unclear. We previously found that administration of erythropoietin induces interleukin-1beta, a cytokine that inhibits erythropoiesis. The present study investigated the involvement of tumour necrosis factor-alpha, another cytokine which inhibits erythropoiesis. Peripheral blood mononuclear cells were obtained from 18 patients on continuous ambulatory peritoneal dialysis, who were being treated with erythropoietin for renal anaemia, and were cultured with various concentrations of erythropoietin (0, 1, 5, 10, and 50 U/ml). Then the tumour necrosis factor-alpha level in the culture supernatant was assayed. The 18 patients were divided into four groups on the basis of the haematocrit after treatment: group A (n = 3), or =27.0%. In group A, the tumour necrosis factor-alpha level in the culture supernatant was increased by incubation with erythropoietin, while it was not increased in other groups. The tumour necrosis factor-alpha level was significantly higher in group A than in the other groups at erythropoietin concentrations of 5 U/ml. These results suggested that induction of tumour necrosis factor-alpha is one of the reasons for unresponsiveness to recombinant human erythropoietin.