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 erythropoie tin therapy in dialysis patients has been studied extensively in recent yea rs, many aspects remain unclear. We previously found that administration of erythropoietin induces interleukin-1 beta, a cytokine that inhibits erythr opoiesis. The present study investigated the involvement of tumour necrosis factor-alpha, another cytokine which inhibits erythropoiesis. Peripheral b lood mononuclear cells were obtained from 18 patients on continuous ambulat ory peritoneal dialysis, who were being treated with erythropoietin for ren al 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 fou r groups on the basis of the haematocrit after treatment: group A (n = 3), <23.0%; group B (n = 5), 23.0-24.9%; group C (n = 7), 25.0-26.9%; and group D (n = 3), 127.0%. In group A, the tumour necrosis factor-alpha level in t he culture supernatant was increased by incubation with erythropoietin, whi le it was not increased in other groups. The tumour necrosis factor-alpha l evel was significantly higher in group A than in the other groups at erythr opoietin concentrations of 5 U/ml. These results suggested that induction o f tumour necrosis factor-alpha is one of the reasons for unresponsiveness t o recombinant human erythropoietin.