ROLE OF CYTOKINES IN THE RESPONSE TO ERYTHROPOIETIN IN HEMODIALYSIS-PATIENTS

Background. Cytokines are regulatory factors of erythropoiesis, especi ally in pathologic conditions. Even though a relevant role for a deran ged cytokine production in the pathogenesis of dialysis anemia has bee n suggested, no data are available that analyze the role of cytokines in the key therapeutic issue of the needs of erythropoietin. The aim o f the present study in hemodialysis patients was, therefore, to examin e the relationship between the dose of recombinant human erythropoieti n (EPO) and the production of cytokines by peripheral blood mononuclea r cells (PBMC). Methods. After the exclusion of subjects with major ac tive causes of EPO resistance, data from 34 hemodialysis patients were available for analysis. Cytokine levels were measured in the supernat ants of stimulated [with bacterial lipopolysaccharide and interferon g amma (IFN-gamma)] and unstimulated PBMC. Mean yearly values of hematoc rit, hemoglobin, transferrin saturation, ferritin, parathormone (PTH) and aluminum levels and EPO doses (U/kg/wek) were calculated. For anal ysis, the 34 patients were divided according to their cutoff requireme nts for EPO: patients with requirements of EPO greater than or equal t o 60 U/kg/week (group A(1), 26 subjects) versus EPO < 60 U/kg/week (gr oup B-1, 8 subjects) and patients with requirements of EPO greater tha n or equal to 100 U/kg/week (group A(2) 18 subjects) versus <100 U/kg/ week (group B-2, 16 subjects). Results. A significant direct correlati on between interleukin-6 (IL-G) and tumor necrosis factor alpha (TNF-a lpha) production values and EPO doses was found (P = 0.039 and P = 0.0 2 respectively). On the other hand, there was a significantly negative correlation between interleukin-l? (IL-12) production values and EPO doses (P = 0.029). Patients of groups A(1) and A(2) had spontaneously higher tumor necrosis factor-alpha (TNF-alpha) and lower IL-12 and IFN gamma production compared to patients from groups B-1 and B-2. Conclu sions. Our data disclose a previously undescribed pattern of cytokine alteration that is relevant to determine increased needs of EPO in hem odialysis patients. The present results have potential applicability i n designing strategies to improve EPO resistance.