Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia

Background. Inadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous as corbic acid (IVAA), but not intravenous iron medication, can effectively ci rcumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients w ith hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a pr ospective study was conducted to establish the guidelines for IVAA adjuvant therapy. Methods. Sixty-five HD patients with serum ferritin levels of more than 500 mu g/liter were recruited and divided into the control (N = 19) and IVAA ( N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% rece ived 300 mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red b lood cell and reticulocyte counts, iron metabolism indices, erythrocyte zin c protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and ox alate were examined before and following the therapy. Results. Thirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fal l in E-ZPP and serum ferritin (baselines vs. 8 weeks, serum iron 68 +/- 37 vs. 124 +/- 64 mu g/dl, TS 27 +/- 10 vs. 48 +/- 19%, E-ZPP 123 +/- 44 vs. 7 0 +/- 13 mu mol/mol heme, and serum ferritin 816 +/- 435 vs. 587 +/- 323 mu g/liter, P < 0.05). Compared with responders, mean values of hemoglobin, r EPO dose, iron metabolism parameters, and E-ZPP showed no significant chang es in controls (N = 15) and in non-responders (N = 19). Thirty-seven patien ts (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a re sponse to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 mu mol/mol heme and TS at a level of less than 25 % were m ore specific to confirm the status of functional iron deficiency in iron-ov erloaded patients. The two criterion values had the highest accuracy to pre dict a response to treatment. Conclusions. Functional iron-deficient erythropoiesis plays a role in rEPO- hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 mu mol/mol heme and TS of less than 25% should be used to guide the IVAA trea tment.