Erythropoietin hyporesponsiveness: From iron deficiency to iron overload

Iron deficiency is the most frequently encountered cause of suboptimal resp onse to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EP O-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 mu g/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. T herefore, patients with iron deficiency will always require intravenous iro n therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been correcte d or excluded, we must remember all of the possible causes of hyporesponsiv eness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction peri od, the major causes blunting the response to rHuEPO should be investigated . Most factors are reversible and remediable, except resistant anemia assoc iated with hemoglobinopathy or bone marrow fibrosis, which requires a furth er increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiov ascular complication, and cancer. Over-treatment with iron should be avoide d in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreo ver, a treatment option of iron supplementation is not warranted in these p atients, as the potential hazards of iron overload will be worsened. We dem onstrated that the mean hematocrit significantly increased from 25.1 +/- 0. 9% to 31 +/- 1.2% after eight weeks of intravenous ascorbate therapy (300 m g three times a week) in 12 hemodialysis patients with serum ferritin level s of more than 500 mu g/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8 +/- 2.5% vs. 44.8 +/- 9.5%, P < 0.05 ) and reductions in erythrocyte zinc protoporphyrin (130 +/- 32 vs. 72 +/- 19 mu mol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2 +/- 4.5 vs. 16. 8 +/- 3.4 x 10(3) units, P < 0.05) at the end of study. It is speculated th at ascorbate supplementation not only facilitates the iron release from sto rage sites and its delivery to hematopoietic tissues, but also increases ir on utilization in erythroid cells. Our study provides a more complete under standing of the pathogenesis of iron overload-related anemia and the develo pment of an adjuvant therapy, intravenous ascorbic acid, to the existing tr eatments.