The relationship of erythropoietin and iron metabolism to red blood cell production in humans.

Erythropoietin (EPO) is the primary regulator of day-to-day red blood cell production. Secreted by peritubular capillary lining cells in the kidney, EPO circulates in the plasma to interact with target cells in the bone marrow to maintain or stimulate erythropoiesis. The primary target of EPO action is the intermediate-stage erythroid burst-forming unit and the erythroid colony-forming unit (CFU-E). The CFU-E is estimated to have 300 to 400 high-affinity EPO receptors per cell and, in healthy individuals, is the cell with the highest number of receptors in the body. There is some controversy as to whether EPO provides a mitogenic signal to the CFU-E or, rather, prevents programmed cell death (apoptosis). Iron is an essential element for hemoglobin synthesis and its importance has been emphasized in individuals receiving recombinant human erythropoietin (rHuEPO). The administration of rHuEPO to patients with chronic renal failure has resulted in a number of changes in iron metabolism, including the reversal of iron overload as iron is mobilized from storage sites for hemoglobin synthesis. In addition, higher doses of rHuEPO create a state of functional (or relative) iron deficiency that is characterized by a low percent transferrin saturation in the face of adequate iron stores. The value of aggressive iron supplementation in patients receiving rHuEPO has been demonstrated in clinical trials of rHuEPO administration in individuals storing blood for autologous use at the time of surgery.