Erythropoietin–hematocrit feedback circuit in the anemia of end–stage renal disease. Deficient erythropoietin (EP) production is thought to be a key factor in the pathogenesis of the anemia of end-stage renal disease. We describe the interrelationships between radioimmunoas-sayed plasma EP levels, reticulocyte counts corrected for anemia (CRC) and hematocrit (HCT) under challenge by hemorrhage, transfusions and hemodialysis in 32 chronically–hemodialyzed patients. Spontaneous hemorrhage resulted in a decrease in HCT (P = 0.001) and increases in both EP (P = 0.006) and CRC levels (P = 0.0065). Transfusions of two units of packed red cells into each of 16 patients suppressed EP (P = 0.0004) and CRC (P < 0.0001) after about 28 and 42 hours, respectively. Repeat transfusions after one to 27 days resulted in similarly significant suppressions of both EP and CRC, except the CRC remained on higher levels for prolonged periods of times. Within a few hours after each transfusion of 2,3-diphosphoglycerate–poor red cells, both EP (P = 0.009) and CRC (P = 0.007) increased temporarily between one to 18 and three to 38 hours, respectively. Hemodialysis resulted in alkalinization (P = 0.008) of blood but not in changes of EP or CRC counts. The data show that, with the EP–HCT feedback loop persisting, increased endogenous hormone levels elicit erythropoietic responses, and that the regulation of EP levels may involve determinants such as oxy-deoxyhemoglobin interactions.