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The majority of patients undergoing hemodialysis have anemia due to decreased production of erythropoietin. This condition is referred to as renal anemia, and is a type of normocytic and normochromic anemia. Renal anemia contributes to a worsening of quality of life (QOL) and has a poor prognosis for survival. Clinical use of erythropoiesis-stimulating agents (ESAs) has markedly improved the QOL and prognosis for survival of hemodialysis patients. ESA is commonly used for treatment of renal anemia, but some hemodialysis patients subsequently develop macrocytic and hypochromic anemia that is not responsive to vitamin B12 and folic acids (Ogura et al., 2007). Macrocytic and hypochromic anemia after ESA treatment is also common in elderly hemodialysis patients (Murata, 1998). However, the mechanism underlying ESA induction of these changes in erythropoiesis is unknown. The correlation between renal anemia and ischemic heart disease, which is referred to as cardiorenal anemia syndrome (CARS) (Silverberg, 2003), suggests that treatment of anemia may also suppress cardiovascular events. However, the results of the Correction of Hemoglobin and Outcome in Renal Insufficiency (CHOIR) study showed that patients with a high hemoglobin level in stage III-IV chronic kidney disease (CKD) after use of large doses of ESA have a poor prognosis for cardiovascular complications (Singh et al., 2006). Also, in a meta-analysis, Phrommintikul et al. reported an increased incidence of cerebrovascular disease in patients treated with ESAs at a high dose, with the incidence not related to the hemoglobin value (Phrommintikul et al., 2007). Recently, the results of a randomized control study (Trial to Reduce cardiovascular Events with Aranesp Therapy: TREAT) in diabetic CKD patients showed that darbepoetin did not have an inhibitory effect on the progression of renal dysfunction and the new onset of cardiovascular events (Pfeffer et al., 2009). Based on the results of the TREAT trial, it was concluded that the cause of the poor prognosis in patients receiving large doses of ESA is an increased incidence of cerebrovascular disorders. However, analyses in the CHOIR and TREAT trials were based on ESA treatment with

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Differences in Erythrocyte Index and Hyporesponsiveness to Erythropoiesis in Hemodialysis Patients Treated with Different Erythropoiesis-Stimulating Agents