Shortened Lifespan of Red Blood Cells and the Effects of Erythropoietin in Rats with Nephrogenic Anemia.

Abstract 1977

Poster Board I-1000

Anemia is a common complication of chronic kidney disease (CKD), mainly due to the inability of the kidneys to secrete enough erythropoietin to adequately stimulate hematopoiesis. Further, given that the lifespan of red blood cells (RBCs) has been reported to be reduced in CKD patients, this reduction in RBC lifespan is believed to be a part of the etiology of renal anemia. In the present study, we focused on RBC survival and measured the lifespan of RBCs in rats with nephrogenic anemia. We also examined the effects of erythropoietin on RBC lifespan in this anemia model. Nephrogenic anemia was induced by oral administration of adenine (600 mg/kg/day for 10 days) to male Wistar rats. Progressive, serious anemia associated with increased levels of plasma creatinine was observed in the rats. On Day 40, the number of RBCs and hemoglobin (HGB) levels were lower in the adenine-treated rats than in normal, control rats (normal: 930×10⁴/μL, anemic: 677×10⁴/μL for RBC and normal: 17.2 g/dL, anemic: 13.4 g/dL for HGB). However, the number of reticulocytes did not change in the anemic rats (normal: 299×10³/μL, anemic: 329×10³/μL, P = 0.102). The percentage of annexin V-binding erythrocytes was increased in anemic rats (normal: 0.77%, anemic 1.76%) and inversely correlated with RBC count and HGB levels, suggesting that apoptosis of RBCs increased as anemia progressed. Taking these findings into account, we measured the lifespan of RBCs in rats with nephrogenic anemia. We transfused 5-chloromethylfluorescein diacetate (CMFDA)-labeled RBCs from normal donor rats into either normal or anemic recipients and determined the number of labeled RBCs present in the peripheral blood at various time points thereafter. The time course of the reduction in the percentage of labeled RBCs in peripheral blood revealed that the half-life (t_1/2) of RBCs in anemic rats was shorter than in normal rats (normal: 22.5 d, anemic: 13.3 d). This reduction in RBC lifespan was also observed in a rat model of cisplatin-induced renal anemia. Injection of anemic rats with recombinant human erythropoietin (rhEPO) restored the number of RBCs and HGB concentration to normal levels. However, the t_1/2of RBCs in these rats was not changed. The clearance of RBCs in anemic rats does not appear to be influenced by rhEPO injection. In conclusion, the survival of RBCs was reduced in rats with nephrogenic anemia, an observation consistent with the shortened survival time of RBCs in renal failure patients. This finding suggests that this model is suitable for investigating drugs which may be used in the treatment of renal anemia. Further, because EPO therapy did not affect the lifespan of RBCs, agents which improve the shortened RBC survival inherent in CKD patients may be useful in treating renal anemia.