SUBTHERAPEUTIC ERYTHROPOIETIN AND INSULIN-LIKE GROWTH-FACTOR-I CORRECT THE ANEMIA OF CHRONIC-RENAL-FAILURE IN THE MOUSE

Chronic renal failure (CRF) is associated with a hyporegenerative anem ia, which is caused primarily by inadequate production of crythropoiet in (EPO) by the diseased kidneys and is responsive to exogenous EPO ad ministration. Little is known about compensatory mechanisms that might supervene in anemia with low levels of EPO. Multiple investigations i n vitro suggest an important role for insulin-like growth factor-1 (IG F-1) as well as EPO in erythropoiesis. Recently, both EPO and IGF-1 in vitro have been found to stimulate erythroid colony forming units in the mouse. However, no studies have examined the effect of IGF-1, sing ly and in combination with EPO, in CRF in vivo. This study examined mi ce with surgically-induced renal failure of six weeks duration that we re treated for three weeks with the combination of subtherapeutic dose s of both EPO and IGF-1. The single administration of each cytokine ca used no significant change in hemoglobin in all CRF mice. In marked co ntrast the combined administration of the two cytokines produced a str iking rise in hemoglobin, resulting in anemia correction in the majori ty of animals. The response to the combination therapy was comparable to the maximal response obtained with a single EPO dose (10 U) in a do se-finding study. Although the data are limited to utilizing one dose of each cytokine and one preparation of IGF-1, the large increase in h emoglobin observed with the combination therapy indicates that these t wo cytokines work in concert to stimulate erythroid precursors in CRF. In addition, untreated CRF mice showed markedly increased serum level s of low molecular weight binding proteins for IGF-I, potentially redu cing the bioavailability of IGF-l. These findings taken together sugge st that the anemia of CRF map represent both an EPO and a functional I GF-1 deficient state.