The anemia of chronic renal failure in sheep. Response to erythropoietin-rich plasma in vivo.

Abstract

Astract. The hypoproliferative anemia in chronic renal failure has been assumed to be the result of decreased erythropoietin (Ep) production by the damaged kidney and ofthe shortening oferythrocyte survival. However, many in vitro studies suggest that erythropoietic inhibitors in uremic plasma may contribute to the anemia. To determine the in vivo relevance of uremic inhibitors, increasing amounts of Ep as Ep-rich plasma were infused into six uremic sheep, and their erythropoietic responses were compared with those of nine normal sheep receiving similar amounts of Ep-rich plasma. Three sheep were studied in both normal and uremic states. Ep-rich plasma was obtained from phenylhydrazine-and phlebotomyinduced anemic sheep. Stable uremia was created by subtotal nephrectomy. Erythropoiesis was quantitated by reticulocyte response, ferrokinetics (plasma iron turnover and marrow transit time), and by hemoglobin C synthesis. Ep-rich plasma stimulated erythropoiesis similarly in uremic and normal sheep, regardless of the degree of uremia. Nondialyzed uremic sheep responded as well as dialyzed animals. The anemia was corrected in the uremic sheep after 15-40 daily infusions of Ep-rich plasma, the total dosage depending on the severity of the anemia. Polycythemia was induced when the infusions were continued. Reticulocytes, plasma iron turnover, and erythrocyte mass changes increased as the amount of Ep-rich plasma was increased. These dose-response effects, coupled with the identical erythropoietic response in normal

Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure.

“…Since the late 80's, the therapy with recombinant human erythropoietin (rHuEPO) has effectively eliminated the need for red cell transfusions (1)(2)(3)(4), thus avoiding commonly associated complications such as infections and iron overload. Patients receiving rHuEPO significantly improve their quality of life, but they exhibit a higher incidence of hypertension seemingly associated with the rHuEPO dosage (5).…”

Gene therapy for long-term expression of erythropoietin in rats.

“…The therapeutic potential for Epo in the treatment of anemia associated with renal failure was demonstrated initially by its administration to anemic uremic rats and sheep (3,4). The availability of recombinant human Epo provided a major advance in the treatment of anemia in renal failure patients receiving dialysis (5).…”

Cloning and expression of the human erythropoietin gene.

“…Epo is the principal hormone involved in the regulation and maintenance of a physiological level of circulating erythrocyte mass (2,3). The hormone is produced primarily by the kidney in the adult and by the liver during fetal life (4)(5)(6) and is maintained in the circulation at a concentration of [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] milliunits/ml of serum (7)(8)(9), or about 0.01 nM under normal physiological conditions. Production of Epo is stimulated under conditions of hypoxia (1,10).…”

“…However, when there is progressive destruction of kidney mass, such as in chronic renal failure, an anemia results due to a decreased production' of Epo (12,13). Uremic, anemic sheep and rats with decreased blood Epo levels respond to treament with Epo (14,15). Thus, a therapeutic role for Epo appears probable in the treatment of anemia associated with renal failure.…”