Use of Recombinant Human Erythropoietin Outside the Setting of Uremia

Abstract

concentration.Abnormally high Epo levels have been reported in patients with aplastic anemia, 11 and dramatic ECOMBINANT human erythropoietin (rHuEpo) became available for clinical trials in 1985 and was introduced into clinical practice for correction of anemia of renal changes in serum levels have been described after chemotherapy 12,13 and during vitamin B12 or iron replacement ther-failure in 1989.More than 300,000 renal patients throughout the world are now receiving rHuEpo. 1 For several reasons apy.14,15 These findings point to an inverse relationship between red blood cell (RBC) precursor mass and serum Epo this use can be presently regarded as the gold standard of Epo therapy.First, renal anemia is the prototype of the Epo-level: the higher the number of RBC precursors, the faster the Epo clearance.16 deficient state.Second, although coexisting conditions may decrease rHuEpo effectiveness, 2,3 more than 95% of renal Inflammatory cytokines may interfere with Epo gene expression.Interleukin-1 (IL-1), tumor necrosis factor a patients treated with rHuEpo have a positive response if adequate doses are administered and become transfusion-(TNFa), and transforming growth factor b (TGFb) have been found to inhibit hypoxia-induced erythropoietin pro-independent.4 Third, the commonly used weekly maintenance dose of less than 100 IU/kg body weight is cost-duction in vitro.17,18 These cytokines also inhibit erythroid progenitor cell proliferation, thus playing a major role in the effective compared with a regular transfusion requirement of 2 to 3 U of blood per month.Finally, quality of life pathogenesis of the anemia of chronic disease.19 At variance, IL-6 was shown to mimic hypoxia in vitro, 17 and elevated improves in dialysis patients whose hemoglobin (Hb) concentration increases from 6 to 7 g/dL to 9 to 10 g/dL. 5 levels in humans are associated with adequate endogenous Epo production.20 Several clinical studies in the last few years have shown that rHuEpo can be remarkably effective also outside ne-Increased plasma viscosity inhibits Epo formation, thus contributing to anemia both in inflammation and monoclonal phrology.6 Because only a portion of nonrenal patients benefit from treatment, there is a need for reliable criteria to gammopathies.21 Chemotherapeutic agents blunt Epo response.22 Cisplatin predict potential responders and ensure appropriate uses of rHuEpo.The aim of this article is to define a rational ap-appears to be particularly toxic, causing a prolonged anemia.23,24 Cyclosporin A also attenuates the production of proach to rHuEpo treatment outside the setting of uremia.Epo, 25,26 and this may contribute to the anemia of patients PATHOPHYSIOLOGY OF Epo PRODUCTION AND undergoing organ transplantation. Theophylline is another Epo-DEFICIENT STATESdrug attenuating the production of Epo.27 Finally, a direct suppression of Epo formation by human immunodeficiency Epo Production virus (HIV) has been observed in vitro, 28 suggesting that this Epo is primarily made by a single organ, the kidney, outmay have a role in the pathogenesis of HIV-related anemia.side the bone marrow and participates in a classic negative feedback control system.[7][8][9] Hypoxia is the fundamental Physiologic Role of Epo in Erythropoiesis: Implications physiologic stimulus that causes a rapid increase in renalfor the Clinical Use of rHuEpo production of Epo through an exponential increase in the number of Epo-producing cells.10 Epo is the primary regulator of erythropoiesis and exerts Factors other than tissue hypoxia might be involved in its effects by binding to a surface receptor present on erythe regulation of Epo production or may influence serum throid progenitors and precursors.29 Although only a few receptors (õ100/cell) are found on early burst-forming unitserythroid (BFU-Es), their number increases with differentia-From the Department of Internal Medicine and Medical Therapy, tion and a peak of about 1,100 receptors/cell is reached at Section of Internal Medicine and Medical Oncology, IRCCS Polithe stages of colony-forming unit-erythroid (CFU-E) and clinico