Erythropoietin

One of the most common and chronic hypoproliferative anemias is the anemia of CKD. This is a hormone deficiency state, in which the diseased kidney is incapable of meeting the endogenous erythropoietin needs of the patient. As a result of erythropoietin deficiency, the moderately shortened lifespan of the circulating red cells, and the obligatory blood loss that accompanies dialysis, CKD patients can experience profound, debilitating anemia. Such patients have benefited greatly from the availability of epoetin alfa, a recombinant human erythropoietin.

Erythropoietin alfa is a 165-amino-acid glycoprotein manufactured by recombinant DNA technology and is identical in structure and biological activity to native erythropoietin. Originally approved by the Food and Drug Administration (FDA) for the treatment of anemia in CKD patients on dialysis, erythropoietin alfa is currently indicated for treating anemia in CKD patients whether on dialysis or not, in cancer patients on chemotherapy, and in zidovudine-treated HIV-infected patients. It is also approved for reducing allogeneic blood transfusions in anemic patients undergoing elective, noncardiac, nonvascular surgery.

Erythropoietin beta and erythropoietin omega are other forms of recombinant human erythropoietin used outside of the United States. Because European researchers sometimes include data on erythropoietin beta, erythropoietin in this monograph refers to erythropoietin alfa and epoetin beta.

For more than a decade, epoetin has been used successfully to manage the anemia of patients with CKD or cancer-related anemia. erythropoietin therapy has dramatically reduced the need for transfusions in these patient groups, has led to an improvement in QOL for those who have responded, and has decreased anemia-associated morbidity.61 epoetin has also been shown to be of benefit in managing anemia in patients with HIV/AIDS,22-24 inflammatory bowel disease,18 and rheumatoid arthritis.16,62 The anemia of the elderly and those undergoing surgery63,64 has also been responsive to therapy with erythropoietin. In some cases, epoetin is given with supplemental iron, a strategy that has been of proven value for a variety of patients, including patients with ESRD on dialysis, patients with rheumatoid arthritis, and some surgical patients.

Erythropoietin, however, has a relatively short circulating half-life and, consequently, it is usually administered several times a week or at least weekly. Most recently, a novel erythropoiesis-stimulating protein (NESP) has been developed that addresses some of the inconvenience of frequent epoetin dosing. Engineered specifically for increased biological activity, darbepoetin alfa has the same number of amino acids as erythropoietin alfa, but they have been molecularly modified to add two additional

N-linked glycosylation sites to the molecule, bringing the total number to five, instead of the usual three. This results in a threefold increase in terminal elimination half-life (23.5 hours vs. 8.5 hours). As a result, darbepoetin alfa allows less frequent dosing than epoetin alfa and is well tolerated. Darbepoetin alfa was approved by the FDA in 2001 for the treatment of patients with the anemia of CKD whether on dialysis or not.65 Study findings to date have shown the medication also to be of benefit in patients with nonmyeloid hematological malignancies or solid tumors.66,67 Darbepoetin alfa is currently undergoing FDA review for use in the treatment of anemia in cancer patients receiving chemotherapy.

Replacement therapy, whether it is iron or erythropoietin, takes time to correct the anemia. Thus, if the anemia is severe and the patient is symptomatic, transfusion therapy with packed red blood cells is an option. Although the safety of blood transfusions has been brought to an extremely high level, exposure to red cell transfusions still carries a measurable risk of allosensitization, and in some patient groups, such as those with HIV/AIDS and cancer, it can have an adverse effect on mortality.

The machinery responsible for red cell production (erythropoiesis) resides in the bone marrow. The erythropoietin molecule interacts and binds to specific receptors on the surface of marrow erythroid progenitor cells, inducing them to proliferate and mature. The key to erythropoietin production is the availability of oxygen, which is transported to tissues in a form bound to the Hb molecule contained within the red cells.

The fundamental stimulus for erythropoietin production is oxygen availability to the kidney. Impaired oxygen delivery to the kidney is caused by a decrease in the number of circulating red cells (anemia), impaired oxygen loading of the red cell Hb or, rarely, impaired flow of red cells to the kidney because of renal artery stenosis.

Erythropoietin not only is responsible for the day-to-day regulation of erythropoiesis, but it also responds dramatically to increase red cell production in the face of an inadequate oxygen supply, thereby meeting tissue oxygen needs. When the Hb concentration falls below 10 g/dL to 12 g/dL, and if kidney function is normal, plasma erythropoietin levels rise logarithmically in inverse proportion to the level of Hb. Under the stimulus of erythropoietin, red blood cell production can increase four- to fivefold within 1 to 2 weeks. However, this can occur only in the presence of adequate substrates, most particularly iron. In order for this feedback system to function properly, there must be normal renal production of erythropoietin, a functioning erythroid marrow, and an adequate supply of substrates for Hb synthesis. A defect in any of these key components can lead to anemia.