Erythropoietin (EPO)

Erythropoietin (EPO), a glycoprotein (~30,400 daltons) produced primarily by the kidney, is the principal factor regulating red blood cell production (erythropoiesis) in mammals.³ Renal production is regulated by changes in oxygen availability. Normally, EPO levels vary inversely with hematocrit. Under conditions of hypoxia, the level of EPO in the circulation increases, leading to increased production of red blood cells. Conversely, a high hematocrit should suppress the release of EPO.

The over-expression of EPO may be associated with certain pathophysiological conditions.⁴ Primary polycythemia (polycythemia vera) is a neoplastic (clonal) blood disorder characterized by EPO-independent, autonomous production of erythrocytic progenitors from abnormal bone marrow stem.⁵ The majority of polycythemia vera cases are caused by oncogenic mutations that constitutively activate the JAKSTAT signal transduction pathway, such as JAK2^V617F, or exon 12 mutations or LNK mutations. In most cases, decreased levels of EPO are found in the serum of affected patients.⁵ Conversely, various types of secondary polycythemias are associated with the production of elevated levels of EPO.^5-8 The overproduction of EPO may be an adaptive response associated with conditions that produce tissue hypoxia, such as living at a high altitude, chronic obstructive pulmonary disease, cyanotic heart disease, sleep apnea, high oxygen affinity hemoglobinopathy, smoking, or localized renal hypoxia. In other instances, elevated EPO levels are the result of production by neoplastic cells. Tumors that have been associated with an inappropriate EPO production include cerebellar hemangioblastomas, uterine leiomyomas, pheochromocytoma, renal cell carcinoma, hepatocellular carcinoma, parathyroid adenomas, and meningiomas.⁶

Deficient EPO production is found in conjunction with certain forms of anemia.^9,10 These include anemia of renal failure, end-stage renal disease,¹¹ hypothyroidism, and malnutrition. EPO levels are often measured in patients with chronic kidney disease to assess the kidneys' continued ability to produce erythropoietin. Anemias of chronic disease (chronic infections, autoimmune diseases, rheumatoid arthritis, AIDS, malignancies), are characterized by a blunted response of erythroid progenitors to EPO. Other forms of anemia can be associated with EPO-independent causes, and affected individuals show elevated levels of EPO. These forms include aplastic anemias, iron deficiency anemias, thalassemia, megaloblastic anemias, pure red cell aplasias, and myelodysplastic syndromes.¹²

Recombinant human EPO (rhEPO) is administered clinically to stimulate red cell production in patients with chronic kidney disease, HIV-infected patients treated with zidovudine, patients undergoing myelosuppressive chemotherapy treatment, and other anemic patients (as an alternative to blood transfusion.)^13,14 Several investigators have reported that in chemotherapy-treated cancer patients, baseline EPO levels of greater than 500 mIU/mL predicts unresponsiveness to EPO therapy. Endogenous serum erythropoietin levels are measured as a qualification criterion for rhEPO treatment of anemia in HIV-infected patients taking zidovudine.¹³

Pretransfusion erythropoietin levels have also been used to predict patients with myelodysplastic syndromes that are likely to respond to rhEPO treatment.^12,15 rhEPO is used by some athletes as a performance enhancing drug in an effort to increase endurance and oxygen capacity by increasing the red blood cell count.¹⁶ This inappropriate use of the drug can result in adverse clinical consequences due to hypertension and increased blood viscosity. Its use has been prohibited by most sports organizations.