Erythropoietin, (EPO), a glycoprotein hormone produced primarily by cells of the peritubular capillary endothelium of the kidney, is responsible for the regulation of red blood cell production. Secondary amounts of the hormone are synthesized in liver hepatocytes of healthy adults. In premature as well as full term infants, the liver is the primary site of EPO production. The kidney becomes the primary site of EPO synthesis shortly after birth. EPO production is stimulated by reduced oxygen content in the renal arterial circulation. Circulating EPO binds to EPO receptors on the surface of erythroid progenitors resulting in replication and maturation to functional erythrocytes by an incompletely understood mechanism.

Clinical conditions that give rise to tissue hypoxia including anemia, lung disease, or cyanotic heart disease, lead to increased levels of serum EPO. In anemia, serum EPO levels do not rise above normal until hemoglobin levels fall below 110 g/L. As may be expected in patients with renal insufficiency, serum EPO levels remain inappropriately low despite the anemia. However, inappropriately low serum EPO levels may also be seen in anemic patients with cancer, as well as those with rheumatoid arthritis, HIV infection, ulcerative colitis, sickle cell anemia, and the anemia of prematurity. The mechanism of the inappropriate EPO response varies. For example, a primary production defect is apparent in renal disease and the anemia of prematurity; suppression of EPO synthesis by inflammatory cytokines (e.g., IL-1, TNF-a ) is believed to occur in certain chronic diseases or cancer. A primary elevation of EPO levels can also occur in association with renal diseases such as hydronephrosis or cysts, or certain tumors, resulting in erthrocytosis. Examples include renal cell carcinoma (hypernephroma), hepatocellular carcinoma, and adrenal gland tumors. Certain bone marrow disorders, such as myelodysplastic syndrome and aplastic anemia, may also be associated with high serum levels of EPO. In the setting of bone marrow disease, high serum EPO levels are presumably due to the reduction in the number of EPO receptor bearing cells, thereby allowing serum levels to rise.

The gene encoding human erythropoietin was cloned in 1985 leading to the production of recombinant human EPO (rhu-EPO). Rhu-EPO has been used successfully in a variety of clinical situations to increase production of red blood cells. Currently, this agent is licensed for use in the treatment of the anemia of renal failure, the anemia associated with HIV infection in zidovudine (AZT) treated patients, and anemia associated with cancer chemotherapy. Administration of rhu-EPO has become routine in the treatment of anemia secondary to renal insufficiency where doses of 50-75 u/kg given three times per week are used to gradually restore hematocrit and eliminate transfusion dependency. Rhu-EPO may also be helpful in the treatment of a variety of anemias where endogenous levels of EPO may be low for the degree of anemia. For example it has been reported that the severity and duration of post-operative anemia is ameliorated with the use of rhu-EPO. It has also been reported to facilitate autologous blood donation prior to elective surgery, but the utility of this approach is somewhat limited.

Differentiation of elevated or depressed levels of erythropoietin in serum can be helpful in assessing therapeutic options for the anemic patient and in the diagnostic evaluation of the patient with erythrocytosis. Enzyme immunoassays which can readily quantitate serum erythropoietin levels are currently available. EPO assays are expressed in International Units or milliimmunochemical units per ml (miu/ml) based on comparison with an International Reference Preparation. The EPO assay can be used to differentiate polycythemia vera (low or normal EPO levels) from polycythemia "secondary" to hypoxia or tumor-induced (elevated EPO levels). In normal patients, serum levels of erythropoietin range from 15-59 miu/ml and can increase 100 to 1000 fold during hypoxia or anemia. In HIV infected patients receiving zidovudine (AZT) therapy, anemic patients with EPO levels below 500 miu/ml have been shown to benefit from rhu-EPO therapy. Between 60-80% of AIDS patients meet this threshold. Studies to determine serum EPO threshold levels beyond which rhu-EPO administration offers little benefit have not been clearly defined for other disease conditions. As a general rule, however, patients with elevated levels would not be expected to respond to treatment.

Reference

Tabbara, I.A.. 1993. Erythropoietin, Biology and Clinical Applications. Arch. Intern. Med. 153: 298-304.