And Disease

Maintenance of normal plasma levels of endogenous EPO requires the synthesis of about 2-3 U/kg/d, or approx 1000-1500 U/wk for a 70-kg man (44). No significant sex differences are found in endogenous EPO concentrations. In a study of athletes (45), regular-to-moderate training did not appear to affect endogenous EPO concentrations.

The overexpression of EPO occurs in a number of adaptive and pathologic conditions. In response to acute hypoxic stress, such as severe blood loss or severe anemia, EPO production can increase 100- to 1000-fold, although the maximal bone marrow response to such stimulation is only a 4- to 6-fold increase in RBC production (46). Overproduction of EPO with accompanying erythrocytosis may be an adaptive response to conditions that produce chronic tissue hypoxia, such as living at high altitude, chronic respiratory diseases, cyanotic heart disease, sleep apnea, smoking, localized renal hypoxia, or hemoglobinopathies with increased oxygen affinity (21). Paraneoplastic production of EPO from tumors and cysts, including renal carcinomas, benign renal tumors, Wilms' tumors, hepatomas, liver carcinomas, cerebellar hemangioblastomas, adrenal gland tumors, and leiomyomas, can also result in high plasma concentrations of the hormone.

In chronic renal disease, up to 60% of patients are anemic (hemoglobin [Hb] concentration <11 g/dL) before beginning dialysis (47). Multiple mechanisms are involved (22), but the most important are the inability of the diseased kidneys to produce an appropriate EPO response for the given degree of anemia or an inability to meet the increased red cell demands of uremic patients (48,49). In addition, the uremic state itself appears to blunt the bone marrow response to EPO, perhaps through polyamines, inflammatory cytokines, and/or parathyroid hormone mediators (22,50). It is of interest that chronically anemic dialysis patients who have acute hypoxic stress (from either acute bleeding or systemic hypoxemia) are able to increase their serum EPO concentrations at least partially, suggesting that kidney failure does not result in a complete inability to produce EPO (51,52).

The anemia of cancer is also of multifactorial etiology. As with other anemias of chronic disease, including those associated with chronic infection and inflammatory disorders, there is decreased production of endogenous EPO (53), cytokine-induced suppression of bone marrow function, disordered iron absorption and metabolism (54), and decreased RBC survival. A number of other factors may also contribute to anemia in patients with cancer (25); however, the amount of endogenous EPO increases transiently during the administration of some chemotherapeutic drugs (55).

Finally, the anemias associated with infant prematurity, pregnancy, allogeneic bone marrow transplantation, and HIV infection are often characterized by inappropriately low EPO concentrations (23).

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