Dynamics of erythropoietin production. Healthy human adults produce about 200 billion red blood cells (RBCs) daily to replace those lost by normal senescence. This process, termed erythropoiesis, is tightly regulated by an oxygen-sensing mechanism that has evolved to maintain RBC numbers (more precisely the hemoglobin [Hb] and hematocrit [Hct]) within a narrow physiological range. Central to this mechanism is erythropoietin (EPO), a cytokine secreted by the kidney in response to low blood oxygen tension. In response to hypoxia, EPO is synthesized in peritubular cells in the kidney and released into the circulation. Hypoxia may occur in the setting of anemia (reduced Hb results in lower oxygen carrying capacity of blood), high affinity Hb variants (reduced oxygen release to tissues), or states of low PO2 (for example, in severe pulmonary disease or right to left shunts in congenital heart disease). Hypoxia-mediated induction of EPO results in increased bone marrow production of erythrocytes (provided there is no suppression of erythropoiesis), increased Hb and and oxygen content of blood, and eventual normalization of EPO production (via negative feedback).
