Where is erythropoietin (EPO) primarily produced?

Erythropoietin Production Sites

Erythropoietin (EPO) is produced primarily in the kidneys (90-95%), specifically by interstitial fibroblastic cells in the renal cortex, with minor production occurring in the liver, spleen, lungs, testicles, and brain. 1

Primary Production Site: The Kidneys

• The kidneys account for 90-95% of EPO production in adults, with synthesis occurring in specialized interstitial fibroblastic cells located in the internal cortex 1
• More specifically, EPO is produced at the tip of the juxtamedullary region of the cortical labyrinth, where the kidney functions as a "critmeter" that senses oxygen tension and regulates red cell mass 2
• The kidney's unique position as the primary EPO production site is physiologically logical because it can sense both oxygen tension and extracellular volume, allowing it to coordinate red cell mass and plasma volume to maintain an optimal hematocrit 2

Secondary Production Sites

• The liver produces EPO as a secondary site, particularly important during fetal development 3
• Smaller amounts are also produced in the spleen, lungs, testicles, and brain 1
• These extrarenal sites become more clinically relevant in patients with kidney disease, though they cannot fully compensate for loss of renal EPO production 4

Regulation of Production

• EPO production is regulated primarily by tissue oxygen availability through hypoxia-inducible factor (HIF), which binds to the 3' enhancer region of the EPO gene and stimulates transcription 5
• Anemia and hypoxia accelerate EPO production by reducing renal oxygen availability, while erythrocytosis suppresses it (though never completely) 3
• The plasma EPO concentration directly reflects EPO production rate and can be used to identify EPO-deficient states 3

Clinical Implications of Production Site

• In renal anemia, serum EPO titers remain inappropriately low despite anemia because the damaged kidneys cannot produce adequate amounts 4
• Following successful renal transplantation, EPO production by the transplanted kidney is often delayed for 8-30 days, so full correction of anemia may not occur for 2-3 months after surgery 1
• Patients with chronic kidney disease require exogenous EPO (epoetin) therapy because their kidneys have lost the capacity for adequate endogenous production 1, 6