What is an erythropoietin (EPO) level?

What is an Erythropoietin (EPO) Level?

An erythropoietin (EPO) level is a blood test that measures the concentration of erythropoietin—a hormone primarily produced by the kidneys that stimulates red blood cell production in the bone marrow. 1, 2

Normal Reference Range

• Normal endogenous EPO levels in healthy adults range between 10-30 mU/mL (or 10-30 IU/L). 1, 3
• No significant sex difference exists in EPO levels, though older subjects may have slightly higher values than younger subjects. 4

Physiologic Role and Regulation

• EPO is a glycoprotein hormone with a molecular weight of 34,000 daltons, produced primarily by peritubular cells in the kidney, with minor production in the liver and brain. 5, 6, 2
• The primary stimulus for EPO production is tissue hypoxia (low oxygen availability), which activates hypoxia-inducible transcription factor (HIF) to trigger EPO gene transcription. 2, 7
• EPO binds to specific receptors on erythroid progenitor cells in the bone marrow, stimulating their proliferation and differentiation into mature red blood cells. 5, 2

Clinical Interpretation Patterns

In Anemia

• In patients with normal kidney function and anemia, serum EPO levels are typically inversely correlated with hemoglobin concentration—meaning lower hemoglobin triggers higher EPO production. 5, 4
• Patients with aplastic anemia show much higher EPO levels relative to their hemoglobin concentration compared to iron deficiency anemia. 5, 4

In Chronic Kidney Disease

• In renal anemia, EPO levels are inappropriately low or normal despite significant anemia, reflecting the kidney's inability to produce adequate EPO. 8, 5, 4
• Measurement of EPO levels in patients with impaired kidney function and normochromic, normocytic anemia rarely guides clinical decision-making, as EPO deficiency is expected. 8, 1

In Polycythemia

• Serum EPO levels <10 mU/mL in polycythemic patients suggest polycythemia vera, while elevated levels indicate secondary polycythemia from hypoxia or autonomous EPO production. 5, 6
• EPO measurement is particularly useful in differentiating polycythemia vera from secondary causes. 5, 6

Critical Thresholds for Treatment Decisions

• EPO levels >500 mU/mL indicate erythropoietin resistance, making exogenous EPO therapy unlikely to be effective. 9, 1
• EPO levels ≤500 mU/mL in anemic patients may predict better response to erythropoiesis-stimulating agents (ESAs). 1

When EPO Measurement is Clinically Useful

EPO levels should be measured in the following specific scenarios:

• Differential diagnosis of polycythemia (distinguishing polycythemia vera from secondary causes). 5, 6
• Predicting response in myelodysplastic syndrome patients being considered for ESA therapy. 8
• Evaluating unexplained anemia when malignancy-related autonomous EPO production is suspected (hepatocellular carcinoma, renal cell cancer, cerebellar hemangioblastoma). 9, 1
• Monitoring treatment response in conditions like pure red cell aplasia, where EPO levels may normalize before hemoglobin recovery. 4

Common Pitfalls to Avoid

• Do not routinely measure EPO levels in chronic kidney disease patients with anemia, as the diagnosis of relative EPO deficiency is clinical and EPO levels do not guide therapy initiation. 8, 1
• A normal EPO level does not exclude secondary polycythemia—evaluation for cardiopulmonary disease, smoking history, and oxygen saturation remains necessary. 9, 1
• EPO levels in cancer-related anemia show considerable variation among patients and do not reliably predict treatment response in most cases. 5