When should an erythropoietin (EPO) level be ordered in a patient with anemia?

When to Order an Erythropoietin Level

Erythropoietin (EPO) levels should generally not be ordered routinely in the evaluation of anemia in patients with chronic kidney disease (CKD), as measurement of serum EPO levels usually is not indicated for clinical decision-making or guiding EPO therapy. 1

Primary Indications for EPO Level Testing

1. Unexplained Anemia with Normal Renal Function

• When a patient has unexplained anemia despite a thorough workup that has ruled out common causes
• When renal function is normal (serum creatinine <2 mg/dL) but anemia persists
• When evaluating for relative EPO deficiency in a patient with otherwise unexplained anemia 2

2. Suspected Abnormal EPO Production

• When evaluating for primary erythrocytosis (polycythemia vera vs. secondary causes)
• When investigating anemia that is disproportionate to the degree of renal dysfunction
• When suspecting EPO-producing tumors (rare)

When NOT to Order EPO Levels

1. Chronic Kidney Disease

• In patients with CKD and anemia (serum creatinine ≥2 mg/dL), EPO deficiency is the presumed cause of anemia after excluding other causes 1
• The NKF-K/DOQI guidelines specifically state: "In patients with impaired kidney function and a normochromic, normocytic anemia, it is rare for the serum EPO level to be elevated. Therefore, measurement of EPO levels in such patients is not likely to guide clinical decision-making or Epoetin therapy." 1

2. Known Causes of Anemia

• When iron deficiency has been confirmed
• When other clear causes of anemia have been identified (B12/folate deficiency, hemolysis, etc.)

Diagnostic Algorithm for Anemia Evaluation

1. Initial Workup for All Anemic Patients:

   • Complete blood count with indices
   • Reticulocyte count
   • Iron studies (ferritin, TSAT)
   • B12 and folate levels
   • Assessment of renal function (creatinine, eGFR)
   • Evaluation for blood loss/hemolysis

2. If Renal Function is Impaired (Creatinine ≥2 mg/dL):

   • EPO deficiency is presumed if anemia is normocytic, normochromic
   • EPO level testing is NOT indicated 1
   • Proceed with EPO replacement therapy if other causes are ruled out

3. If Renal Function is Normal (Creatinine <2 mg/dL):

   • Consider EPO level testing if anemia remains unexplained after thorough evaluation 2
   • Low or inappropriately normal EPO levels in the setting of anemia may indicate relative EPO deficiency

Special Considerations

Inadequate Response to EPO Therapy

If a patient on EPO therapy shows inadequate response despite adequate iron stores, consider the following conditions before measuring EPO levels 1:

• Infection/inflammation
• Chronic blood loss
• Osteitis fibrosa
• Aluminum toxicity
• Hemoglobinopathies
• Folate or vitamin B12 deficiency
• Multiple myeloma
• Malnutrition
• Hemolysis

Cancer Patients

• In cancer patients with anemia, EPO levels may be inappropriately low relative to the degree of anemia 1, 3
• However, EPO levels are not routinely recommended before initiating EPO therapy in cancer patients 1

Pitfalls to Avoid

1. Ordering EPO levels in CKD patients with anemia

   • This is unnecessary as EPO deficiency is expected
   • Focus instead on ruling out other contributing factors like iron deficiency

2. Relying solely on EPO levels for treatment decisions

   • EPO levels do not reliably predict response to EPO therapy
   • Clinical factors and other laboratory parameters are more important for guiding treatment

3. Failure to check iron status before EPO level

   • Iron deficiency is the most common cause of inadequate response to EPO
   • Always assess and correct iron deficiency before attributing anemia to EPO deficiency

4. Misinterpreting "normal" EPO levels

   • A normal EPO level in an anemic patient is actually inappropriate
   • EPO levels should be elevated in response to anemia if production is normal

By following these guidelines, clinicians can avoid unnecessary testing while appropriately identifying patients who may benefit from EPO level assessment.