In a patient with Chronic Kidney Disease (CKD), when to choose erythropoietin (EPO) and when to choose iron supplementation for anemia management?

Management of Anemia in CKD: Iron Supplementation vs. Erythropoietin

Always assess and optimize iron status BEFORE initiating erythropoietin therapy, as iron deficiency is the most common cause of ESA hyporesponsiveness and effective erythropoiesis requires both adequate iron and erythropoietin. 1, 2

Step 1: Assess Iron Status First

Check both transferrin saturation (TSAT) and serum ferritin simultaneously—never rely on ferritin alone, as it can be falsely elevated by inflammation in CKD patients. 3

• TSAT reflects iron immediately available for erythropoiesis, while ferritin only reflects storage 3
• Ferritin acts as an acute-phase reactant in CKD and can mask functional iron deficiency 3
• Functional iron deficiency (TSAT ≤20-30% despite ferritin >100 ng/mL) is extremely common in CKD 3

Step 2: Decision Algorithm Based on Iron Parameters

Scenario A: Iron Deficiency Present (TSAT ≤30% and Ferritin ≤500 ng/mL)

Start with iron supplementation FIRST, before initiating ESA therapy. 1, 3

Route selection:

• CKD Stage 3-5 (non-dialysis): Trial of oral iron for 1-3 months OR IV iron (IV iron preferred when feasible) 1, 4
• Hemodialysis patients: IV iron is mandatory—oral iron is inadequate and not indicated 1
• Peritoneal dialysis patients: Oral iron acceptable, but IV iron if oral fails 1

Why iron first?

• 59.4% of non-dialysis CKD patients respond to IV iron alone without ESA, with hemoglobin increases of 7-10 g/L 3
• Iron deficiency is the most common cause of ESA hyporesponsiveness 5, 6
• Starting ESA without adequate iron wastes medication and increases ESA dose requirements 1, 6

Scenario B: Adequate Iron Stores (TSAT >30% and Ferritin >100 ng/mL)

Initiate ESA therapy when hemoglobin <10 g/dL in dialysis patients or based on symptoms/transfusion avoidance goals in non-dialysis patients. 1, 2

• Starting dose for adults: 50-100 Units/kg three times weekly IV or subcutaneously 2
• IV route recommended for hemodialysis patients 2
• Target hemoglobin 10-11 g/dL (do NOT exceed 11 g/dL due to increased cardiovascular risks and mortality) 1, 2

Scenario C: Normal Ferritin but Low TSAT (Functional Iron Deficiency)

This represents functional iron deficiency requiring iron supplementation despite "normal" ferritin—do NOT withhold iron. 3

• Start IV iron trial (e.g., 500 mg initially, then 500 mg 4 weeks later) 3
• Check hemoglobin 2-4 weeks after completing iron course 3
• If inadequate response after iron repletion, then add ESA therapy 3

Step 3: Maintenance Strategy for Patients on ESA Therapy

All patients on ESA therapy require ongoing iron supplementation to maintain adequate iron availability for erythropoiesis. 1

Target iron parameters during ESA therapy:

• Non-dialysis and peritoneal dialysis: TSAT >20% and ferritin >100 ng/mL 7
• Hemodialysis: TSAT >20% and ferritin >200 ng/mL 7

Monitoring frequency:

• Check TSAT and ferritin at least every 3 months in all patients on ESA therapy 1, 7, 2
• Check hemoglobin weekly until stable, then at least monthly 2

Maintenance iron dosing:

• Hemodialysis patients typically require 25-125 mg IV iron weekly to maintain target iron levels 1
• Approximately 400-500 mg supplemental iron needed every 3 months to replace ongoing losses 1

Step 4: When to Withhold Iron

Stop iron supplementation when ferritin >500 ng/mL or TSAT >50%—patients are unlikely to respond with further hemoglobin increases beyond these thresholds. 4, 7

• Withhold IV iron for up to 3 months, then re-measure iron parameters before resuming 1
• When resuming, reduce IV iron dose by one-third to one-half 1

Critical Pitfalls to Avoid

Never assume normal ferritin means adequate iron in CKD—always check TSAT to assess functional iron availability. 3

Never start ESA therapy without first evaluating and optimizing iron status—this is the FDA-labeled requirement. 2

Do not check ferritin within 4 weeks of IV iron administration—results will be falsely elevated and misleading. 3, 7

Oral iron is inadequate for hemodialysis patients—blood losses exceed absorption capacity even with 200 mg elemental iron daily. 1

Do not target hemoglobin >11 g/dL with ESA therapy—this increases risks of death, stroke, and serious cardiovascular events. 1, 2

Special Considerations for Hemodialysis Patients

Hemodialysis patients have unique iron requirements due to substantial ongoing blood losses 1:

• Approximately 400 mg iron lost every 3 months from blood tests, dialyzer retention, and GI bleeding 1
• Additional 600 mg iron needed during first 3 months of ESA therapy to support RBC production 1
• Oral iron absorption is inversely correlated with body iron stores and cannot meet demands when ferritin >200 ng/mL or TSAT >20% 1