How to manage anemia in patients with Chronic Kidney Disease (CKD) characterized by low hemoglobin and normal ferritin levels?

Management of Anemia in CKD with Low Hemoglobin and Normal Ferritin

For CKD patients with low hemoglobin and normal ferritin, check the transferrin saturation (TSAT) immediately—if TSAT is ≤30%, initiate erythropoiesis-stimulating agent (ESA) therapy with concurrent iron supplementation, as normal ferritin does not exclude functional iron deficiency in CKD. 1, 2, 3

Critical First Step: Assess Iron Availability, Not Just Stores

• Normal ferritin does NOT mean adequate iron for erythropoiesis in CKD patients. 1, 4
• Measure TSAT alongside ferritin—TSAT reflects iron availability to bone marrow, while ferritin only reflects storage 1
• In CKD, ferritin acts as an acute-phase reactant and can be falsely elevated by inflammation, masking true functional iron deficiency 1, 4
• Functional iron deficiency is defined as TSAT ≤20-30% despite ferritin >100 ng/mL, and this is extremely common in CKD 1, 4

Treatment Algorithm Based on TSAT Results

If TSAT ≤30% and Ferritin ≤500 ng/mL:

Start with a trial of intravenous iron first, before initiating ESA therapy: 1, 5, 6

• IV iron is preferred over oral iron for CKD patients, particularly those approaching dialysis 1, 5
• Administer IV iron as a course (e.g., 500 mg initially, then 500 mg 4 weeks later) 1
• Check hemoglobin 2-4 weeks after completing the iron course to assess response 1, 6
• 59.4% of non-dialysis CKD patients respond to IV iron alone without ESA, with hemoglobin increases of 7-10 g/L 1
• If oral iron is chosen instead (acceptable but less effective), prescribe 200 mg elemental iron daily divided into 2-3 doses on an empty stomach for 1-3 months 5

If Hemoglobin Fails to Improve After Iron Trial:

Initiate ESA therapy with continued iron supplementation: 2, 3

• Start epoetin alfa 50-100 Units/kg three times weekly IV (preferred route for hemodialysis patients) or darbepoetin alfa 0.45 mcg/kg weekly IV 2, 3
• For non-dialysis CKD, consider ESA only when hemoglobin <10 g/dL and transfusion risk is significant 3
• Continue iron supplementation during ESA therapy—administer supplemental iron when ferritin <100 mcg/L or TSAT <20% 2, 3
• The majority of CKD patients require ongoing iron supplementation throughout ESA therapy 2, 3

If TSAT >30% and Ferritin is Normal (100-500 ng/mL):

This scenario suggests adequate iron availability—proceed directly to ESA therapy: 1

• Iron supplementation is not required when TSAT >30% and ferritin is adequate 1
• Start ESA at standard doses as above 2, 3
• Target hemoglobin should not exceed 11 g/dL due to increased cardiovascular risks and mortality 2, 3

Monitoring Strategy

Weekly hemoglobin monitoring until stable, then monthly: 2, 3

• Check hemoglobin weekly after initiating or adjusting ESA therapy until stable 2, 3
• Once stable, monitor hemoglobin at least monthly 2, 3
• Monitor ferritin and TSAT at least every 3 months in all CKD patients on ESA therapy 7, 5
• If checking iron parameters after IV iron, wait 4-8 weeks before rechecking ferritin, as it becomes falsely elevated immediately post-infusion 7

Dose Adjustments and Response Assessment

Avoid aggressive hemoglobin targets—use the lowest ESA dose to reduce transfusion need: 2, 3

• If hemoglobin rises >1 g/dL in any 2-week period, reduce ESA dose by 25% 2, 3
• If hemoglobin has not increased >1 g/dL after 4 weeks of ESA therapy, increase dose by 25% 2, 3
• If no response after 12 weeks of dose escalation, further ESA increases are unlikely to help—evaluate for ESA hyporesponsiveness 2, 3, 8
• Reduce or interrupt ESA if hemoglobin approaches or exceeds 11 g/dL 2, 3

Common Causes of ESA Hyporesponsiveness to Evaluate

If ESA therapy fails despite adequate dosing, systematically evaluate: 8

• Functional iron deficiency (TSAT <20% despite normal/high ferritin)—most common cause 8, 4
• Inflammation or infection—increases hepcidin and blocks iron utilization 8, 4
• Secondary hyperparathyroidism 8
• Inadequate dialysis (for dialysis patients) 8
• Malnutrition 8
• Concomitant medications interfering with erythropoiesis 8
• Occult gastrointestinal bleeding—particularly important in non-dialysis CKD with iron deficiency 1

Critical Pitfalls to Avoid

• Never assume normal ferritin means adequate iron in CKD—always check TSAT to assess functional iron availability 1, 4
• Do not target hemoglobin >11 g/dL with ESA therapy—this increases death, stroke, and cardiovascular events 2, 3
• Avoid checking ferritin within 4 weeks of IV iron administration—results will be falsely elevated and misleading 7
• Do not withhold iron if TSAT is low despite normal ferritin—this represents functional iron deficiency requiring treatment 1, 4
• Do not continue escalating ESA doses indefinitely without response—after 12 weeks of escalation, investigate other causes rather than increasing further 2, 3