How should I initiate and titrate erythropoiesis‑stimulating agents in a chronic kidney disease patient with symptomatic anemia (hemoglobin ≤10 g/dL) and adequate iron stores (ferritin > 100 ng/mL, transferrin saturation > 20%)?

How to Step Up EPO in CKD Patients

Pre-Treatment Requirements Before ESA Initiation

Before initiating or escalating erythropoiesis-stimulating agents (ESAs), you must first ensure iron stores are adequate: transferrin saturation ≥20% and ferritin ≥100 ng/mL. 1

• Check iron status immediately in all CKD patients with anemia before starting ESA therapy, as iron deficiency is the most common cause of ESA hyporesponsiveness. 1, 2
• Administer supplemental iron when transferrin saturation is <20% or ferritin is <100 ng/mL before initiating or escalating ESA doses. 2
• The majority of CKD patients will require supplemental iron during ESA therapy. 2
• Intravenous iron is superior to oral iron in CKD patients, particularly those on hemodialysis, because elevated hepcidin levels block intestinal iron absorption. 3, 4

ESA Initiation Criteria

Initiate ESA therapy when hemoglobin remains <10 g/dL after correcting iron deficiency and excluding other reversible causes of anemia. 1, 2

For Dialysis Patients:

• Start ESA when hemoglobin is <10 g/dL. 2
• The recommended starting dose is 50-100 Units/kg three times weekly (intravenous or subcutaneous). 2
• The intravenous route is preferred for hemodialysis patients. 2

For Non-Dialysis CKD Patients:

• Consider initiating ESA only when hemoglobin is <10 g/dL and the rate of decline suggests imminent need for transfusion. 2
• The recommended starting dose is 50-100 Units/kg three times weekly (intravenous or subcutaneous). 2

For Pediatric CKD Patients:

• Initiate ESA only when hemoglobin is <10 g/dL. 2
• The recommended starting dose is 50 Units/kg three times weekly for patients ≥1 month old. 2

Target Hemoglobin Range

Target hemoglobin of 10-12 g/dL; never intentionally exceed 11 g/dL in routine practice due to increased cardiovascular mortality. 1, 2

• Reduce or interrupt ESA dose when hemoglobin approaches or exceeds 11 g/dL in adult dialysis patients. 2
• Reduce or interrupt ESA dose when hemoglobin exceeds 10 g/dL in non-dialysis CKD patients. 2
• Reduce or interrupt ESA dose when hemoglobin approaches or exceeds 12 g/dL in pediatric patients. 2
• Targeting hemoglobin >11 g/dL increases risk of death, myocardial infarction, stroke, and thromboembolism without improving quality of life. 1

Monitoring After Initiation or Dose Adjustment

Monitor hemoglobin weekly until stable, then at least monthly. 2

• Do not increase ESA dose more frequently than once every 4 weeks; decreases can occur more frequently. 2
• Avoid frequent dose adjustments based on single hemoglobin excursions. 2

Dose Escalation Algorithm

If Hemoglobin Has Not Increased by >1 g/dL After 4 Weeks:

• Increase ESA dose by 25%. 2
• First reassess iron stores (TSAT and ferritin) before escalating. 1, 2

If No Response After 12 Weeks of Dose Escalation:

• Further dose increases are unlikely to improve response and may increase risks. 2
• Classify the patient as ESA-hyporesponsive and avoid repeated escalations beyond double the initial dose. 1
• Evaluate for ongoing blood loss, infection, inflammation, or malignancy. 1

Dose Reduction Algorithm

If Hemoglobin Rises Rapidly (>1 g/dL in Any 2-Week Period):

• Reduce ESA dose by 25% or more immediately to prevent cardiovascular complications. 2
• Rapid correction (>3 g/dL per month) increases cardiovascular risk. 1

If Hemoglobin Approaches Target:

• Reduce dose by 25% when hemoglobin approaches 11 g/dL (dialysis) or 10 g/dL (non-dialysis). 2

If Hemoglobin Exceeds Target:

• Withhold ESA until hemoglobin declines to just below target, then resume at 25% lower dose. 2

Iron Supplementation During ESA Therapy

Maintain TSAT ≥20% and ferritin ≥100 ng/mL throughout ESA therapy. 1, 2

• For patients on high ESA doses (≥300 Units/kg/week or ≥20,000 Units/week), consider adding iron even when ferritin is 100-800 ng/mL and TSAT is <25%. 1
• Functional iron deficiency can occur despite ferritin 100-700 ng/mL when ESA therapy increases iron demand beyond mobilizable stores. 5, 6
• Diagnostic trial for functional iron deficiency: give weekly IV iron 50-125 mg for 8-10 doses; lack of erythropoietic response indicates inflammatory block. 5, 6

Common Pitfalls to Avoid

• Starting ESAs without correcting iron deficiency first is the leading cause of ESA hyporesponsiveness. 1
• Correcting anemia too rapidly (>3 g/dL per month or >1 g/dL in 2 weeks) increases cardiovascular events. 1, 2
• Targeting hemoglobin >11.5 g/dL provides no quality of life benefit and increases mortality risk. 1
• Ignoring blood pressure monitoring during ESA therapy can lead to uncontrolled hypertension. 1
• Escalating ESA doses without reassessing iron status perpetuates hyporesponsiveness. 1, 2

Safety Monitoring

Monitor blood pressure closely and treat aggressively during ESA therapy. 1

• ESAs increase risk of thromboembolism by 50-75%, hypertension, stroke, and myocardial infarction. 1
• Use extreme caution in patients with cardiovascular disease or stroke history. 1