How to treat anemia (low hemoglobin) in patients with Chronic Kidney Disease (CKD)?

Treatment of Anemia in Chronic Kidney Disease

Treat CKD-related anemia by first correcting iron deficiency (when TSAT ≤30% and ferritin ≤500 ng/mL), then initiate erythropoiesis-stimulating agents (ESAs) only when hemoglobin remains below 10 g/dL despite iron repletion, targeting hemoglobin levels of 10-12 g/dL to reduce transfusion needs while minimizing cardiovascular risks. 1, 2

Step 1: Initial Evaluation Before Any Treatment

Before initiating anemia treatment, obtain baseline laboratory tests including complete blood count, absolute reticulocyte count, serum ferritin, transferrin saturation (TSAT), and serum vitamin B12 and folate levels. 1, 3 This evaluation identifies reversible causes of anemia beyond EPO deficiency, such as iron deficiency, vitamin deficiencies, blood loss, infection, inflammation, hyperparathyroidism, aluminum toxicity, hemolysis, bone marrow disorders, or malignancy. 1, 2

Common pitfall: Starting ESAs without correcting iron deficiency first is the leading cause of ESA hyporesponsiveness. 2

Step 2: Iron Supplementation as First-Line Treatment

Iron supplementation is the mandatory first intervention when TSAT ≤30% and ferritin ≤500 ng/mL in patients not yet on ESA therapy. 4, 1, 3

Route of Iron Administration:

• For dialysis patients: Intravenous iron is preferred. 3
• For non-dialysis CKD patients: Either IV iron or a 1-3 month trial of oral iron is acceptable. 4, 1, 3

Monitor iron status (TSAT and ferritin) at least every 3 months during treatment, and more frequently when initiating therapy. 1, 3 When administering IV iron, monitor patients for 60 minutes after infusion with resuscitative facilities and trained personnel available. 3

Step 3: ESA Therapy Initiation Criteria

Initiate ESA therapy only after iron stores have been corrected, other reversible causes of anemia have been treated, and hemoglobin remains below 10 g/dL. 4, 1, 2

Specific Initiation Thresholds:

• Dialysis patients: Start ESAs when hemoglobin is <10 g/dL. 5
• Non-dialysis CKD patients: Consider ESAs only when hemoglobin is <10 g/dL AND the rate of hemoglobin decline indicates likelihood of requiring transfusion. 5
• Pediatric patients: Start when hemoglobin is <10 g/dL. 5

Critical contraindications: Do not use ESAs in patients with active malignancy, history of stroke, or uncontrolled hypertension. 1

Step 4: Target Hemoglobin Range

Target hemoglobin levels between 10-12 g/dL, ideally around 11 g/dL. 4, 1, 2 Never intentionally exceed 13 g/dL due to increased cardiovascular risk and mortality. 2 If hemoglobin approaches or exceeds 11 g/dL in dialysis patients or 10 g/dL in non-dialysis patients, reduce or interrupt the ESA dose. 5

Targeting hemoglobin >11.5 g/dL increases the risk of death, myocardial infarction, stroke, and thromboembolism without improving quality of life. 2, 5

Step 5: ESA Dosing and Administration

Starting Doses:

• Adult dialysis patients: 0.45 mcg/kg IV or subcutaneously weekly, or 0.75 mcg/kg every 2 weeks. 5
• Adult non-dialysis patients: 0.45 mcg/kg IV or subcutaneously every 4 weeks. 5
• Pediatric patients: 0.45 mcg/kg weekly, or 0.75 mcg/kg every 2 weeks for non-dialysis patients. 5

The intravenous route is recommended for hemodialysis patients. 5

Step 6: Monitoring and Dose Adjustment

Monitor hemoglobin weekly after starting or changing ESA doses until stable, then at least monthly. 1, 2, 5 Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently. 5

Dose Adjustment Algorithm:

• If hemoglobin rises >1 g/dL in any 2-week period: Reduce dose by 25% or more. 5
• If hemoglobin increases <1 g/dL after 4 weeks: Increase dose by 25%. 5
• If no response after 12 weeks of escalation: Discontinue ESA and evaluate for other causes of anemia. 5

Critical safety point: Correcting anemia too rapidly (>3 g/dL per month) increases cardiovascular events. 2

Step 7: Managing ESA Hyporesponsiveness

Classify patients as ESA-hyporesponsive if hemoglobin does not increase from baseline after the first month of appropriate weight-based ESA dosing. 1, 2 Avoid repeated dose escalations beyond double the initial dose. 2

Investigate these causes:

• Absolute or functional iron deficiency (most common) 1, 6
• Infection or inflammation 1, 6
• Hyperparathyroidism 1, 6
• Inadequate dialysis 6
• Malnutrition 6
• Blood loss or hemolysis 1
• Bone marrow disorders or malignancy 1
• Aluminum toxicity 1
• Vitamin B12 or folate deficiency 1

Step 8: Blood Transfusion Considerations

Avoid red blood cell transfusions when possible to minimize allosensitization and transfusion-related risks, particularly in transplant candidates. 4, 1 Consider transfusion when ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure), risks of ESA therapy outweigh benefits (e.g., active malignancy, previous stroke), or immediate correction of severe symptomatic anemia is required. 4, 1, 2

For patients with hemoglobin 6 g/dL, assess for symptoms requiring urgent transfusion (angina, heart failure, severe fatigue limiting activities of daily living) rather than starting ESA therapy immediately, as ESAs take 2-4 weeks to show meaningful hemoglobin increases. 2

Critical Safety Monitoring

Monitor blood pressure closely and treat aggressively during ESA therapy, as ESAs increase the risk of thromboembolism by 50-75%, hypertension, stroke, and myocardial infarction. 2 These cardiovascular risks are particularly elevated in patients with pre-existing cardiovascular disease or stroke history. 2