Treatment of Anemia in Chronic Kidney Disease
Treat CKD-related anemia with iron supplementation first (when TSAT ≤30% and ferritin ≤500 ng/mL), followed by erythropoiesis-stimulating agents (ESAs) if needed, targeting hemoglobin 10-12 g/dL—never exceeding 13 g/dL—to reduce transfusion needs while minimizing cardiovascular risks and mortality. 1
Initial Evaluation and Iron Repletion
Before initiating any anemia treatment, perform the following baseline tests 1:
- Complete blood count with hemoglobin, red cell indices, white blood cell count, differential, and platelet count
- Absolute reticulocyte count
- Serum ferritin level
- Transferrin saturation (TSAT)
- Serum vitamin B12 and folate levels
Iron supplementation is the first-line intervention when TSAT ≤30% and ferritin ≤500 ng/mL in patients not yet on ESA therapy 1. For non-dialysis CKD patients, either intravenous iron or a 1-3 month trial of oral iron is appropriate 1. For hemodialysis patients, intravenous iron is the preferred route 1. The choice depends on severity of iron deficiency, venous access availability, prior oral iron response, side effects, patient compliance, and cost 1.
Monitor iron status (TSAT and ferritin) at least every 3 months during treatment 1.
ESA Therapy Initiation
Initiate ESA therapy when:
- Iron stores have been corrected 1, 2
- Other reversible causes of anemia have been treated 1
- Hemoglobin remains below 10 g/dL despite iron repletion 1
Critical contraindications and cautions for ESA use 1:
- Active malignancy (especially when cure is anticipated)
- History of stroke
- Uncontrolled hypertension 2
The decision to start ESAs should weigh the benefits of avoiding transfusions and reducing anemia symptoms against cardiovascular risks, including death, myocardial infarction, stroke, and thromboembolism 1, 2, 3.
Hemoglobin Targets and Dosing
Target hemoglobin range: 10-12 g/dL (or 11-12 g/dL per some guidelines) 1. Never target hemoglobin >13 g/dL 1, 2, 3. Targeting hemoglobin >11 g/dL increases risks of death, serious cardiovascular events, and stroke without additional benefit 2, 3.
Initial ESA Dosing:
For epoetin alfa (dialysis and non-dialysis patients) 2:
- Adults: 50-100 Units/kg three times weekly
- Pediatric patients: 50 Units/kg three times weekly
- Intravenous route recommended for hemodialysis patients
For darbepoetin alfa 3:
- Individualized dosing based on hemoglobin level
- Can be administered less frequently than epoetin alfa
Alternative once-weekly dosing for non-dialysis CKD 4:
- Epoetin alfa 10,000 Units subcutaneously once weekly
- Titrate to 20,000 Units once weekly if hemoglobin increase <1 g/dL after 5 weeks
Monitoring and Dose Adjustments:
Monitor hemoglobin weekly until stable, then at least monthly 1, 3. Do not increase ESA dose more frequently than once every 4 weeks, though decreases can occur more frequently 3.
If hemoglobin rises rapidly (>1 g/dL in any 2-week period): Reduce ESA dose by 25% or more 3.
If hemoglobin has not increased by >1 g/dL after 4 weeks: Increase dose by 25% 3.
Avoid frequent dose adjustments; a single hemoglobin excursion may not require dosing changes 3.
Novel HIF-Prolyl Hydroxylase Inhibitors (HIF-PHIs)
Newer agents including roxadustat, vadadustat, and daprodustat have demonstrated non-inferiority to ESAs in maintaining hemoglobin levels 1. These oral agents increase endogenous erythropoietin production, improve iron availability, and reduce hepcidin levels 5. Phase 3 trials showed comparable efficacy to darbepoetin alfa in both dialysis and non-dialysis populations 1. However, long-term cardiovascular safety data are still being evaluated 1.
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.
Investigate the following causes 1:
- Absolute or functional iron deficiency (most common)
- Infection or inflammation
- Hyperparathyroidism (severe)
- Aluminum toxicity
- Folate or vitamin B12 deficiency
- Blood loss (occult or overt)
- Hemolysis
- Bone marrow disorders
- Malignancy
- Malnutrition
ACE inhibitors may contribute to ESA resistance in some patients, though evidence is conflicting 1. Monitor patients on ACE inhibitors closely and adjust ESA dosing as needed 1.
Transfusion Therapy
Avoid red blood cell transfusions when possible to minimize allosensitization (especially in transplant candidates) and transfusion-related risks 1.
Consider transfusion when 1:
- ESA therapy is ineffective (hemoglobinopathies, bone marrow failure, ESA resistance)
- Risks of ESA therapy outweigh benefits (active malignancy, previous stroke)
- Immediate correction of anemia is required 2, 3
The percentage of CKD patients requiring transfusion decreased significantly (from 11.1% to 3.7%) with once-weekly epoetin alfa therapy 4.
Common Pitfalls
Do not use ESAs in cancer patients when cure is anticipated or when receiving only hormonal agents, biologics, or radiotherapy without myelosuppressive chemotherapy 2, 3. ESAs shortened overall survival and increased tumor progression in multiple cancer types 2, 3.
Do not use benzyl alcohol-containing multi-dose vials in neonates, infants, pregnant women, or lactating women 2.
Hypertension risk increases with all ESAs compared to placebo 6. Control blood pressure before initiating and throughout ESA therapy 2.
Monitor for seizures, particularly in CKD patients, as ESAs increase seizure risk 2.