Management of CKD-Related Anemia
Iron supplementation is the first-line treatment for CKD-related anemia, followed by erythropoiesis-stimulating agents (ESAs) only after iron repletion fails to achieve target hemoglobin levels of 10-12 g/dL. 1
Initial Evaluation
Before initiating any anemia treatment, obtain the following baseline tests 1, 2:
- Complete blood count with absolute reticulocyte count
- Serum ferritin level
- Transferrin saturation (TSAT)
- Serum vitamin B12 and folate levels
Correct or exclude other reversible causes of anemia before starting ESA therapy, including vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, hypothyroidism, and hemoglobinopathies 3, 2.
Iron Supplementation Strategy
When to Initiate Iron Therapy
Start iron supplementation when TSAT ≤30% and ferritin ≤500 ng/mL in patients not yet on ESA therapy 1, 2. ESAs increase iron utilization and can unmask or worsen iron deficiency, making adequate iron stores essential before ESA initiation 1.
Route of Administration
For hemodialysis patients: Use intravenous iron proactively rather than reactive strategies 1, 2. The PIVOTAL trial demonstrated superiority of proactive IV iron administration in this population 3.
For non-dialysis CKD patients: Either intravenous iron or a 1-3 month trial of oral iron is appropriate 1, 2. Newer oral iron compounds like ferric citrate may offer advantages over traditional oral preparations 3.
Iron Monitoring
Evaluate iron status at least every 3 months during treatment, and more frequently when initiating therapy or when iron stores may become depleted 2. When administering IV iron, monitor patients for 60 minutes after infusion with resuscitative facilities and trained personnel available 2.
ESA Therapy
Indications for ESA Initiation
Initiate ESA therapy only after:
- Iron stores have been corrected (ferritin >100 mcg/L or TSAT >20%) 4
- Other reversible causes have been treated 2
- Hemoglobin remains below 10 g/dL despite iron repletion 1, 2
For adult CKD patients not on dialysis, consider initiating ESA treatment only when hemoglobin is <10 g/dL and the rate of hemoglobin decline indicates likelihood of requiring RBC transfusion 4.
Hemoglobin Targets
Target hemoglobin level between 10-12 g/dL 1. The KDIGO guideline explicitly recommends against targeting hemoglobin >12 g/dL, as multiple trials (including TREAT, CHOIR, and CREATE) demonstrate increased cardiovascular events and mortality with higher targets 1, 4. For dialysis patients specifically, aim to avoid falling below 9.0 g/dL 2.
ESA Options and Dosing
Epoetin alfa (short-acting):
- Starting dose: 50-100 units/kg subcutaneously or intravenously 3 times weekly 5
- Subcutaneous administration is more effective than intravenous for short-acting ESAs 1
Darbepoetin alfa (long-acting):
- Starting dose for dialysis patients: 0.45 mcg/kg IV or SC weekly, or 0.75 mcg/kg every 2 weeks 4
- Starting dose for non-dialysis patients: 0.45 mcg/kg IV or SC every 4 weeks 4
- Intravenous route is recommended for hemodialysis patients 4
Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs):
- Oral agents that offer convenience, particularly for non-dialysis CKD patients 1
- May improve iron utilization for erythropoiesis and reduce hepcidin regardless of inflammation status 6, 7
ESA Dose Adjustments
Monitor hemoglobin weekly until stable after initiating or adjusting therapy, then at least monthly 4. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently 4.
If hemoglobin rises rapidly (>1 g/dL in any 2-week period): Reduce the dose by 25% or more 4.
If hemoglobin has not increased by >1 g/dL after 4 weeks: Increase the dose by 25% 4.
If no response over a 12-week escalation period: Increasing the dose further is unlikely to improve response and may increase risks; evaluate for ESA hyporesponsiveness 4.
Critical Contraindications for ESA Use
Absolute contraindications include 1:
- Active malignancy (particularly when cure is anticipated)
- History of stroke
- Uncontrolled hypertension
Use ESAs with great caution in patients with history of malignancy 3.
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.
Investigate the following causes 6, 8:
- Absolute or functional iron deficiency (most common)
- Infection or inflammation
- Severe hyperparathyroidism
- Inadequate dialysis
- Malnutrition
- Concomitant medications
Functional iron deficiency is characterized by TSAT ≤20% with elevated ferritin levels, often due to inflammation-induced hepcidin elevation that sequesters iron in the reticuloendothelial system 8. HIF-PHIs may be particularly beneficial in this setting as they reduce hepcidin and improve iron availability 6, 7.
Transfusion Therapy
Avoid red blood cell transfusions when possible to minimize allosensitization (critical for transplant candidates) and transfusion-related risks 3, 1.
Consider transfusions only when 3:
- ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure, ESA resistance)
- The risks of ESA therapy outweigh benefits (e.g., active malignancy, previous stroke)
- Immediate correction of anemia is required
Special Populations
Pediatric patients (<18 years):
- Initiate iron when TSAT ≤20% and ferritin ≤100 ng/mL 2
- Starting ESA dose: 0.45 mcg/kg SC or IV weekly, or 0.75 mcg/kg every 2 weeks for non-dialysis patients 4
- Target hemoglobin <12 g/dL 4
Patients with CKD and cancer: