Treatment of Anemia in Chronic Kidney Disease
Iron supplementation is the first-line treatment for CKD-related anemia, followed by erythropoiesis-stimulating agents (ESAs) if needed, with a target hemoglobin of 10-12 g/dL to reduce transfusion needs while minimizing cardiovascular risks. 1, 2
Initial Evaluation
Before initiating any anemia treatment, obtain the following baseline tests 1, 3:
- Complete blood count with absolute reticulocyte count
- Serum ferritin level
- Transferrin saturation (TSAT)
- Serum vitamin B12 and folate levels
These tests identify iron deficiency and exclude other correctable causes of anemia (vitamin deficiency, inflammatory conditions, bleeding) that must be addressed before considering ESA therapy. 3
Iron Supplementation Strategy
When to Start Iron
Initiate iron supplementation when TSAT ≤30% and ferritin ≤500 ng/mL in patients not yet on ESA therapy. 1, 2, 3 ESAs increase iron utilization and can unmask or worsen iron deficiency, making iron repletion essential before ESA initiation. 2
Route of Administration
For non-dialysis CKD patients: Either intravenous iron or a 1-3 month trial of oral iron is appropriate. 1, 2
For hemodialysis patients: Intravenous iron is the preferred route, with proactive administration superior to reactive strategies. 2, 3
Monitoring Iron Status
Monitor TSAT and ferritin at least every 3 months during treatment, and more frequently when initiating therapy or when iron stores may become depleted. 1, 3
Safety Precautions for IV Iron
When administering IV iron, monitor patients for 60 minutes after infusion with resuscitative facilities and trained personnel available to minimize the risk of adverse reactions. 3
ESA Therapy
When to Initiate ESAs
Start ESA therapy only after: 1, 2
- Iron stores have been corrected
- Other reversible causes of anemia have been treated
- Hemoglobin remains below 10 g/dL despite iron repletion
Do not initiate ESA therapy if hemoglobin is ≥10.0 g/dL. 3
Hemoglobin Target
Target hemoglobin levels between 10-12 g/dL. 1, 2 Multiple trials demonstrate that targeting hemoglobin >12 g/dL increases cardiovascular events and mortality. 2 The FDA label for epoetin alfa explicitly warns that no trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase risks of death, serious adverse cardiovascular reactions, and stroke when targeting hemoglobin >11 g/dL. 4
Critical Contraindications
ESAs are contraindicated in patients with: 1, 2
- Active malignancy
- History of stroke
- Uncontrolled hypertension
The FDA label warns that ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. 4
ESA Options
Epoetin alfa (short-acting): Subcutaneous administration is more effective than intravenous for short-acting ESAs. 2 Once-weekly dosing has been shown safe and effective in non-dialysis CKD patients. 5
Darbepoetin alfa (long-acting): Allows less frequent administration due to longer half-life. 2, 6
Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs): Offer oral convenience, particularly for non-dialysis CKD patients, and may improve iron utilization for erythropoiesis. 2, 7 However, optimal iron management strategies for HIF-PHI therapy require further investigation. 8
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
Investigate the following causes 1, 3:
- Absolute or functional iron deficiency (most common)
- Infection or inflammation
- Severe hyperparathyroidism
- Aluminum toxicity
- Folate or vitamin B12 deficiency
- Blood loss
- Hemolysis
- Bone marrow disorders
- Malignancy
- Malnutrition
Avoid high ESA doses driven by hyporesponsiveness, as these are associated with increased rates of hospitalization, cardiovascular events, and mortality. 6, 7
Transfusion Therapy
Avoid red blood cell transfusions when possible to minimize allosensitization and transfusion-related risks. 1, 2
Consider transfusion only when: 1, 2
- ESA therapy is ineffective
- Risks of ESA therapy outweigh benefits
- Immediate correction of anemia is required
Common Pitfalls to Avoid
Do not start ESAs before correcting iron deficiency. Iron supplementation must be the first intervention, as ESAs cannot work effectively without adequate iron stores. 1, 2, 3
Do not target hemoglobin >12 g/dL. This increases cardiovascular risks and mortality without improving quality of life. 2, 4
Do not continue ESAs at high doses in hyporesponsive patients. Instead, investigate and address underlying causes of hyporesponsiveness. 1, 7
Do not use ESAs in patients with active malignancy. The FDA warns of increased tumor progression and shortened survival. 4