What is the primary treatment for anemia due to kidney disease?

Treatment of Anemia in Chronic Kidney Disease

Iron supplementation is the first-line treatment for anemia in chronic kidney disease, followed by erythropoiesis-stimulating agents (ESAs) if 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:

• Complete blood count with absolute reticulocyte count
• Serum ferritin level
• Transferrin saturation (TSAT)
• Serum vitamin B12 and folate levels

The fundamental pathophysiology is erythropoietin deficiency from failing kidneys, which cannot produce adequate amounts of this hormone needed for red blood cell production 2. However, iron deficiency and inflammation are critical contributing factors that must be addressed first 3, 2.

Step 1: Iron Supplementation (First-Line)

Initiate iron therapy when TSAT ≤30% and ferritin ≤500 ng/mL in patients not yet on ESA therapy 1. This approach is critical because ESAs increase iron utilization and can unmask or worsen iron deficiency, particularly in inflammatory states 3.

Iron Administration Options:

• For non-dialysis CKD patients: Either intravenous iron or a 1-3 month trial of oral iron is appropriate 1
• For hemodialysis patients: The PIVOTAL trial demonstrated that proactive intravenous iron (administered unless ferritin >700 mg/L or TSAT >40%) was superior to reactive strategies triggered only when TSAT <20% and ferritin <200 mg/L 3
• For non-dialysis CKD patients: The FIND-CKD study showed that intravenous iron targeting ferritin 400-600 mg/L was superior to targeting 100-200 mg/L or using oral iron for achieving hemoglobin increases ≥1 g/dL 3

Monitor iron status (TSAT and ferritin) at least every 3 months during treatment 1.

Step 2: ESA Therapy (Second-Line)

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

Target Hemoglobin:

Target hemoglobin levels between 10-12 g/dL 3, 1. Higher targets increase cardiovascular risks and mortality based on multiple trials showing that full anemia correction with ESAs is associated with adverse outcomes 3.

ESA Options and Dosing:

Epoetin alfa (short-acting) 4:

• Starting dose: 50-100 Units/kg three times weekly (intravenous or subcutaneous)
• Subcutaneous administration is more effective than intravenous for short-acting ESAs 3
• Approved for CKD patients on dialysis and not on dialysis to decrease transfusion needs 4

Darbepoetin alfa (long-acting) 5:

• For correction phase: 0.45 mcg/kg once weekly or 0.75 mcg/kg every 2 weeks
• Allows extended dosing intervals compared to epoetin 3
• Dose requirements are independent of administration route 6

Hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) 3:

• Oral dosing offers convenience, particularly for non-dialysis CKD patients 3
• May improve iron utilization for erythropoiesis, especially with oral iron 3
• May be more effective in chronic inflammatory states (CRP >5 mg/L) 3
• Less clinical experience compared to ESAs; potential risks include tumor growth enhancement, retinopathy worsening, and cyst growth in autosomal dominant polycystic kidney disease 3

Critical Contraindications for ESA Use:

• Active malignancy 1
• History of stroke 1
• Uncontrolled hypertension 1

Step 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 systematically 1, 2:

• Absolute or functional iron deficiency (most common—inflammation-induced hepcidin elevation blocks iron absorption and release from macrophages) 2
• Infection or active inflammation 1
• Severe hyperparathyroidism 1, 2
• Aluminum toxicity from dialysate or phosphate binders 1, 2
• Folate or vitamin B12 deficiency (impairs DNA synthesis in erythroblasts) 1, 2
• Occult blood loss (gastrointestinal bleeding, repeated phlebotomy, dialyzer blood retention) 1, 2
• Hemolysis or shortened red blood cell survival 1, 2
• Bone marrow disorders 1
• Malignancy 1
• Malnutrition 1
• Hypothyroidism 2

High ESA doses driven by hyporesponsiveness should be avoided due to increased risks of hospitalization, cardiovascular events, and mortality 7.

Step 4: Transfusion Therapy (Last Resort)

Avoid red blood cell transfusions when possible to minimize allosensitization and transfusion-related risks 1.

Consider transfusion only when 1:

• ESA therapy is ineffective despite addressing hyporesponsiveness
• Risks of ESA therapy outweigh benefits
• Immediate correction of anemia is required

Common Pitfalls to Avoid

• Do not initiate ESAs before correcting iron deficiency—this leads to ESA hyporesponsiveness and unnecessarily high doses 3, 1
• Do not target hemoglobin >12 g/dL—multiple trials demonstrate increased cardiovascular events and mortality with higher targets 3, 1
• Do not ignore inflammation as a cause of functional iron deficiency—hepcidin elevation from inflammation blocks iron utilization even when stores are adequate 3, 2
• Do not use ESAs in patients with active malignancy receiving chemotherapy when cure is the anticipated outcome 4