What condition least affects Erythropoiesis-Stimulating Agent (ESA) resistance in a patient with chronic kidney disease undergoing dialysis?

ESA Resistance in Chronic Kidney Disease

Hypoparathyroidism (Option C) is the correct answer—it does NOT affect ESA resistance, whereas inadequate iron stores, inflammation, and inadequate dialysis are all well-established causes of ESA hyporesponsiveness. 1, 2, 3

Understanding ESA Resistance

ESA hyporesponsiveness is defined as requiring doses exceeding 300 IU/kg/week of epoetin or 1.5 mg/kg/week of darbepoetin to maintain target hemoglobin levels. 3 Approximately 5-10% of end-stage renal disease patients exhibit this resistance, contributing significantly to morbidity and mortality. 3

Established Causes of ESA Resistance

Iron Deficiency (Option A - DOES Cause Resistance)

Inadequate iron stores are the single most common cause of ESA hyporesponsiveness. 1, 2, 3

• Absolute or functional iron deficiency prevents adequate erythropoiesis even with ESA therapy. 3
• Iron supplementation is required when transferrin saturation is ≤20-30% or ferritin is ≤100-500 ng/mL. 4
• Starting ESAs without correcting iron deficiency first is the leading cause of treatment failure. 1, 4
• Maintaining adequate iron stores is the most important strategy for reducing ESA requirements and enhancing efficacy. 3

Inflammation (Option B - DOES Cause Resistance)

Chronic inflammation is the second most common cause of ESA resistance in dialysis patients. 3

• Inflammatory cytokines interfere with iron metabolism and erythropoiesis. 3
• Interventions that may improve inflammation-related ESA resistance include biocompatible hemodialysis membranes, ultrapure dialysate, ascorbic acid therapy, vitamin E supplementation, and statin therapy. 3
• Chronic inflammatory states must be evaluated and treated before initiating ESA therapy. 2

Inadequate Dialysis (Option D - DOES Cause Resistance)

Inadequate dialysis is a recognized cause of ESA hyporesponsiveness. 3

• Uremic toxins accumulate with inadequate dialysis clearance, suppressing erythropoiesis. 3
• This is one of several secondary causes that must be addressed when patients fail to respond to ESA therapy. 3

Why Hypoparathyroidism Does NOT Cause ESA Resistance

Hyperparathyroidism (not hypoparathyroidism) is associated with ESA resistance. 3

• Severe hyperparathyroidism causes bone marrow fibrosis and impaired erythropoiesis, leading to ESA hyporesponsiveness. 3
• Hypoparathyroidism is not mentioned in any guideline or research evidence as a cause of ESA resistance. 1, 2, 3
• The American Journal of Kidney Diseases specifically lists severe hyperparathyroidism—not hypoparathyroidism—as a reversible cause of anemia requiring correction before ESA initiation. 1

Other Recognized Causes of ESA Resistance

Additional causes that clinicians should consider when evaluating ESA hyporesponsiveness include: 3

• Primary bone marrow disorders and myelosuppressive agents 3
• Hemoglobinopathies and hemolysis 3
• Hypersplenism 3
• ACE inhibitors and angiotensin receptor blockers 3
• Ongoing blood loss or occult malignancy 4

Clinical Algorithm for ESA Hyporesponsiveness

When a patient fails to respond to ESA therapy: 4, 3

1. Reassess iron stores immediately—check transferrin saturation and ferritin 4
2. Evaluate for inflammation—check CRP, assess for infection or inflammatory conditions 3
3. Verify dialysis adequacy—calculate Kt/V and assess clearance 3
4. Screen for hyperparathyroidism—check intact PTH levels 3
5. Rule out blood loss—assess for GI bleeding, menstrual losses 4
6. Consider bone marrow evaluation if other causes excluded 3

Avoid repeated dose escalations beyond double the initial dose without identifying the underlying cause of resistance. 4