How should I manage an adult with chronic kidney disease‑related anemia who is not responding to roxadustat?

Management of Roxadustat Non-Response in CKD-Related Anemia

When roxadustat fails to achieve target hemoglobin (10-12 g/dL) despite dose escalation, first optimize iron status with IV iron (or 1-3 month oral iron trial in non-dialysis patients) targeting TSAT >30% and ferritin >100 ng/mL, then consider switching to an alternative HIF-PHI or ESA rather than continuing ineffective roxadustat therapy. 1, 2

Step 1: Define Non-Response and Verify Adequate Dosing

• Non-response means failure to achieve hemoglobin ≥11.0 g/dL or an increase ≥1.0 g/dL (if baseline >8.0 g/dL) or ≥2.0 g/dL (if baseline ≤8.0 g/dL) after 24 weeks of therapy 3
• Confirm the patient has received adequate dose titration over at least 4-week intervals, with stepwise increases based on current hemoglobin and rate of change 1, 2
• Verify starting dose was appropriate: 70 mg three times weekly for patients 45-70 kg or 100 mg three times weekly for patients ≥70 kg 2
• ESA-naïve patients should have started at lower doses than those converting from ESAs 1, 2

Step 2: Assess and Correct Iron Deficiency (Primary Intervention)

Iron optimization is the critical first step before declaring true roxadustat failure, as HIF-PHIs work by improving iron utilization and lowering hepcidin 1, 4

• Measure TSAT and ferritin immediately 2, 5
• Initiate IV iron when TSAT ≤30% and ferritin ≤500 ng/mL 5
• For non-dialysis patients, a 1-3 month trial of oral iron is acceptable if IV access is problematic 5
• Roxadustat theoretically should be more effective than ESAs in functional iron deficiency states by lowering hepcidin levels 1, 4
• However, preliminary data suggesting HIF-PHIs overcome ESA hyporesponsiveness in inflammatory states involved only patients with slightly elevated C-reactive protein; sicker, more inflamed patients may still respond poorly 1

Step 3: Identify and Address Contributing Factors

Evaluate for conditions that impair erythropoiesis regardless of therapy:

• Active inflammation or infection: Check C-reactive protein, as marked systemic inflammation limits roxadustat efficacy 1, 5
• Hyperparathyroidism: Severe secondary hyperparathyroidism causes bone marrow fibrosis 1
• Folate or B12 deficiency: Measure levels and supplement if deficient 1
• Occult blood loss: Assess for gastrointestinal bleeding, particularly in dialysis patients 1
• Hemoglobinopathies: Consider if family history or ethnic background suggests thalassemia or sickle cell trait 5
• Bone marrow disorders: Evaluate if pancytopenia or other cytopenias are present 5

Step 4: Monitor for Roxadustat-Specific Safety Issues

Before escalating therapy, ensure the patient has not developed complications that warrant discontinuation:

• Central hypothyroidism: Check TSH and free T4, as roxadustat's structural similarity to T3 can downregulate TRH 1, 2
• Sepsis risk: Roxadustat carries an approximate 2-fold increased risk of sepsis and septic shock in non-dialysis CKD patients 1
• Hyperkalemia: Monitor potassium levels, though centralized laboratory analysis has not consistently reproduced early reports of increased hyperkalemia 1

Step 5: Consider Alternative HIF-PHI or Switch to ESA

If iron is optimized and contributing factors are addressed but hemoglobin remains <10 g/dL after 24-52 weeks:

• Switch to an alternative HIF-PHI (daprodustat, vadadustat, or desidustat) if available, as marked differences exist in potency and pharmacokinetics between agents 1, 5, 6
• Switch to ESA therapy (epoetin alfa or darbepoetin alfa) as these remain effective alternatives with decades of clinical experience 5, 7, 8
• Do not combine roxadustat with ESAs, as combination therapy is not recommended 2
• Discontinue roxadustat before initiating ESA to avoid overlapping erythropoietic stimulation 2

Step 6: Transfusion Considerations

Reserve red blood cell transfusions for specific scenarios:

• Hemoglobinopathies unresponsive to erythropoietic agents 5
• Bone marrow failure syndromes 5
• True ESA/HIF-PHI resistance after exhausting pharmacologic options 5
• Minimize transfusions in transplant-eligible patients to reduce allosensitization risk 5

Common Pitfalls to Avoid

• Premature discontinuation: Allow at least 24 weeks of optimized therapy before declaring failure, as phase 3 trials used this timeframe to assess response 3
• Inadequate iron supplementation: Many apparent "non-responders" simply have untreated functional iron deficiency 1, 4
• Ignoring inflammation: Patients with severe systemic inflammation may require treatment of the underlying inflammatory condition before anemia improves 1
• Overlooking dose titration: Roxadustat requires stepwise dose adjustments every 4 weeks based on hemoglobin response; static dosing leads to suboptimal outcomes 1, 2
• Continuing ineffective therapy: If no hemoglobin improvement occurs after 24 weeks despite optimization, switch agents rather than persisting with roxadustat 2, 5

Monitoring During Management

• Check hemoglobin every 4 weeks during dose titration and problem-solving 2, 5
• Measure TSAT and ferritin at least every 3 months, more frequently when adjusting iron therapy 5
• Temporarily discontinue roxadustat if hemoglobin exceeds 12-13 g/dL 1, 2
• Monitor for treatment-emergent adverse events, particularly infections in non-dialysis patients 1, 8