How is desidustat used to treat anemia in adults with chronic kidney disease, including dosing, monitoring, contraindications, and alternative therapies?

Desidustat for Anemia in Chronic Kidney Disease

Desidustat is an oral HIF-prolyl hydroxylase inhibitor approved in India for treating anemia in adults with CKD (both dialysis-dependent and non-dialysis patients), dosed at 100 mg three times weekly with titration to maintain hemoglobin 10-12 g/dL, but its use is limited by the absence of large cardiovascular outcomes trials and should be avoided in patients with active malignancy, polycystic kidney disease, and pediatric populations. 1, 2, 3

Mechanism and Clinical Advantages

Desidustat stabilizes hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase enzymes, which stimulates endogenous erythropoietin production and enhances iron absorption through hepcidin reduction. 3, 4 The oral route eliminates subcutaneous injections required with ESAs, providing significant convenience particularly for non-dialysis and peritoneal dialysis patients. 1, 2 Unlike injectable ESAs, desidustat avoids high peak serum EPO concentrations, potentially reducing cardiovascular risks. 2

Dosing Protocol

Initial Dosing

• Start at 100 mg orally three times weekly for ESA-naïve patients with baseline hemoglobin 7-11 g/dL. 1, 5
• Lower starting doses are appropriate for ESA-naïve patients compared to those transitioning from other ESAs. 2

Titration Strategy

• Adjust dose every 4 weeks based on hemoglobin level and rate of change, targeting 10-12 g/dL. 1, 2
• Temporarily discontinue if hemoglobin exceeds 12-13 g/dL. 1, 2
• Consider discontinuation if hemoglobin targets are not achieved despite dose escalation. 2

Monitoring Requirements

• Monitor hemoglobin every 4 weeks during titration phase. 1
• Check iron status (TSAT and ferritin) at least every 3 months during treatment. 6
• Regular hemoglobin monitoring is necessary to maintain the 10-12 g/dL target range throughout treatment. 2, 6

Efficacy Data

In the DREAM-ND trial, desidustat demonstrated non-inferiority to darbepoetin with a mean hemoglobin increase of 1.95 g/dL versus 1.83 g/dL, meeting prespecified non-inferiority criteria. 1, 5 The responder rate (≥1 g/dL increase) was 77.78% with desidustat versus 68.48% with darbepoetin (p=0.0181). 5

In dialysis-dependent patients (DREAM-D trial), desidustat showed non-inferiority to epoetin alfa with hemoglobin change of 0.95 g/dL versus 0.80 g/dL, with significantly higher responder rates (59.22% vs 48.37%, p=0.0382). 7

Absolute Contraindications

Do not use desidustat in the following populations:

• Active or recent malignancy - HIF activation may enhance tumor growth; avoid when anticipated treatment outcome is cure, including with primary and adjuvant chemotherapy for potentially curable malignancies. 1, 2
• Polycystic kidney disease - HIF activation may potentially enhance cyst expansion based on preclinical models. 1, 2
• Pediatric patients (<18 years) - excluded from all phase 3 trials with no safety or efficacy data available. 1, 2
• Kidney transplant recipients - limited data and potential concerns about HIF-PHI effects on immune cell function. 2

Critical Safety Considerations

Cardiovascular Safety Gap

The major limitation of desidustat is the absence of large cardiovascular outcomes trials comparable to daprodustat, vadadustat, and roxadustat. 1, 2 Exercise caution when prescribing to patients with cardiovascular disease history due to lack of long-term cardiovascular safety data. 1

Hemoglobin Targets

Never exceed hemoglobin targets of 12 g/dL - multiple large trials demonstrate increased cardiovascular events, stroke, and mortality when hemoglobin exceeds this threshold. 6 Available data do not support targeting higher hemoglobin levels with HIF-PHIs than currently recommended targets established with ESAs. 2

Drug Interactions and Special Populations

• Evaluate potential drug-drug interactions when co-administered with other oral medications due to HIF-PHI class effects. 1, 2
• Use caution in patients with marked systemic inflammation; trial participants with elevated C-reactive protein showed only modest hemoglobin responses. 1
• Do not use in ESA-hyporesponsive patients without supporting evidence, as efficacy data in this subgroup are limited. 1

Critical Pitfall: Never Combine with ESAs

Never combine desidustat with erythropoietin or other ESAs - this creates additive erythropoietic stimulation, substantially increasing risk of exceeding safe hemoglobin targets and associated cardiovascular events, stroke, and mortality. 6 Each agent should be used as monotherapy only.

Alternative Therapies

When desidustat is contraindicated or unavailable:

• ESAs (epoetin alfa, darbepoetin alfa) remain standard alternatives, though requiring subcutaneous injection and potentially causing higher peak EPO levels. 1, 2
• Other HIF-PHIs with more extensive cardiovascular safety data include roxadustat, vadadustat, and daprodustat, which have completed large cardiovascular outcomes trials. 8, 1
• Correct iron deficiency first (TSAT ≤30%, ferritin ≤500 ng/mL) before initiating any erythropoietic agent. 6

Practical Implementation

Before initiating desidustat:

1. Confirm hemoglobin 7-11 g/dL (non-dialysis) or 8-11 g/dL (dialysis-dependent). 5, 7
2. Verify adequate iron stores (TSAT and ferritin). 6
3. Screen for contraindications (malignancy, polycystic kidney disease, age <18 years). 1, 2
4. Assess cardiovascular disease history and counsel on limited long-term safety data. 1

During treatment:

• Administer 100 mg three times weekly on non-consecutive days in fasting conditions. 4, 5
• Titrate dose every 4 weeks to maintain hemoglobin 10-12 g/dL. 1, 2
• Monitor for adverse events including potential HIF-PHI class effects on thrombosis risk. 8