What is the role of Desidustat (hypoxia-inducible factor prolyl hydroxylase inhibitor) in treating anemia related to chronic kidney disease (CKD) in adult or geriatric patients?

Desidustat for CKD-Related Anemia

Desidustat is an effective oral HIF-prolyl hydroxylase inhibitor approved for treating anemia in adult CKD patients (both dialysis-dependent and non-dialysis-dependent), offering comparable efficacy to ESAs with the practical advantage of oral administration, though long-term cardiovascular safety data remain more limited than other HIF-PHIs. 1, 2, 3

Mechanism and Clinical Efficacy

Desidustat stabilizes hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase enzymes, which stimulates endogenous erythropoietin production and enhances iron absorption and utilization by reducing hepcidin levels. 4, 5

Key efficacy data from the DREAM-ND trial (588 patients, 24 weeks):

• Hemoglobin increase from baseline (weeks 16-24): 1.95 g/dL with desidustat vs. 1.83 g/dL with darbepoetin (difference: 0.11 g/dL; 95% CI: -0.12,0.34), meeting non-inferiority criteria 4, 2
• Hemoglobin responders (≥1 g/dL increase): 77.78% with desidustat vs. 68.48% with darbepoetin (p=0.0181) 2
• Significant reduction in hepcidin levels at weeks 12 and 24 (p=0.0032 and p=0.0016, respectively) 2

Dosing Protocol

Starting dose: 100 mg orally three times weekly (every alternate day) 4, 6

Dose adjustments:

• Lower starting doses should be considered for ESA-naïve patients compared to those converting from ESAs 1
• Titrate based on hemoglobin response to maintain target range of 10-12 g/dL 1, 7
• Temporarily discontinue if hemoglobin exceeds 12-13 g/dL 1
• Consider discontinuation if hemoglobin targets are not achieved despite dose escalation 1

Monitoring requirements:

• Hemoglobin levels: Regular monitoring to maintain 10-12 g/dL target 1, 7
• Iron status (TSAT and ferritin): Every 3 months during treatment 7

Clinical Advantages Over ESAs

Oral administration eliminates the need for subcutaneous injections, particularly beneficial for non-dialysis and peritoneal dialysis patients who would otherwise require clinic visits or self-injection. 4, 1

Lower peak EPO concentrations compared to injectable ESAs may theoretically reduce cardiovascular risks associated with high EPO spikes. 4, 1

Enhanced iron utilization through hepcidin suppression may be advantageous in inflammatory states where ESA resistance occurs. 4, 2, 8

Efficacy in ESA-hyporesponsive states: Preclinical data demonstrate desidustat can overcome EPO resistance caused by inflammation, reduce anti-EPO antibodies, and maintain hemoglobin levels after ESA cessation. 8

Absolute Contraindications

Do not use desidustat in:

• Patients with polycystic kidney disease (HIF activation may enhance cyst expansion based on preclinical models) 1, 9
• Pediatric patients under 18 years (excluded from clinical trials) 1
• Patients with active or potentially curable malignancies receiving primary or adjuvant chemotherapy (HIF's pleiotropic effects on cellular growth and differentiation pose theoretical tumor enhancement risk) 4, 1, 9

Use with extreme caution in:

• Kidney transplant recipients (limited data; potential effects on immune cell function) 1, 9

Critical Safety Considerations

Never combine desidustat with ESAs (including erythropoietin). This creates additive erythropoietic stimulation, substantially increasing risk of exceeding safe hemoglobin targets (>12 g/dL), which is associated with increased cardiovascular events, stroke, and mortality. 7

Hemoglobin targets must remain 10-12 g/dL. Multiple large trials demonstrate increased cardiovascular events and mortality when hemoglobin exceeds 12 g/dL, and available data do not support targeting higher hemoglobin levels with HIF-PHIs than currently recommended for ESAs. 1, 7

Pleiotropic HIF effects beyond erythropoiesis include potential impacts on cellular differentiation and growth, vascular homeostasis, inflammation, and metabolism, which could modify cardiovascular disease, thrombosis, and malignancy risks. 4

Limited long-term cardiovascular safety data compared to other HIF-PHIs like roxadustat, vadadustat, and daprodustat, which have undergone larger cardiovascular outcomes trials. 1

Practical Implementation

Before initiating desidustat:

• Correct iron deficiency (TSAT ≤30%, ferritin ≤500 ng/mL should be addressed) 7
• Exclude reversible causes of anemia 7
• Confirm hemoglobin <10 g/dL 7
• Screen for polycystic kidney disease, active malignancy, and recent cancer treatment 1, 9

Evaluate potential drug-drug interactions when prescribing desidustat with other oral medications, as polypharmacy concerns exist with oral HIF-PHIs. 4, 1

Adherence monitoring is more challenging with oral therapy compared to in-clinic ESA administration, requiring patient education and follow-up. 4

Regulatory Status

Desidustat received its first approval in India (March 2022) for treating anemia in adults with CKD, both dialysis-dependent and non-dialysis-dependent. 3 It is currently in clinical development in China for CKD-related anemia, Mexico for COVID-19, and the USA for chemotherapy-induced anemia. 3