What are the pleiotropic effects of desidustat (hypoxia‑inducible factor prolyl‑hydroxylase inhibitor) in an adult patient with chronic kidney disease and anemia (hemoglobin 7–11 g/dL)?

Pleiotropic Effects of Desidustat in CKD-Related Anemia

Desidustat, as a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), exerts pleiotropic effects beyond erythropoiesis that include enhanced iron metabolism, reduced inflammation, decreased oxidative stress, and potential anti-fibrotic properties, though these broader effects carry theoretical risks for cardiovascular disease, thrombosis, and malignancy that require careful monitoring. 1

Primary Erythropoietic Effects

Mechanism of Action:

• Desidustat stabilizes HIF by inhibiting prolyl hydroxylase domain enzymes, which increases endogenous erythropoietin (EPO) production rather than providing exogenous EPO like traditional ESAs 1, 2
• This results in substantially lower peak serum EPO concentrations compared to injectable epoetins, potentially reducing cardiovascular risks associated with high EPO peaks 1
• In the DREAM-ND trial, desidustat 100 mg three times weekly produced a mean hemoglobin increase of 1.95 g/dL versus 1.83 g/dL with darbepoetin, meeting non-inferiority criteria 1, 3

Iron Metabolism and Utilization

Enhanced Iron Handling:

• Desidustat reduces hepatic and serum hepcidin levels, the master regulator of iron homeostasis, thereby improving iron availability for erythropoiesis 4, 5
• It increases liver ferroportin expression, facilitating iron release from storage sites into circulation 6
• Enhanced enteric iron absorption occurs through HIF-mediated upregulation of intestinal iron transporters 1
• Desidustat demonstrates more efficient iron utilization compared to oral iron supplementation (FeSO4), increasing circulating iron without excessive tissue iron deposition that can cause hemosiderosis 5

Clinical Implication: This may provide theoretical advantages in chronic inflammatory states where functional iron deficiency predominates, though KDIGO notes that trial data supporting superior efficacy in inflammation remain limited 1

Anti-Inflammatory Effects

Cytokine Modulation:

• Desidustat significantly reduces pro-inflammatory cytokines including IL-1β and IL-6 in preclinical models of both acute and chronic kidney injury 4
• It decreases myeloperoxidase (MPO) activity, a marker of neutrophil activation and tissue inflammation 4
• In lipopolysaccharide (LPS)-induced inflammation models, desidustat improved iron metabolism while reducing inflammatory markers 5

Mechanism: HIF stabilization modulates inflammatory pathways through effects on cellular metabolism and immune cell function, though the extent of non-erythropoietic signaling pathway activation in humans remains difficult to predict and measure 1

Oxidative Stress Reduction

• Desidustat treatment reduces oxidative stress markers in kidney tissue in preclinical models of kidney injury 4
• This antioxidant effect may contribute to renoprotection beyond anemia correction alone 4

Anti-Fibrotic Properties

Renal Fibrosis Reduction:

• In adenine-induced CKD models, desidustat reduced renal fibrosis as demonstrated by histological analysis and decreased hydroxyproline content (a marker of collagen deposition) 4
• It decreased kidney injury molecule-1 (KIM-1), a biomarker of tubular injury and fibrosis 4

Caveat: These anti-fibrotic effects are documented only in preclinical models; whether desidustat impacts CKD progression in humans remains unknown and requires further investigation 1

Erythropoiesis-Stimulating Agent (ESA) Resistance

Overcoming Hyporesponsiveness:

• Desidustat inhibits EPO resistance caused by chronic inflammation and improves anemia in preclinical models refractory to recombinant human EPO 6
• It reduces anti-EPO antibody formation and decreases the EPO dose requirement to maintain target hemoglobin 6
• After cessation of rhEPO treatment, desidustat maintained normal hemoglobin levels in animal models 6

Clinical Context: KDIGO emphasizes that clinical data supporting HIF-PHI efficacy in ESA-hyporesponsive patients remain limited, and no evidence supports combining desidustat with ESAs in practice 1, 7

Bone Marrow Effects

• Desidustat increases erythroid cell populations in bone marrow, particularly iron-dependent polychromatic normoblasts and orthochromatic normoblasts 5
• This demonstrates direct effects on erythroid differentiation and maturation beyond simply increasing EPO levels 5

Potential Risks from Pleiotropic HIF Activation

Cardiovascular and Thrombotic Concerns:

• HIF-mediated effects on vascular homeostasis, hemodynamics, and cellular metabolism could modify cardiovascular disease and thrombosis risk 1
• Unlike daprodustat, roxadustat, and vadadustat, desidustat lacks large cardiovascular outcomes trials, making long-term cardiovascular safety uncertain 3
• Target hemoglobin must remain 10-12 g/dL, as exceeding 12 g/dL increases cardiovascular events, stroke, and mortality 8, 7

Malignancy Risk:

• HIF effects on cellular differentiation and growth raise theoretical concerns about tumor promotion 1
• Desidustat should not be used when cure is anticipated, including with primary and adjuvant chemotherapy for potentially curable malignancies 8

Polycystic Kidney Disease:

• HIF activation enhances cyst expansion in preclinical models of polycystic kidney disease 1
• KDIGO recommends avoiding desidustat in polycystic kidney disease patients until adequate safety data emerge 1, 8

Retinopathy and Other Concerns:

• Potential risk of worsening retinopathy exists due to HIF effects on vascular homeostasis 1
• Theoretical concerns about immune modulation in transplant recipients, though desidustat's specific effects on graft rejection remain unknown 1

Monitoring Requirements

Essential Parameters:

• Hemoglobin every 4 weeks during dose titration, maintaining 10-12 g/dL target 8, 3
• Iron status (transferrin saturation and ferritin) at least every 3 months 7
• Temporarily discontinue if hemoglobin exceeds 12-13 g/dL 8, 3
• Evaluate for drug-drug interactions when co-administered with other oral medications 1, 3

Populations Requiring Caution or Avoidance

• Pediatric patients: Excluded from all phase 3 trials; insufficient safety and efficacy data 1, 8, 3
• Kidney transplant recipients: Limited experience with immunosuppression; potential for graft rejection or malignancy 1, 8
• Active or recent malignancy: Avoid due to HIF effects on cellular growth 3
• Polycystic kidney disease: Do not use until safety data available 1, 8