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HIF-2α inhibitor (investigational)

Casdatifan

CASD

HIF-2α inhibitor (investigational) · approved 2026 · 4 references

An investigational next-generation HIF-2α inhibitor for clear-cell RCC, with class-based anemia/edema effects under study.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Mild
Reversibility
Variable
Onset
Not established; class anemia/hypoxia effects emerge during ongoing therapy.

Signature kidney injury & incidence

Prerenal / Hemodynamic AKI.

Renal-specific data are not established. By analogy to the first-in-class HIF-2α inhibitor belzutifan, expected on-target effects include anemia (belzutifan: ~27-90% across trials) and hypoxia, plus possible fluid retention/edema; these are class effects rather than direct nephron injury. No casdatifan-specific renal incidence is published.

Source: McKay et al., Am Soc Clin Oncol Educ Book 2025

Reported injury signatures: Prerenal / Hemodynamic AKI.

Onset timing & rechallenge

Variable / unpredictable — Renal onset is not established; class anemia/hypoxia effects emerge during ongoing therapy.

Mechanism of kidney injury

Predicted/indirect: HIF-2α inhibition reduces erythropoietin (on-target anemia) and VEGF signaling, with possible hemodynamic and fluid-balance effects. Any AKI is anticipated to be prerenal/hemodynamic rather than a structural tubular lesion. When combined with VEGFR-TKIs (e.g., cabozantinib), the TKI partner contributes hypertension and glomerular (podocyte VEGF-deprivation) proteinuria — the more renally relevant combination effect.

Clinical presentation

Anemia and hypoxia as the recognized class effects; if present, modest creatinine changes with bland sediment; in combination regimens, watch for TKI-driven hypertension and proteinuria.

Management

Supportive; manage anemia and hypoxia per class experience, treat hypertension/proteinuria if a TKI partner is used, and correct prerenal factors. No drug-specific renal therapy is defined.

Risk factors

  • Pre-existing CKD (common in RCC after nephrectomy / solitary kidney)
  • Combination with VEGFR-TKIs (additive hypertension/proteinuria)
  • Baseline anemia

Prevention

  • Account for solitary kidney / reduced nephron mass common in RCC

Renal dose adjustment

Not established (investigational). HIF-2α inhibitors are hepatically metabolized; meaningful renal-clearance dependence is not expected, but formal renal-impairment dosing has not been published. Many ccRCC patients have reduced nephron mass after nephrectomy, which is relevant to baseline GFR interpretation.

Dialyzability & ESKD dosing

Not characterized; a protein-bound, hepatically cleared small molecule is unlikely to be appreciably dialyzed. No ESKD dosing data.

Differential diagnosis

In combination regimens, attribute hypertension/proteinuria to the VEGFR-TKI partner (podocyte/glomerular effect) and anemia/hypoxia to the HIF-2α agent; distinguish prerenal creatinine changes from any TKI-related TMA/glomerular injury.

Monitoring

  • Hemoglobin and oxygen saturation (on-target anemia/hypoxia)
  • Creatinine and, in combinations, blood pressure and urine protein/ACR
  • Volume status/edema

Key trials & series

  • ARC-20 ccRCC platform study (monotherapy and with cabozantinib)
  • Phase 3 casdatifan + cabozantinib (NCT07011719)

Clinical pearls

  • On-target anemia and hypoxia are the hallmark HIF-2α class effects (EPO/VEGF suppression), not direct nephrotoxicity.
  • The renally important combination effect is the VEGFR-TKI partner's hypertension and proteinuria — monitor BP and urine protein.
  • A drug that treats kidney cancer while its own renal-safety profile is still being defined — reason from belzutifan by analogy.

Anticancer mechanism

Oral, potent, selective hypoxia-inducible factor-2α (HIF-2α) inhibitor that allosterically prevents HIF-2α/ARNT (HIF-1β) heterodimerization. HIF-2α is a key oncogenic driver in VHL-deficient clear-cell renal cell carcinoma (ccRCC); blocking it suppresses VEGF-, cyclin-D1- and EPO-driven programs. In development (ARC-20 platform; phase 3 with cabozantinib, NCT07011719); not yet approved.

Note

INVESTIGATIONAL (yearApproved set to 2026 as a near estimate per contract). No renal-specific literature; framing is conservative HIF-2α-class reasoning by analogy to belzutifan. Treat as hypothesis-level.

Guidelines & consensus

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

4 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Emerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor-Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas.McKay RR et al. · Am Soc Clin Oncol Educ Book · 2025 · PMID 40198857
  2. 2.Discovery of Casdatifan, Part II: A Potent and Orally Bioavailable Inhibitor of Hypoxia Inducible Factor-2α.Mailyan AK et al. · J Med Chem · 2026 · PMID 42246926
  3. 3.Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.Jonasch E et al. · N Engl J Med · 2021 · PMID 34818478
  4. 4.Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis.Choueiri TK et al. · Nat Med · 2021 · PMID 33888901
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.