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
Clinical presentation
Management
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
Dialyzability & ESKD dosing
Differential diagnosis
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
Note
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 Summaries may be superseded; consult the current full text and individualize to the patient.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.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.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.Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.Jonasch E et al. · N Engl J Med · 2021 · PMID 34818478
- 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