Bosutinib
Bosulif · BCR-ABL TKI
Reversible eGFR decline.
PSEUDOPRE
MildOpen →
Mutant IDH1/2 inhibitor
Vorasidenib
Voranigo · IDH1/2 inhibitor
A brain-penetrant IDH inhibitor whose kidney footprint is a benign creatinine bump, not true AKI.
Mildtargeted-modern · approved 2024
Grade 2 IDH1- or IDH2-mutant astrocytoma or oligodendroglioma in adults and pediatric patients =12 years following surgery
Signature kidney injury
Pseudo-AKI
Direct nephrotoxicity is minimal. No vorasidenib-specific AKI signal has been reported in the literature; in the registrational INDIGO phase 3 trial the predominant grade =3 toxicity was hepatic (ALT elevation in ~9.6%), not renal. A mild, reversible serum-creatinine increase — attributable to inhibition of renal tubular creatinine secretion (OCT2/MATE transporters), a recognized class effect of IDH inhibitors such as ivosidenib, rather than to a true fall in GFR — is the expected renal finding. A precise renal-event incidence is not separately quantified.
Source: 37272516
Mechanism of kidney injury
Vorasidenib has no established intrinsic tubular, glomerular, or vascular nephrotoxic mechanism. Any rise in serum creatinine is best understood as a pseudo-AKI: IDH inhibitors of this class (e.g., ivosidenib) inhibit organic cation transporter 2 (OCT2) and multidrug and toxin extrusion (MATE) proteins on the proximal tubule, blocking tubular secretion of creatinine. This elevates measured serum creatinine and lowers the creatinine-based estimated GFR without an actual decline in true glomerular filtration. Beyond this, kidney involvement is largely prerenal/hemodynamic in nature and uncommon.
Clinical presentation
Typically asymptomatic. The most likely renal-laboratory finding is a modest, stable rise in serum creatinine without oliguria, electrolyte derangement, proteinuria, hematuria, or active urinary sediment. True AKI, interstitial nephritis, or electrolyte wasting are not characteristic. The dominant on-treatment toxicities are hepatic (transaminase elevation) and neurologic, not renal.
Anticancer mechanism
Vorasidenib is an oral, blood-brain-barrier-penetrant inhibitor of the neomorphic mutant IDH1 (R132) and IDH2 (R172) enzymes. Mutant IDH converts alpha-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (D-2-HG), which dysregulates DNA and histone demethylation and blocks cellular differentiation. By suppressing D-2-HG production, vorasidenib restores epigenetic regulation and slows growth of IDH-mutant grade 2 gliomas, delaying progression and time to next intervention.
Management
For an isolated creatinine rise without other signs of kidney injury, recognize pseudo-AKI: confirm with a cystatin C-based eGFR or by checking that urinalysis and electrolytes are bland, and avoid unnecessary drug interruption. Manage true AKI, if it arises, by the usual approach — assess volume status, review the medication list, and exclude obstruction and other causes. Hepatotoxicity (the actual signature toxicity) is managed by the label-directed ALT monitoring schedule with dose modification or interruption; renal dosing changes are generally not required.Lesion-level management framework
Risk factors
- Concurrent nephrotoxins or other OCT2/MATE-inhibiting drugs
- Baseline CKD where small creatinine shifts cross dosing thresholds
- Volume depletion (prerenal physiology)
- Reliance on creatinine-based eGFR rather than cystatin C for monitoring
Prevention
- Establish a baseline serum creatinine and confirm trajectory before attributing changes to AKI
- Maintain euvolemia and avoid concurrent nephrotoxins
- Consider cystatin C-based GFR if a transporter-mediated creatinine rise is suspected
- Monitor hepatic panel closely, as ALT elevation is the principal dose-limiting toxicity
Clinical depth
Renal dose adjustment
No dedicated renal-impairment dose adjustment is established for mild-to-moderate impairment; vorasidenib is hepatically metabolized (CYP1A2/CYP3A) and dose modifications in the label are driven by hepatotoxicity, not renal function. Data in severe renal impairment and dialysis are lacking. A creatinine-based eGFR fall from blocked tubular secretion should not by itself trigger renal dose reduction.
Dialyzability & ESKD dosing
Not characterized. Vorasidenib is a small molecule but is highly protein-bound and extensively hepatically cleared, so it is unlikely to be meaningfully removed by hemodialysis; no formal dialysis data exist.
Differential diagnosis
Distinguish a benign transporter-mediated creatinine rise (pseudo-AKI: stable creatinine, normal cystatin C-based GFR, bland sediment, no electrolyte wasting) from true intrinsic AKI. Consider prerenal azotemia from volume depletion, concomitant nephrotoxins, contrast or other glioma-directed therapies, and — given frequent corticosteroid and anticonvulsant co-medication in glioma patients — drug-related interstitial nephritis from those agents rather than from vorasidenib itself.
Monitoring
- Serum creatinine / eGFR at baseline and periodically, interpreted with awareness of possible transporter-mediated elevation
- Hepatic panel (ALT/AST/bilirubin) per label — the principal toxicity to monitor
- Electrolytes if clinically indicated
- Cystatin C-based GFR when a creatinine rise needs clarification
Key trials & series
- INDIGO (NCT04164901): phase 3 randomized, double-blind, placebo-controlled trial of vorasidenib 40 mg once daily in residual/recurrent grade 2 IDH-mutant glioma; improved imaging-based PFS and time to next intervention; predominant grade =3 toxicity was ALT elevation, with no notable renal safety signal
Clinical pearls
- Vorasidenib's signature organ toxicity is hepatic (ALT elevation), not renal — keep nephrotoxicity expectations low.
- An isolated creatinine bump on an IDH inhibitor is most likely pseudo-AKI from blocked OCT2/MATE tubular secretion, mirroring ivosidenib; confirm with cystatin C before acting.
- No vorasidenib-specific AKI, interstitial nephritis, or electrolyte-wasting reports exist; renal claims here are reasoned from class behavior and registrational safety data.
- In glioma patients, concurrent corticosteroids and antiepileptics are more probable culprits for renal lab changes than vorasidenib itself.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
Pseudo-AKIPrerenal / Hemodynamic AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of mutant idh1/2 inhibitors.
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Differentiation syndrome
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- QT prolongation
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkVorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma.Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. · N Engl J Med 2023 · PMID 37272516Pivotal INDIGO phase 3 registrational trial establishing efficacy and the safety profile (hepatic ALT elevation as the dominant grade =3 toxicity; no notable renal signal), supporting the minimal-direct-nephrotoxicity assessment.PMIDVorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial.Cloughesy TF, van den Bent MJ, Touat M, et al. · Lancet Oncol 2025 · PMID 41175888Secondary and exploratory endpoint analysis of INDIGO, providing additional double-blind efficacy, quality-of-life, and tolerability data on vorasidenib.PMIDThe Role of Mutant IDH Inhibitors in the Treatment of Glioma.Nakhate V, Lasica AB, Wen PY. · Curr Neurol Neurosci Rep 2024 · PMID 39302605Review of mutant IDH inhibitors and practical implications of the INDIGO trial, contextualizing vorasidenib's class effects and tolerability among IDH inhibitors.PMIDCurrent and emerging therapies in IDH-mutant glioma.Nakhate V, Youssef G, Wen PY. · Neurotherapeutics 2026 · PMID 42085879Up-to-date review situating vorasidenib as the first targeted therapy for IDH-mutant glioma and summarizing its toxicity profile, supporting the conservative renal assessment.