Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
IDH2 inhibitor
Enasidenib
Idhifa · Enasi
An IDH2 inhibitor that cures by forcing leukemic blasts to mature — and that maturation itself can flood the kidneys.
ModerateIDH2 inhibitor · approved 2017
IDH2-mutated relapsed/refractory AML
Signature kidney injury
Prerenal / Hemodynamic AKI
Representative incidence10%
IDH-inhibitor differentiation syndrome (the main route to AKI) occurs in roughly 10% of enasidenib-treated AML patients (10.4% any-grade in a pooled trial analysis; ~7% grade ≥3 in the first-in-human study). Tumor lysis is a secondary risk. Direct tubular nephrotoxicity is not well quantified.
Source: Montesinos et al., Blood Adv 2024 (10.4% any-grade)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Prerenal / Hemodynamic AKI
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Mechanism of kidney injury
Drug-induced differentiation of IDH2-mutant blasts triggers a cytokine-driven systemic inflammatory (differentiation) syndrome with capillary leak, fluid shifts, hypotension and weight gain, producing hemodynamic (prerenal) AKI that can progress to ischemic ATN. Concurrent rapid cytoreduction can release urate/phosphate and add tumor-lysis intratubular injury; hyperleukocytosis amplifies the inflammatory cascade.
Clinical presentation
Differentiation syndrome with dyspnea/hypoxia, pulmonary infiltrates, fever, peripheral edema, weight gain, pleural/pericardial effusions and a rising creatinine; sometimes hyperuricemia/hyperphosphatemia/hyperkalemia from tumor lysis. Indirect hyperbilirubinemia (UGT1A1 inhibition) is a characteristic accompanying lab finding but is not renal.
Onset
Differentiation syndrome typically days to weeks after starting (median onset ~30 days; reported range days to ~4–5 months).
Reversibility
Reversible
Anticancer mechanism
Oral, first-in-class allosteric inhibitor of mutant isocitrate dehydrogenase-2 (IDH2). Mutant IDH2 neomorphically converts α-ketoglutarate to the oncometabolite 2-hydroxyglutarate (2-HG), which causes DNA/histone hypermethylation and blocks myeloid differentiation; enasidenib lowers 2-HG and releases this block, driving leukemic blasts to terminally mature in IDH2-mutated acute myeloid leukemia (AML).
Management
Start dexamethasone (e.g., 10 mg IV q12h) at first suspicion of differentiation syndrome; supportive hemodynamics, diuresis for fluid overload and oxygen. Hold enasidenib for severe/refractory syndrome and resume once resolved. Manage tumor lysis with IV hydration and rasburicase or allopurinol; correct electrolytes.
Risk factors
- High bone-marrow or peripheral blast burden
- Hyperleukocytosis
- Elevated LDH
- Rapid leukemic response
- Volume depletion
Prevention
- Vigilance for early differentiation-syndrome symptoms
- Prompt corticosteroids at first suspicion
- Cytoreduction (e.g., hydroxyurea) for hyperleukocytosis
- TLS prophylaxis with hydration and urate-lowering therapy
Note · Renal injury is a downstream consequence of differentiation syndrome and tumor lysis rather than direct tubular toxicity. Inducing differentiation (not cytotoxicity) is the therapeutic mechanism, so the same biology that drives response drives the renal risk.
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment is established; enasidenib was not studied in severe renal impairment/ESKD. Standard dose is 100 mg orally once daily, modified for toxicity (including differentiation syndrome and indirect hyperbilirubinemia), not for CrCl.
Dialyzability & ESKD dosing
Not characterized; enasidenib is highly protein-bound and hepatically metabolized, so it is not expected to be appreciably removed by hemodialysis. No HD-specific dosing guidance exists.
Differential diagnosis
Distinguish differentiation syndrome from sepsis/pneumonia (overlapping fever, infiltrates, hypotension), cardiogenic pulmonary edema, and transfusion reactions; the constellation of weight gain, effusions and rising WBC during blast maturation favors differentiation syndrome. Separate prerenal/differentiation AKI from tumor-lysis crystal nephropathy by the electrolyte/uric-acid profile.
Monitoring
- Daily symptom/weight/oxygenation assessment for differentiation syndrome during the first 1–2 months
- CBC with differential (track blast maturation and rising WBC)
- Tumor-lysis labs (uric acid, potassium, phosphate, calcium, creatinine) during early response
- Total/indirect bilirubin (UGT1A1 inhibition mimics hyperbilirubinemia)
Key trials & series
- Stein et al., Blood 2017 — first-in-human AG221-C-001 phase 1/2 (registrational R/R AML data, 40.3% ORR, 7% grade ≥3 differentiation syndrome)
- Montesinos et al., Blood Adv 2024 — pooled 4-trial analysis defining 10.4% differentiation-syndrome incidence
Clinical pearls
- Differentiation syndrome — not direct nephrotoxicity — is the reason enasidenib threatens the kidney; treat early with steroids and do not necessarily stop the drug.
- Indirect hyperbilirubinemia from UGT1A1 inhibition is expected and benign; do not confuse it with hepatorenal or hemolytic processes.
- A rising WBC during therapy reflects intended blast maturation, not relapse — but it heralds differentiation-syndrome and tumor-lysis risk.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Prerenal / Hemodynamic AKIAcute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of idh2 inhibitors.
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Differentiation syndrome
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- QT prolongation
Evidence
8 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEnasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.Stein EM et al. · Blood 2017 · PMID 28588020First-in-human phase 1/2 registrational trial: 40.3% ORR, differentiation as mechanism of response, 7% grade ≥3 differentiation syndrome.PMIDDifferentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials.Montesinos P et al. · Blood Adv 2024 · PMID 38507688Pooled analysis of 4 trials: 10.4% any-grade differentiation syndrome, risk factors and management.PMIDHow I treat acute myeloid leukemia with differentiation therapy.Issa GC et al. · Blood 2025 · PMID 38976876Practical review of differentiation syndrome across ATRA/ATO and IDH/FLT3 inhibitors, including renal insufficiency and steroid management.PMIDDifferentiation syndrome with lower-intensity treatments for acute myeloid leukemia.Fathi AT et al. · Am J Hematol 2021 · PMID 33625753Review of differentiation syndrome with IDH and FLT3 inhibitors, diagnostic criteria and end-organ (renal) effects.PMIDEnasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia.Dogra R et al. · Anticancer Agents Med Chem 2018 · PMID 30360730Mechanism, pharmacokinetics and toxicity review (differentiation syndrome, electrolyte changes).PMIDDifferentiation Syndrome in Acute Leukemia: APL and Beyond.Woods AC et al. · Cancers (Basel) 2023 · PMID 37835461Review of differentiation-syndrome pathogenesis including acute renal failure with IDH/retinoid/arsenic agents.PMIDEfficacy and tolerability of isocitrate dehydrogenase inhibitors in patients with acute myeloid leukemia: A systematic review of clinical trials.Aiman W et al. · Leuk Res 2023 · PMID 37100025Systematic review quantifying grade ≥3 differentiation syndrome and QT effects of IDH inhibitors.PMIDAcute Kidney Injury Associated with Anticancer Therapies: Small Molecules and Targeted Therapies.Kala J et al. · Kidney360 2024 · PMID 39186376Onconephrology review of AKI mechanisms across targeted agents including IDH inhibitors.
Related agents
Other agents sharing the same signature kidney injury.