Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
IDH1 inhibitor
Ivosidenib
Tibsovo · Ivo
An IDH1 inhibitor whose kidney risk is indirect — differentiation syndrome and tumor lysis driving AKI.
ModerateIDH1 inhibitor · approved 2018
IDH1-mutant acute myeloid leukemiaIDH1-mutant cholangiocarcinoma
Signature kidney injury
Prerenal / Hemodynamic AKI
Differentiation (IDH) syndrome is a recognized, potentially fatal complication — reported in roughly 10-19% of AML patients across IDH-inhibitor experience (e.g. ~10.4-11.7% with the IDH2 inhibitor enasidenib in pooled/phase 1-2 analyses) — and can drive AKI through capillary leak, fluid overload, hypotension, and inflammation; tumor lysis can also occur with cytoreduction.
Source: DiNardo et al., N Engl J Med 2018
Mechanism of kidney injury
Kidney injury is largely indirect. Differentiation syndrome — driven by a cytokine surge from rapidly differentiating myeloblasts — causes systemic inflammation, capillary leak, hemodynamic instability, and fluid overload that produce a prerenal/hemodynamic AKI (sometimes with concurrent ATN). Tumor lysis syndrome from rapid blast clearance adds uric acid and phosphate load with crystal/electrolyte-mediated AKI.
Clinical presentation
Differentiation syndrome: dyspnea/hypoxia, fever, peripheral edema, pulmonary infiltrates, weight gain, hypotension, and rising creatinine, often with leukocytosis; median onset ~30 days (range days to ~4 months). Tumor lysis: hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and AKI. QT prolongation is a separate class effect.
Onset
Differentiation syndrome typically days to weeks after starting therapy (median ~30 days); tumor lysis early during cytoreduction.
Reversibility
Variable
Anticancer mechanism
Inhibits mutant isocitrate dehydrogenase-1 (IDH1), lowering the oncometabolite 2-hydroxyglutarate and inducing myeloid differentiation. Approved for IDH1-mutant acute myeloid leukemia and IDH1-mutant cholangiocarcinoma.
Management
Prompt systemic corticosteroids (e.g. dexamethasone ~10 mg IV q12h) and supportive care for differentiation syndrome, with diuresis for fluid overload, leukapheresis/hydroxyurea for marked leukocytosis, and drug interruption if severe or unresponsive; TLS management with aggressive hydration, rasburicase or allopurinol, electrolyte correction, and renal replacement therapy if refractory.
Risk factors
- High leukemic/blast burden and high LDH
- Rapid response/cytoreduction
- Baseline renal impairment
- Volume-overload states
Prevention
- Vigilance for differentiation syndrome from the first weeks
- TLS prophylaxis (IV hydration, urate-lowering therapy)
- Monitor electrolytes, daily weights, oxygenation, and WBC
Note · Kidney injury is predominantly secondary to differentiation syndrome and tumor lysis rather than direct tubular toxicity. IDH2-inhibitor (enasidenib) data are used as class-informative context for differentiation-syndrome incidence and management.
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment established; no change recommended for mild-moderate impairment, and severe impairment/dialysis are not well studied. Dose interruption is driven by differentiation syndrome, QTc prolongation, and other toxicities rather than a CrCl rule.
Dialyzability & ESKD dosing
Highly protein-bound oral small molecule; not meaningfully dialyzed. Renal replacement therapy is used to manage AKI/TLS metabolic derangements, not to clear the drug.
Differential diagnosis
IDH differentiation-syndrome AKI (capillary leak, fluid overload, hypotension, leukocytosis, pulmonary infiltrates) vs tumor-lysis AKI (hyperuricemia/hyperphosphatemia/hyperkalemia) vs sepsis or nephrotoxin-related ATN in a neutropenic leukemia patient. The two on-target syndromes frequently overlap and can coexist.
Monitoring
- Daily clinical assessment for differentiation syndrome (dyspnea, edema, weight, oxygenation, WBC) during the first weeks
- Electrolytes, uric acid, phosphate, calcium, and creatinine for tumor lysis during cytoreduction
- ECG/QTc (QT prolongation is a recognized class effect)
Key trials & series
- AG120-C-001 (registrational ivosidenib in relapsed/refractory IDH1-mutant AML — DiNardo NEJM 2018)
- Roboz 2020 frontline IDH1-mutant AML cohort
- Fathi 2018 / Montesinos 2024 IDH-inhibitor differentiation-syndrome analyses (enasidenib, class-informative)
Clinical pearls
- The kidney is an innocent bystander: AKI here is driven by differentiation syndrome and tumor lysis, not direct tubular toxicity.
- Start corticosteroids early and do not necessarily stop the drug — most differentiation syndrome is managed without permanent discontinuation.
- Layer TLS prophylaxis (hydration plus urate-lowering) at initiation in high-burden disease, and watch for the two syndromes overlapping.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of idh1 inhibitors.
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Differentiation syndrome
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- QT prolongation
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkDurable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.DiNardo CD et al. · N Engl J Med 2018 · PMID 29860938Pivotal trial describing IDH differentiation syndrome and leukocytosis as key on-target safety events.PMIDIvosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.Roboz GJ et al. · Blood 2020 · PMID 31841594Frontline AML data reporting differentiation syndrome among notable adverse events.PMIDDifferentiation syndrome with lower-intensity treatments for acute myeloid leukemia.Fathi AT et al. · Am J Hematol 2021 · PMID 33625753Expert review of IDH/FLT3-inhibitor differentiation syndrome, including AKI, diagnostic criteria, and corticosteroid management.PMIDDifferentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study.Fathi AT et al. · JAMA Oncol 2018 · PMID 29346478Characterizes IDH-inhibitor differentiation syndrome (~12%), median onset 30 days, and corticosteroid-based management — class-informative for ivosidenib.PMIDDifferentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials.Montesinos P et al. · Blood Adv 2024 · PMID 38507688Pooled analysis quantifying IDH-inhibitor differentiation-syndrome incidence (~10.4%), risk factors, and management across trials.PMIDIvosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.Abou-Alfa GK et al. · Lancet Oncol 2020 · PMID 32416072Pivotal ClarIDHy trial extending ivosidenib to IDH1-mutant cholangiocarcinoma; registrational safety dataset.
Related agents
Other agents sharing the same signature kidney injury.