Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
KIT / PDGFRA inhibitor
Avapritinib
Ayvakit · AVA
Potent KIT/PDGFRA inhibitor for D842V-driven GIST and mastocytosis — renal-relevant effects are edema and CNS bleeding/cognitive effects rather than direct nephrotoxicity.
MildMutation-selective KIT/PDGFRA era · approved 2020
Unresectable/metastatic GIST harboring a PDGFRA exon 18 (including D842V) mutationAdvanced systemic mastocytosis (aggressive SM, SM with associated hematologic neoplasm, mast cell leukemia)
Signature kidney injury
Prerenal / Hemodynamic AKI
Edema (periorbital/peripheral) is very common, and intracranial hemorrhage and cognitive/CNS effects are notable labeled toxicities; nausea/diarrhea contribute to volume shifts. Direct nephrotoxicity is not a defined signal and AKI, when it occurs, is secondary (fluid shifts, GI losses, mastocytosis mediator release).
Source: Heinrich et al., Lancet Oncol 2020 (NAVIGATOR); DeAngelo et al., Nat Med 2021 (EXPLORER)
Mechanism of kidney injury
Avapritinib has no characteristic primary renal lesion. Its renal relevance is indirect: (1) prominent fluid retention/edema reflects vascular permeability changes and can be accompanied by intravascular volume shifts; (2) gastrointestinal toxicity (nausea, diarrhea) causes volume depletion and prerenal azotemia; (3) in mastocytosis, mast-cell mediator-release (flushing, hypotension) can transiently impair renal perfusion. The signature CNS toxicities (intracranial bleeding, cognitive effects) are not renal but dominate the safety profile.
Clinical presentation
Periorbital and peripheral edema, fatigue, nausea/diarrhea, and cognitive effects (memory/attention) or, rarely, intracranial hemorrhage. Renally, a prerenal creatinine rise with GI losses or hypotension; edema may coexist with intravascular depletion.
Onset
Edema and cognitive effects across treatment; GI-related prerenal changes track intercurrent toxicity.
Reversibility
Reversible
Anticancer mechanism
Oral selective inhibitor of KIT and PDGFRA activation-loop mutants (notably PDGFRA exon 18/D842V and KIT exon 17), conformations resistant to imatinib. It is active in PDGFRA D842V-mutant GIST and advanced systemic mastocytosis.
Management
Treat prerenal AKI with volume repletion and control of GI losses; manage edema with dose modification and supportive measures (avoid over-diuresis that worsens prerenal physiology). Hold/reduce for cognitive effects or any intracranial hemorrhage. Mast-cell mediator events are treated with antihistamines/supportive care; renal effects generally reverse with hemodynamic stabilization.
Risk factors
- Volume depletion from nausea/diarrhea
- Pre-existing CKD and concurrent nephrotoxins
- Mast-cell mediator-release events in mastocytosis
- Older age and baseline cognitive/vascular vulnerability
Prevention
- Manage GI toxicity and maintain hydration
- Monitor for and manage edema; dose-modify for significant fluid retention
- Neurologic assessment for cognitive effects/bleeding; dose-reduce per label
- Mediator-release prophylaxis in mastocytosis as indicated
Note · The renal link is indirect — fluid shifts/edema, GI-loss prerenal physiology, and mastocytosis mediator release rather than a direct renal lesion. The defining toxicities (intracranial bleeding, cognitive effects) are non-renal.
Clinical depth
Renal dose adjustment
No dose adjustment for mild-moderate renal impairment; severe impairment/ESKD not well studied (hepatic CYP3A4 metabolism). Modifications driven by edema, CNS effects and cytopenias.
Dialyzability & ESKD dosing
Highly protein-bound; not expected to be dialyzable. No established ESKD dosing.
Differential diagnosis
Separate prerenal AKI (volume-responsive) from edema with intravascular depletion (avoid aggressive diuresis), and from mediator-release hypotension in mastocytosis. CNS symptoms require distinguishing cognitive toxicity from intracranial hemorrhage by imaging.
Monitoring
- Volume status, weight and edema assessment
- Cognitive/neurologic status; prompt imaging for new neurologic symptoms (bleed)
- Serum creatinine and electrolytes with GI toxicity
- CBC per schedule
Key trials & series
- NAVIGATOR (Heinrich, Lancet Oncol 2020) — registrational GIST trial (PDGFRA D842V)
- EXPLORER/PATHFINDER (DeAngelo, Nat Med 2021; Gotlib, Nat Med 2021) — advanced systemic mastocytosis safety/efficacy
Clinical pearls
- Edema with concurrent GI losses can mask intravascular volume depletion — assess true volume status before diuresing.
- Intracranial hemorrhage and cognitive effects are the signature (non-renal) toxicities — they drive dose decisions.
- In mastocytosis, mediator-release events can transiently impair renal perfusion.
- There is no characteristic direct avapritinib nephropathy; AKI is secondary.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAvapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial.Heinrich MC et al. · Lancet Oncol 2020 · PMID 32615108Registrational GIST trial defining efficacy and the edema/CNS safety profile.PMIDAvapritinib versus regorafenib in locally advanced unresectable or metastatic GIST (VOYAGER): a randomised, open-label, phase 3 trial.Kang YK et al. · J Clin Oncol 2021 · PMID 34343033Phase 3 comparative safety dataset.PMIDSafety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.DeAngelo DJ et al. · Nat Med 2021 · PMID 34873345Advanced systemic mastocytosis safety including edema and CNS effects.PMIDAvapritinib in advanced systemic mastocytosis: the phase 2 PATHFINDER trial.Gotlib J et al. · Nat Med 2021 · PMID 34873347Pivotal mastocytosis efficacy/safety confirming the toxicity pattern.PMIDManagement of adverse events associated with avapritinib.Joseph CP et al. · Oncologist 2021 · PMID 33301227Practical management of edema, cognitive effects and bleeding.PMIDOnconephrology: The Intersections Between the Kidney and Cancer.Rosner MH et al. · CA Cancer J Clin 2021 · PMID 32998135Framework for hemodynamic/secondary AKI from targeted agents.
Related agents
Other agents sharing the same signature kidney injury.