Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
KRAS G12C inhibitor
Adagrasib
Krazati · Adagra
A KRAS-G12C inhibitor whose kidney signal is mostly a creatinine bump and dehydration — but watch for a real glomerular signal.
MildKRAS G12C inhibitor · approved 2022
KRAS-G12C-mutated NSCLCKRAS-G12C-mutated colorectal cancer
Signature kidney injury
Prerenal / Hemodynamic AKI
Renal effects are usually mild: a creatinine rise (partly from inhibited tubular creatinine secretion) plus prerenal AKI from GI losses. The KRYSTAL-1 registrational program reported renal-related lab changes; a dedicated PubMed-indexed pseudo-AKI/albuminuria study for adagrasib does not yet exist, so the precise incidence is unquantified.
Source: Jänne et al., NEJM 2022 (KRYSTAL-1)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
Glomerulus
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
Adagrasib can raise serum creatinine partly by blocking tubular creatinine secretion ('pseudo-AKI' without true GFR loss). Clinically meaningful AKI is most often prerenal, from diarrhea/nausea/vomiting–related volume depletion, and the long half-life sustains GI toxicity. A real glomerular/albuminuria signal is increasingly described in real-world experience and should not be dismissed as pure pseudo-AKI without checking the urine.
Clinical presentation
Mild, early creatinine elevation; sometimes new albuminuria. Overt AKI usually accompanies significant GI fluid losses. QTc prolongation and GI toxicity are the other prominent adverse events.
Onset
Early — within the first weeks of therapy.
Reversibility
Reversible
Anticancer mechanism
Covalent KRAS G12C inhibitor with a long (~23 h) half-life and CNS penetration, irreversibly trapping mutant KRAS in its inactive GDP-bound state and blocking MAPK signaling in KRAS-G12C–mutated NSCLC and colorectal cancer.
Management
Volume repletion and GI-toxicity control. Distinguish a pure creatinine rise from true GFR decline (cystatin C-based eGFR, measured GFR); check urinalysis for proteinuria/active sediment before attributing change to benign pseudo-AKI. Dose-modify (from 600 mg twice daily) for severe GI, QTc or renal events.
Risk factors
- Diarrhea/nausea/vomiting with dehydration
- Concurrent nephrotoxins
- Pre-existing CKD
- Other tubular-secretion inhibitors (compounding pseudo-creatinine rise)
Prevention
- Hydration and early antiemetic/antidiarrheal support
- Baseline and serial creatinine plus urinalysis for albuminuria
- Consider cystatin C if pseudo-AKI is suspected
- Monitor QTc and electrolytes
Note · The creatinine increase may overstate true renal impairment via blocked tubular secretion, but real glomerular/albuminuria signals are emerging — so the key teaching point is to check the urine and a cystatin C before concluding it is 'just pseudo-AKI.'
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment is established; standard is 600 mg orally twice daily, modified for GI/QTc/hepatic toxicity. A measured (rather than creatinine-estimated) GFR is preferred when dosing renally cleared co-medications, because adagrasib inflates serum creatinine.
Dialyzability & ESKD dosing
Not characterized; highly protein-bound, hepatically metabolized (CYP3A4) small molecule, unlikely to be appreciably dialyzed. No ESKD dosing guidance exists.
Differential diagnosis
Pseudo-AKI (blocked OCT2/MATE-mediated creatinine secretion, normal cystatin C-based eGFR, bland urine) vs true AKI: prerenal azotemia from GI losses (responds to volume) vs a glomerular lesion (new albuminuria/proteinuria). Cystatin C and urinalysis are the discriminators.
Monitoring
- Serum creatinine AND cystatin C / measured GFR when true function is in question
- Urinalysis for albuminuria/proteinuria (do not assume pseudo-AKI)
- QTc (ECG) given QT-prolongation risk
- Volume status and GI symptom severity
Key trials & series
- Jänne et al., NEJM 2022 — KRYSTAL-1 NSCLC registrational cohort (renal/creatinine-related AEs)
- Yaeger et al., NEJM 2022 — KRYSTAL-1 colorectal cohort (± cetuximab)
Clinical pearls
- Adagrasib raises creatinine partly by blocking its tubular secretion — but confirm with cystatin C and a urinalysis rather than assuming pseudo-AKI.
- The long half-life sustains diarrhea/nausea; most genuine AKI is prerenal volume depletion.
- An inflated serum creatinine can cause inappropriate dose reductions of co-administered renally cleared drugs — use measured GFR for those decisions.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Vasculature / Endothelium
Glomerular & peritubular capillaries
Glomerulus
Filtration barrier (podocytes + endothelium)
Injury signatures
Prerenal / Hemodynamic AKIGlomerular Injury / ProteinuriaAcute Tubular NecrosisPseudo-AKI
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAdagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS G12C Mutation.Jänne PA et al. · N Engl J Med 2022 · PMID 35658005KRYSTAL-1 registrational NSCLC trial documenting creatinine elevations and renal-related adverse events.PMIDAdagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.Yaeger R et al. · N Engl J Med 2022 · PMID 36546659KRYSTAL-1 colorectal registrational cohort; adverse-event profile including GI toxicity.PMIDPractical Guidance for the Management of Adverse Events in Patients with KRASG12C-Mutated Non-Small Cell Lung Cancer Receiving Adagrasib.Zhang J et al. · Oncologist 2023 · PMID 36892150Clinical-investigator guidance on adagrasib toxicity, including GI losses and electrolyte/renal monitoring.PMIDThe Pharmacologic Inhibition of KRAS Mutants as a Treatment for Cancer: Therapeutic Principles and Clinical Results.Kasper S et al. · Dtsch Arztebl Int 2025 · PMID 40009739Cross-drug KRAS-inhibitor review (adagrasib vs sotorasib efficacy and adverse events).PMIDAcute Kidney Injury Associated with Anticancer Therapies: Small Molecules and Targeted Therapies.Kala J et al. · Kidney360 2024 · PMID 39186376Onconephrology review of targeted-agent AKI including pseudo-AKI from impaired creatinine secretion.PMIDOnconephrology: Update in Anticancer Drug-Related Nephrotoxicity.García-Carro C et al. · Nephron 2022 · PMID 35717937Onconephrology review framing pseudo-AKI vs true injury and urinary evaluation.
Related agents
Other agents sharing the same signature kidney injury.