Bosutinib
Bosulif · BCR-ABL TKI
Reversible eGFR decline.
PSEUDOPRE
MildOpen →
TRK/ROS1 TKI
Entrectinib
Rozlytrek · ENTR
A TRK/ROS1 TKI that nudges creatinine up by curbing tubular secretion — a benign pseudo-AKI pattern.
MildTRK/ROS1 tyrosine kinase inhibitor · approved 2019
NTRK fusion-positive solid tumorsROS1-positive non-small cell lung cancer
Signature kidney injury
Pseudo-AKI
A mild blood-creatinine increase is recognized and is attributed to reduced tubular creatinine secretion rather than true GFR decline (a pseudo-AKI pattern). It is typically modest, early and reversible; a meaningful structural-AKI rate is not established.
Source: Mercier et al., Cancer Chemother Pharmacol 2022
Mechanism of kidney injury
Inhibition of proximal-tubule cationic creatinine transport (OCT2/MATE-type effect, as seen across several TKIs) reduces creatinine secretion into the tubular lumen and raises serum creatinine without injuring the nephron. Filtration (true GFR) is preserved; the change is an analytical/physiologic artifact, not tubular damage.
Clinical presentation
Modest, early, stable creatinine elevation with bland urinalysis and preserved measured GFR (cystatin C unchanged); no electrolyte derangement or proteinuria.
Onset
Within the first weeks of therapy; reversible on discontinuation.
Reversibility
Reversible
Anticancer mechanism
Oral, CNS-penetrant multikinase inhibitor of TRK (NTRK1/2/3), ROS1 and ALK. Approved for NTRK fusion-positive solid tumors (tumor-agnostic) and ROS1-positive NSCLC.
Management
Recognize as pseudo-AKI: do not stop effective therapy for an isolated stable creatinine rise with bland sediment. Confirm with cystatin C/measured GFR if needed. No specific renal treatment.
Risk factors
- Baseline CKD (makes the creatinine shift more conspicuous)
- Concurrent drugs affecting creatinine secretion
Prevention
- Anticipate the benign creatinine rise; avoid unnecessary interruption
- Confirm preserved true GFR with cystatin C/measured GFR if uncertain
Note · ASON-flagged pseudo-AKI pattern. The exposure-response analysis is cited for the recognized creatinine effect; the mechanism is inferred from the broader TKI creatinine-secretion literature (tucatinib as the proven analog).
Clinical depth
Renal dose adjustment
No renal dose adjustment for mild-to-moderate impairment; entrectinib is hepatically (CYP3A4) metabolized with low renal clearance. The creatinine rise should not be misread as AKI requiring dose reduction. Limited data in severe impairment/dialysis.
Dialyzability & ESKD dosing
Not characterized; highly protein-bound, lipophilic, non-renally cleared — unlikely to be appreciably dialyzed. No ESKD dosing guidance.
Differential diagnosis
Pseudo-AKI vs true AKI: an early, modest, stable creatinine rise with bland sediment and a normal cystatin C-based/measured GFR indicates the secretion artifact, not injury. Discordant creatinine-up / cystatin C-stable is the giveaway.
Monitoring
- Serum creatinine with cystatin C as a confirmatory test if a rise prompts concern
- Urinalysis (expected bland)
- QTc and LVEF per label (the clinically important toxicities)
Key trials & series
- Integrated ALKA/STARTRK-1/STARTRK-2 analyses — registrational efficacy/safety (clinical context)
- Mercier, Cancer Chemother Pharmacol 2022 — exposure-response/safety documenting the creatinine signal
Clinical pearls
- Like tucatinib, entrectinib raises creatinine via blocked proximal-tubular secretion — confirm with cystatin C and keep treating.
- The dominant real toxicities are QTc prolongation, weight gain and CNS effects, not the kidney.
- Don't dose-reduce or stop for an isolated stable creatinine bump with a bland urinalysis.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Pseudo-AKIPrerenal / Hemodynamic AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of trk/ros1 tkis.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Visual disturbance (crizotinib)
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- CNS effects (lorlatinib)
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEfficacy and safety exposure-response analyses of entrectinib in patients with advanced or metastatic solid tumors.Mercier F et al. · Cancer Chemother Pharmacol 2022 · PMID 35118559Exposure-response/safety analysis documenting the creatinine-increase signal consistent with reduced tubular secretion.LandmarkTucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects.Topletz-Erickson AS et al. · J Clin Pharmacol 2020 · PMID 32989831Mechanistic analog: demonstrates OCT2/MATE inhibition as the cause of TKI-related creatinine rise without true GFR loss.PMIDQuantitative Consideration of Clinical Increases in Serum Creatinine Caused by Renal Transporter Inhibition.Nakada T et al. · Drug Metab Dispos 2023 · PMID 36859345Quantitative framework showing TKI OCT2/MATE inhibition can raise creatinine above AKI thresholds without true functional change.PMIDOnconephrology: mitigation of renal injury in chemotherapy administration.Selamet U et al. · Curr Opin Nephrol Hypertens 2023 · PMID 38095483Onconephrology review distinguishing transporter-mediated creatinine elevations from true TKI nephrotoxicity.