Bosutinib
Bosulif · BCR-ABL TKI
Reversible eGFR decline.
PSEUDOPRE
MildOpen →
ROS1/TRK TKI
Repotrectinib
Augtyro · Repo
A ROS1/TRK TKI whose creatinine bump often reflects blocked tubular secretion, not true injury.
MildROS1/TRK tyrosine-kinase inhibitor · approved 2023
ROS1-positive NSCLCNTRK-fusion solid tumors
Signature kidney injury
Pseudo-AKI
An apparent rise in serum creatinine is described that often reflects inhibition of tubular creatinine secretion rather than a true fall in GFR (pseudo-AKI). Genuine intrinsic nephrotoxicity is not a characteristic feature and is not well quantified. This pattern is increasingly recognized across kinase inhibitors (e.g., ALK TKIs, where most creatinine-based eGFR changes do not require treatment change).
Source: Drilon et al. (TRIDENT-1) / class pseudo-AKI literature
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / Endothelium
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting Duct
Pseudo-AKI
The great mimic — a rise in creatinine from blocked tubular secretion (OCT2/MATE), NOT true injury. The GFR is intact; confirm with cystatin C before stopping effective therapy.
Mechanism of kidney injury
Creatinine is freely filtered but also actively secreted by proximal-tubular transporters — organic cation transporter 2 (OCT2) at the basolateral membrane and MATE1/MATE2-K at the apical membrane. Several kinase inhibitors inhibit OCT2/MATE-mediated secretion, raising serum creatinine without reducing true glomerular filtration — a benign, reversible 'pseudo-AKI.' Repotrectinib's early creatinine rise is best understood in this framework (the tucatinib OCT2/MATE precedent demonstrates the phenomenon directly). Because cystatin C is not secreted by these transporters, a cystatin-C-based estimate that remains normal confirms preserved true GFR.
Clinical presentation
A modest, early, stable rise in serum creatinine without other features of tubular injury; urinalysis is typically bland (no significant proteinuria, hematuria or casts), and cystatin-C-based eGFR is preserved.
Onset
Early after initiation; stable thereafter (a step change, not a progressive decline).
Reversibility
Reversible
Anticancer mechanism
Next-generation, compact macrocyclic ROS1 and NTRK (TRKA/B/C) tyrosine-kinase inhibitor designed to retain activity against solvent-front and other resistance mutations (e.g., ROS1 G2032R). Approved for ROS1-positive NSCLC and NTRK-fusion solid tumors.
Management
Confirm the pattern: bland urinalysis, an early stable creatinine step, and a normal cystatin-C-based eGFR. No specific renal therapy is needed for transporter-mediated creatinine elevation; reserve dose changes and workup for a true progressive decline, abnormal sediment, or other signs of injury. (Neurologic CNS effects, not renal injury, are repotrectinib's main on-target toxicity.)
Risk factors
- Pre-existing CKD (complicates interpretation)
- Concurrent OCT2/MATE-affecting drugs (e.g., metformin, trimethoprim, cimetidine)
Prevention
- Recognize the pseudo-AKI pattern before reacting
- Obtain a baseline creatinine to gauge the step change
- Consider cystatin C when true GFR is in question
- Avoid unnecessary dose changes for an isolated, stable creatinine rise
Note · The creatinine signal is typically a tubular-secretion-blockade artifact (pseudo-AKI), not true injury; renal-specific literature for repotrectinib is thin, and the concept rests on well-described class behavior. Misreading it as AKI risks unnecessary dose reduction.
Clinical depth
Renal dose adjustment
No renal dose adjustment for mild–moderate impairment; severe impairment/ESKD not well studied. Critically, an isolated transporter-mediated creatinine rise should NOT, by itself, trigger renal dose reduction — confirm true GFR first.
Dialyzability & ESKD dosing
Hepatically metabolized small molecule; dialyzability not characterized and not clinically relevant to the (artifactual) creatinine rise. No established ESKD dosing.
Differential diagnosis
Pseudo-AKI from OCT2/MATE inhibition (early, stable, bland sediment, normal cystatin-C eGFR) vs true AKI (progressive creatinine, abnormal sediment, falling cystatin-C eGFR) vs pre-renal/volume causes; cystatin C is the decisive discriminator.
Monitoring
- Baseline and on-treatment serum creatinine (interpret as a step change)
- Cystatin C / cystatin-C-based eGFR if true GFR is uncertain
- Urinalysis to confirm a bland sediment
- Review of co-medications affecting OCT2/MATE
Key trials & series
- TRIDENT-1 (registrational ROS1/NTRK trial)
- Topletz-Erickson tucatinib OCT2/MATE pharmacology study (class pseudo-AKI proof of concept)
- Pinard/Kitchlu ALK-TKI creatinine cohort (analogous kinase-inhibitor creatinine kinetics)
Clinical pearls
- An early, stable creatinine bump with a bland urinalysis is usually pseudo-AKI from blocked tubular creatinine secretion — not real injury.
- Cystatin C settles the question: it is not OCT2/MATE-secreted, so a normal cystatin-C eGFR confirms preserved true GFR.
- Do not dose-reduce reflexively for an isolated creatinine rise — that can under-treat the cancer for an artifact.
- Co-meds like metformin, trimethoprim and cimetidine share the OCT2/MATE pathway and can compound the effect.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Pseudo-AKIPrerenal / Hemodynamic AKIElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of ros1/trk tkis.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Visual disturbance (crizotinib)
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- CNS effects (lorlatinib)
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkDrug-induced rise in serum creatinine: cystatin C to the rescue? Evidence, pitfalls and knowledge gaps.Van Regemorter E et al. · Eur J Intern Med 2025 · PMID 41224604Narrative review of pseudo-AKI from targeted agents (TKIs, PARP, CDK4/6) via tubular-secretion inhibition, and use of cystatin C to discern true vs pseudo-AKI.PMIDTucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects.Topletz-Erickson AR et al. · J Clin Pharmacol 2020 · PMID 32989831Demonstrates kinase-inhibitor OCT2/MATE blockade raising serum creatinine without true GFR change — the mechanistic proof of pseudo-AKI.PMIDReal-World Creatinine-Based Estimates of Acute and Chronic Kidney Dysfunction in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer Receiving Tyrosine Kinase Inhibitors.Pinard L et al. · Clin Lung Cancer 2025 · PMID 40382267Cohort showing kinase-inhibitor creatinine-based eGFR changes often do not require treatment change and recover after cessation — analogous to repotrectinib.PMIDRepotrectinib: a promising new therapy for advanced nonsmall cell lung cancer.Rais T et al. · Ann Med Surg (Lond) 2024 · PMID 39649881Review of repotrectinib efficacy and safety in ROS1-positive NSCLC.PMIDRenal Side Effects of Novel Molecular Targeted Oncologic Agents.Fenoglio R et al. · G Ital Nefrol 2023 · PMID 38007829Onconephrology overview underscoring that creatinine changes on targeted agents may not reflect true injury and that biopsy clarifies real lesions.PMIDConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Onconephrology reference framing interpretation of creatinine-based GFR changes during cancer therapy.