Bosutinib
Bosulif · BCR-ABL TKI
Reversible eGFR decline.
PSEUDOPRE
MildOpen →
TRK inhibitor
Larotrectinib
Vitrakvi · LARO
A tumor-agnostic TRK inhibitor whose creatinine bump is pseudo-AKI — blocked tubular secretion, not damage; check cystatin C.
MildTRK inhibitor · approved 2018
Solid tumors with an NTRK gene fusion (tumor-agnostic), metastatic or where surgery would cause severe morbidity, with progression or no satisfactory alternatives
Signature kidney injury
Pseudo-AKI
The larotrectinib-specific creatinine effect is not separately quantified; the mechanism is extrapolated from the TKI class (the tucatinib OCT2/MATE study and crizotinib's ~21% early, reversible, secretion-driven rise). The clinically important real toxicities are hepatic (transaminase elevation) and neurologic, not renal.
Source: Drilon et al., NEJM 2018
Mechanism of kidney injury
Pseudo-AKI: the drug inhibits proximal-tubule cation transporters OCT2 (basolateral) and MATE1/MATE2-K (apical) that secrete creatinine into the tubular lumen. Blocking secretion lowers tubular creatinine clearance, raising serum creatinine and lowering creatinine-based eGFR without any reduction in true GFR. Cystatin C (not handled by these transporters) and measured GFR remain normal — an artifactual creatinine elevation, not structural injury.
Clinical presentation
A mild rise in creatinine early after starting (by analogy with related TKIs, within ~2 weeks) that then plateaus, with no oliguria, no electrolyte derangement, a bland urinalysis, no drug-attributable proteinuria, and an asymptomatic patient.
Onset
Early (days to weeks), stable/plateauing, and fully reversible on interruption or discontinuation.
Reversibility
Reversible
Anticancer mechanism
Highly selective ATP-competitive pan-TRK inhibitor (TRKA/B/C; NTRK1/2/3). In fusion-positive tumors the constitutively active TRK kinase drives oncogenesis; activity is tumor-agnostic, driven solely by the NTRK gene fusion.
Management
Confirm pseudo-AKI by measuring cystatin C (or measured GFR), which remain normal despite the elevated creatinine; with a bland sediment and no other AKI features, reassure and continue therapy. Reserve workup/interruption for true AKI signals (rapidly rising or large creatinine increase, active sediment, electrolyte abnormalities, proteinuria, symptoms).
Risk factors
- Reduced baseline renal reserve (makes a small secretory shift more noticeable)
- Concurrent OCT2/MATE-inhibiting or nephrotoxic drugs
Prevention
- Recognize the pattern: a modest, stable creatinine rise in an asymptomatic patient
- Confirm with cystatin C and/or measured GFR before reacting
- Do not reflexively hold or renally dose-reduce for the isolated finding
Note · No larotrectinib-specific pseudo-AKI case report is indexed in PubMed; the renal-mechanism citations (tucatinib OCT2/MATE, crizotinib, ALK-inhibitor review) are class-level supporting evidence — the honest state of the literature.
Clinical depth
Renal dose adjustment
No dose adjustment is required for mild/moderate renal impairment (no change to the starting dose). Adults 100 mg PO twice daily; children 100 mg/m2 (max 100 mg) twice daily. Note that moderate-to-severe hepatic impairment does require dose reduction — a useful contrast, since the creatinine bump can be mistaken for a renal-dosing trigger.
Dialyzability & ESKD dosing
Not established; a small-molecule, lipophilic, highly protein-bound drug not expected to be meaningfully dialyzable.
Differential diagnosis
Pseudo-AKI (mild, early, plateauing creatinine; normal cystatin C/measured GFR; bland urine; reversible; asymptomatic — continue drug) versus true AKI to exclude (tumor lysis, prerenal volume depletion, obstruction, concomitant nephrotoxins/contrast), where cystatin C/measured GFR are also reduced, the sediment/proteinuria may be abnormal, and the rise is progressive.
Monitoring
- Periodic serum creatinine and LFTs (transaminase elevation is the main grade 3 toxicity)
- Cystatin C if creatinine rises, to distinguish pseudo-AKI from true injury
- Neurologic effects (dizziness, gait/cognition)
Key trials & series
- Pooled registrational analysis (Drilon, NEJM 2018) — phase 1, SCOUT and NAVIGATE; 75% ORR
- Expanded pooled analysis (Hong, Lancet Oncol 2020) — 79% ORR with durable safety
Clinical pearls
- A small, early, stable creatinine bump usually reflects inhibited tubular creatinine secretion, not damage — check cystatin C before reacting.
- Cystatin-C-based eGFR (or measured GFR) is the tiebreaker: normal means pseudo-AKI — reassure and continue; do not reflexively hold or renally dose-reduce.
- The larotrectinib-specific creatinine effect is not separately quantified; the mechanism is class-level (tucatinib OCT2/MATE; crizotinib's early, reversible rise).
- The clinically important real toxicities are hepatic (ALT/AST) and CNS/neurologic — not the kidney.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Pseudo-AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of trk inhibitors.
Ophthalmic
Keratopathy, uveitis, retinopathy
- Visual disturbance (crizotinib)
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- CNS effects (lorlatinib)
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEfficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.Drilon A et al. · N Engl J Med 2018 · PMID 29466156Landmark registrational pooled report (phase 1, SCOUT, NAVIGATE); 75% ORR tumor-agnostic.PMIDLarotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.Laetsch TW et al. · Lancet Oncol 2018 · PMID 29606586Primary SCOUT pediatric phase 1 defining the dose and efficacy.PMIDLarotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials.Hong DS et al. · Lancet Oncol 2020 · PMID 32105622Expanded pooled analysis (79% ORR) with durable safety.PMIDTRK Inhibition: A New Tumor-Agnostic Treatment Strategy.Kummar S et al. · Target Oncol 2018 · PMID 30276762Mechanistic/regulatory review of NTRK fusions and the tumor-agnostic paradigm.PMIDTucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects.Topletz-Erickson AR et al. · J Clin Pharmacol 2020 · PMID 32989831Proof-of-concept: a TKI raises creatinine via OCT2/MATE block while iohexol GFR/cystatin C remain unchanged — the pseudo-AKI mechanism.PMIDRenal Effects of Crizotinib in Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer.Camidge DR et al. · J Thorac Oncol 2019 · PMID 30822515An early (~21%) creatinine rise that plateaued and reversed — supports the pseudo-AKI pattern.PMIDThe renal effects of ALK inhibitors.Izzedine H et al. · Invest New Drugs 2016 · PMID 27468827Onconephrology review of TKI creatinine elevation: pseudo-AKI versus true injury.