Blocked tubular secretion, not injury
Pseudo-AKI: the creatinine rises and the kidney is fine
Creatinine does not only filter — a fifth of it is pushed into the urine by tubular transporters, and a drug that blocks those transporters raises the number without touching the glomerulus, producing a rise that looks like acute kidney injury on every axis except the one that matters.
- 41% → 71%
- Trial eligibility, creatinine vs cystatin CApplying a GFR cutoff of 40 mL/min to patients on MATE-1-inhibiting TKIs, eligibility rose from 7 of 17 by creatinine to 12 of 17 by cystatin C — the artifact was excluding patients from treatment, not protecting them.PMID 37748692
- 15 of 17
- Paired samples where cystatin C read higherIn patients with creatinine and cystatin C drawn concurrently on TKI therapy, the cystatin C-based GFR was the higher of the two in almost every case; in a third of them by 30 mL/min or more.PMID 37748692
- 23%
- Fall in creatinine clearance with tucatinibIn 18 healthy subjects, creatinine clearance fell transiently while iohexol-measured GFR and cystatin C-based eGFR were unchanged — the clearest available separation of the marker from the function.PMID 32989831
- 10%
- Meeting creatinine-based AKI criteriaOf 863 patients on MATE-1-inhibiting TKIs, 90 met KDIGO creatinine criteria for AKI; 72% of those were stage 1.PMID 37748692
Teaching case · illustrative composite, not a real patient
A 63-year-old man with ALK-rearranged non-small-cell lung cancer starts lorlatinib. His baseline creatinine is 0.9 mg/dL. At the four-week visit it is 1.3 mg/dL, and at eight weeks 1.35 mg/dL, where it stays. He feels well. Urine output is normal, the dipstick is bland, there is no proteinuria and no haematuria, and the renal ultrasound is unremarkable. He is on no new nephrotoxin, is not volume-depleted, and has had no contrast.
The rise meets KDIGO stage 1 by creatinine alone, and the reflex is to hold the drug. Instead, cystatin C is sent: the cystatin C-based eGFR is 88 mL/min/1.73 m², against 58 by creatinine. The creatinine has plateaued rather than climbed, appeared within weeks of starting rather than after an ischaemic or septic insult, and carries no urinary findings. Lorlatinib is continued at full dose. Creatinine remains at its new plateau for the next two years without functional decline.
Teaching point — A creatinine rise on a MATE-1/OCT2-inhibiting agent that (a) appears within weeks of starting, (b) plateaus rather than progresses, (c) has a bland urinary sediment, and (d) is contradicted by a cystatin C-based eGFR is a secretion artifact, not injury. The consequential error is the reverse of the usual one: not missing nephrotoxicity, but treating a normal kidney as a damaged one and withdrawing an effective drug. Confirm before you stop.
How it happens
The pathophysiology as a cascade — select a step to follow the mechanism.
Glomerular filtration is the larger route, but a meaningful fraction of creatinine reaches the urine by active secretion across the proximal tubule. Any measure that treats creatinine as filtered-only will misread a change in that second route as a change in the first.
PMID 32989831 (opens PubMed in a new tab)Organic cation transporter 2 on the basolateral membrane takes creatinine up from blood. It is the entry step of the secretory route, and it is inhibitable.
PMID 32989831 (opens PubMed in a new tab)The multidrug and toxin extrusion proteins complete the transfer across the apical membrane. Several oncology TKIs inhibit MATE1 at concentrations below those needed to inhibit OCT2 — for tucatinib the creatinine IC50 is 0.0855 µM at MATE1 against 0.107 µM at OCT2 — so the exit step is often the one that is blocked.
PMID 32989831 (opens PubMed in a new tab)Creatinine that cannot be secreted stays in the blood. The number rises, the KDIGO criteria are met, and the glomerulus has not been touched — demonstrated most cleanly by the unchanged iohexol-measured GFR alongside a 23% fall in creatinine clearance.
PMID 32989831 (opens PubMed in a new tab)Because cystatin C does not use the OCT2/MATE route, an eGFR calculated from it is unaffected by the block — which is why the two markers separate on drug and why the separation is the diagnostic test rather than an incidental finding.
PMID 37748692 (opens PubMed in a new tab)
How we learned it
- 2021
Tucatinib is shown to inhibit OCT2 and MATE1/2-K with no effect on measured GFR
A phase 1 study separates the marker from the function directly: creatinine clearance falls 23% while iohexol-measured GFR and cystatin C-based eGFR do not move.
PMID 32989831 (opens PubMed in a new tab) - 2024
Pseudo-AKI is named as a class phenomenon of targeted agents
An editorial frames the diagnostic problem as one of choosing the filtration marker rather than of grading the creatinine, and adds tepotinib to the list of implicated agents.
PMID 37007700 (opens PubMed in a new tab) - 2024
863 patients on MATE-1-inhibiting TKIs are analysed systematically
The largest characterisation to date, and the first to quantify what the artifact costs: recalculating with cystatin C moved most patients above a trial-eligibility threshold they had failed on creatinine.
PMID 37748692 (opens PubMed in a new tab) - 2025
Real-world ALK-inhibitor cohort finds the creatinine changes rarely warrant stopping
Across 191 ALK-inhibitor treatments in 114 patients, 20 (10% of treatments) met creatinine-based AKI criteria within 90 days but only 4 treatment changes were attributed to it; 28 patients (14%) met CKD criteria within a year, none requiring dialysis, and overall survival did not differ by AKI status.
PMID 40382267 (opens PubMed in a new tab)
The landmark studies
Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function
Chen M et al. · J Thorac Oncol 2024 · PMID 37748692
Creatinine-based GFR understated kidney function in almost every patient with a paired cystatin C, and the gap was large enough to change trial eligibility. The authors recommend recalculating GFR with cystatin C before looking for another cause or reducing the TKI.
863 patients; 90 (10%) met creatinine AKI criteria (72% stage 1); cystatin C GFR higher in 15/17 paired samples, by ≥30 mL/min in 33%; eligibility at a 40 mL/min cutoff 41% → 71%
Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects
Topletz-Erickson A et al. · J Clin Pharmacol 2021 · PMID 32989831
Tucatinib inhibits OCT2- and MATE1-mediated transport of creatinine at sub-micromolar concentrations; in subjects, creatinine clearance fell while GFR measured by iohexol clearance — which does not depend on these transporters — did not.
Creatinine transport IC50 0.107 µM (OCT2) and 0.0855 µM (MATE1); creatinine clearance −23%; iohexol GFR and cystatin C eGFR unchanged
Real-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 40382267
Creatinine-defined AKI and CKD events were common after starting an ALK inhibitor but seldom changed management, never required dialysis among the CKD events, and did not affect survival — supporting continuation despite creatinine-based eGFR changes.
20 (10%) AKI within 90 days with 4 treatment changes; 28 (14%) CKD with 10 treatment changes; 0 dialysis; overall survival not different by AKI status
Pseudo-AKI associated with targeted anti-cancer agents — the truth is in the eye of the filtration marker
Vanhoutte T et al. · Clin Kidney J 2024 · PMID 37007700
Frames the problem as marker selection rather than creatinine grading, and argues that distinguishing pseudo-AKI from true AKI is a prerequisite for managing patients on targeted therapy.
Narrative; adds tepotinib to the list of implicated agents
Drug-induced rise in serum creatinine: cystatin C to the rescue? Evidence, pitfalls and knowledge gaps
Van Regemorter E et al. · Eur J Intern Med 2026 · PMID 41224604
A creatinine rise after starting a drug may be unrelated to any fall in GFR, and mistaking one for the other leads to medical misjudgment with clinically significant consequences — the general form of the problem this dive covers in oncology.
Narrative; reviews antibacterial, antiviral, antifungal, antiparasitic and other agents alongside the oncology drugs
What the data says now
No FAERS panel for this syndrome. Its 11 covered agents were queried — no signal reaches significance for these phenotypes. A negative reporting result, not a missing one, and not evidence of safety: spontaneous reporting badly undercounts ATN and AIN, most of which file as generic acute kidney injury. Pseudo-AKI could not be queried in any case — outside the clinician-reviewed MedDRA term map; absence is a boundary of that map, not evidence against the association.
Patients meeting creatinine-based AKI criteria on MATE-1-inhibiting TKIs
Oncogene-driven lung cancer on brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib or tepotinib
PMID 37748692 (opens PubMed in a new tab)Paired samples in which cystatin C-based GFR exceeded creatinine-based GFR
Patients on MATE-1-inhibiting TKI therapy with concurrent creatinine and cystatin C
PMID 37748692 (opens PubMed in a new tab)Persistence of the gap over time
Three patients followed for three years on MATE-1-inhibiting TKIs
PMID 37748692 (opens PubMed in a new tab)Creatinine-defined AKI after starting an ALK inhibitor
114 patients with advanced ALK-rearranged NSCLC, 2013-2022
PMID 40382267 (opens PubMed in a new tab)Dialysis requirement among ALK-inhibitor CKD events
Same cohort, CKD within one year
PMID 40382267 (opens PubMed in a new tab)How it's managed
- 1
Send a cystatin C before you stop the drug
A cystatin C-based eGFR is unaffected by OCT2/MATE blockade, so it separates the artifact from injury directly. The published recommendation is to recalculate GFR with cystatin C BEFORE searching for other causes of kidney injury and before reducing or stopping the TKI — the order matters, because the reflex hold is what does the harm.
Systematic analysis of 863 patients; explicit authors' recommendation · PMID 37748692 (opens PubMed in a new tab)
- 2
Read the shape of the curve, not just the threshold
A secretion artifact appears within weeks of starting the drug and then plateaus at a new baseline. True injury progresses, or follows an identifiable insult. A creatinine that rose once and then held for months is behaving like a blocked transporter, not a damaged nephron.
Long-term paired sampling shows a stable offset rather than a progressive divergence · PMID 37748692 (opens PubMed in a new tab)
- 3
Check that the urine is bland
Pseudo-AKI produces no proteinuria, no haematuria and no cellular casts, because nothing is injured. An active sediment moves the diagnosis back towards true injury and away from this dive.
Mechanistic — the glomerulus and tubule are structurally intact · PMID 32989831 (opens PubMed in a new tab)
- 4
Do not withhold trial enrolment on a creatinine-based GFR alone
Applying a 40 mL/min cutoff to the same patients, creatinine excluded 10 of 17 while cystatin C excluded 5 — the marker, not the kidney, was deciding eligibility. Where a protocol's threshold is creatinine-based, a documented cystatin C is the argument for reassessment.
Virtual clinical-trial eligibility analysis · PMID 37748692 (opens PubMed in a new tab)
- 5
Continue the drug when the workup is consistent
In a real-world ALK-inhibitor cohort most creatinine-defined events did not change management, none led to dialysis, and survival was unaffected — the authors conclude that most patients may continue therapy despite creatinine-based eGFR changes.
Retrospective cohort of 114 patients, 191 treatments · PMID 40382267 (opens PubMed in a new tab)
- 6
Keep looking if the picture does not fit
Pseudo-AKI is a diagnosis of positive features, not of exclusion by drug class. These agents can also cause real injury, and a rising rather than plateaued creatinine, an active sediment, or a cystatin C that falls WITH the creatinine all point at true AKI and its own workup.
The cohorts above contain genuine AKI and CKD events alongside the artifact · PMID 40382267 (opens PubMed in a new tab)
What the guidelines say
Society and consensus recommendations addressing this syndrome.
Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.
Every citation on this page is a real, PubMed-verified reference. The teaching case is an illustrative composite, not a real patient. Medical-education content — not medical advice.