Bosutinib
Bosulif · BCR-ABL TKI
Reversible eGFR decline.
PSEUDOPRE
MildOpen →
ALK TKI
Lorlatinib
Lorbrena · LORL
A third-generation ALK/ROS1 inhibitor whose renal relevance is tied to edema and prominent metabolic effects.
MildALK/ROS1 tyrosine kinase inhibitor · approved 2018
ALK-positive non-small-cell lung cancer
Signature kidney injury
Pseudo-AKI
Lorlatinib is characterized by prominent metabolic effects - hypercholesterolemia and hypertriglyceridemia occur in the majority of patients (the leading grade 3/4 toxicity in the CROWN trial) - plus peripheral edema. Direct renal toxicity is limited and, like other ALK inhibitors, creatinine elevations are generally mild and reversible. Renal effects are not well quantified specifically for lorlatinib.
Source: Shaw et al., N Engl J Med 2020 (CROWN); Bonilla et al., Clin Kidney J 2022
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
Kidney involvement is largely indirect: prominent edema and severe dyslipidemia reflect off-target metabolic effects, and any creatinine change is consistent with the ALK-inhibitor pattern of reduced tubular creatinine secretion rather than structural injury. Edema can reflect fluid shifts relevant to perfusion; marked hypertriglyceridemia rarely contributes to pancreatitis.
Clinical presentation
Peripheral edema, hypercholesterolemia/hypertriglyceridemia, weight change, and CNS/cognitive effects; mild creatinine elevations; overt AKI is uncommon.
Onset
Metabolic effects and edema appear within weeks of starting therapy.
Reversibility
Reversible
Anticancer mechanism
Third-generation, highly CNS-penetrant macrocyclic ALK/ROS1 inhibitor active against most resistance mutations including the compound G1202R/L1196M. Used in ALK-positive non-small-cell lung cancer, first-line and after prior ALK inhibitors.
Management
Manage dyslipidemia with lipid-lowering therapy (statins, and fibrates/omega-3 for severe hypertriglyceridemia) and edema with supportive measures and dose adjustment as needed. Renal function is generally preserved; reserve renal-directed dose changes for true AKI.
Risk factors
- Pre-existing dyslipidemia or metabolic syndrome
- Chronic kidney disease
- Concurrent nephrotoxins
Prevention
- Baseline and on-treatment lipid monitoring; start statin/fibrate per thresholds
- Monitor for edema and weight gain
- Monitor creatinine and recognize benign, secretion-mediated rises
Note · Edema and metabolic effects dominate; lorlatinib-specific renal data are limited and extrapolated from the ALK-inhibitor class.
Clinical depth
Renal dose adjustment
No starting-dose change for mild-to-moderate renal impairment. For severe renal impairment (eGFR <30 mL/min not on dialysis), reduce the dose (e.g., from 100 mg to 75 mg once daily) per labeling. Avoid strong CYP3A inducers/inhibitors.
Dialyzability & ESKD dosing
Hepatically metabolized and protein-bound; not expected to be meaningfully dialyzed, and ESKD data are limited - monitor clinically.
Differential diagnosis
Separate benign secretion-mediated creatinine rise (cystatin C-based eGFR preserved) from true AKI; attribute edema and metabolic derangement to drug effect rather than renal failure.
Monitoring
- Fasting lipid panel at baseline, then periodically (triglycerides, cholesterol)
- Weight and edema assessment
- Serum creatinine periodically
- Mood/cognition (CNS effects)
Key trials & series
- CROWN (phase 3 lorlatinib vs crizotinib, first-line; dyslipidemia the leading grade 3/4 AE)
- Pinard et al. real-world ALK-inhibitor AKI/CKD cohort (includes lorlatinib)
Clinical pearls
- Lorlatinib’s signature toxicities are metabolic (severe dyslipidemia) and edema - lipid management is central, the kidney usually spared.
- Reduce the dose when eGFR <30; otherwise no renal adjustment.
- An isolated creatinine bump is likely a transporter artifact, as with the ALK class.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
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 alk 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.
LandmarkFirst-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer.Shaw AT et al. · N Engl J Med 2020 · PMID 33207094CROWN registrational trial; hyperlipidemia and edema are the dominant lorlatinib toxicities relevant to its renal/metabolic profile.PMIDAnaplastic lymphoma kinase inhibitors and their effect on the kidney.Bonilla M et al. · Clin Kidney J 2022 · PMID 35892021ALK-inhibitor renal review providing class context for lorlatinib renal/edema effects.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 40382267Real-world cohort including lorlatinib: mostly mild, reversible creatinine-based renal changes.PMIDThe renal effects of ALK inhibitors.Izzedine H et al. · Invest New Drugs 2016 · PMID 27468827Class review of ALK-inhibitor renal adverse effects.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int 2015 · PMID 25671763Onco-nephrology class context for targeted-agent renal/metabolic effects.PMIDPharmacological nephrotoxicity profile in a comprehensive cancer center: What changed in two decades and predictors for the need for haemodialysis and mortality.Ferreira A et al. · Nefrologia (Engl Ed) 2025 · PMID 40783302Cancer-center AKI series reflecting the growing role of TKIs in drug-induced AKI.