Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
EGFR TKI
Afatinib
Gilotrif · AFA
An irreversible pan-ErbB TKI whose main renal risk is dehydration-driven prerenal AKI from severe diarrhea, plus class hypomagnesemia.
MildEGFR TKI · approved 2013
EGFR-mutant metastatic non-small cell lung cancer (including selected uncommon EGFR mutations)Squamous NSCLC after platinum-based chemotherapy
Signature kidney injury
Prerenal / Hemodynamic AKI
Diarrhea is very common with afatinib (the dominant class toxicity, all-grade in the large majority and grade >=3 in roughly 10-15% in LUX-Lung trials), and the consequent dehydration can precipitate prerenal AKI. Pharmacovigilance data identify afatinib as carrying the strongest renal-failure/AKI signal among EGFR agents, frequently co-reported with diarrhea; trial-based renal incidence is not separately quantified.
Source: Crosnier et al., Cancers 2021
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Prerenal / Hemodynamic AKI
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Mechanism of kidney injury
Predominantly a hemodynamic, prerenal injury. Severe secretory diarrhea (a pan-ErbB on-target effect on intestinal chloride secretion) together with reduced oral intake causes volume depletion and renal hypoperfusion; sustained ischemia can progress to acute tubular necrosis. Concurrent gastrointestinal and renal electrolyte losses (hypokalemia, hypomagnesemia—the latter also via the EGFR/TRPM6 distal-tubule mechanism) accompany the toxicity.
Clinical presentation
Rising creatinine with clinical volume depletion in the setting of significant diarrhea; low urine output, concentrated urine with a low fractional excretion of sodium early, and electrolyte derangements (hypomagnesemia, hypokalemia). Improves promptly with rehydration when caught early.
Onset
Days to weeks after starting therapy, tracking with the onset and severity of diarrhea (often within the first cycles).
Reversibility
Reversible
Anticancer mechanism
Irreversible inhibitor of the ErbB family (EGFR/HER1, HER2, HER4) tyrosine kinases, covalently blocking signaling in EGFR-mutant tumors and overcoming some resistance. Used for EGFR-mutant non-small cell lung cancer, including selected uncommon mutations.
Management
Treat diarrhea promptly and restore volume with oral or intravenous fluids; correct electrolytes including magnesium and potassium. Hold afatinib for severe diarrhea or AKI and resume at a reduced dose after recovery. Most cases resolve with volume repletion once the underlying gastrointestinal toxicity is controlled.
Risk factors
- Severe or unmanaged diarrhea
- Older age and frailty
- Pre-existing chronic kidney disease
- Concurrent diuretics or other nephrotoxins
Prevention
- Early, aggressive antidiarrheal management (e.g., loperamide) per protocol
- Patient education on hydration and prompt reporting of diarrhea
- Dose interruption/reduction for severe diarrhea
- Monitoring of creatinine and electrolytes (including magnesium) during gastrointestinal toxicity
Note · The renal signal is largely indirect (volume depletion from diarrhea) rather than a primary nephropathy; afatinib also shares the EGFR-class potential for distal-tubule hypomagnesemia.
Clinical depth
Renal dose adjustment
No initial renal dose reduction for mild-moderate impairment; for severe renal impairment (eGFR ~15-29) a reduced starting dose (30 mg daily) is advised per labeling, with titration as tolerated. The practical priority is holding/reducing for grade >=2-3 diarrhea to prevent prerenal AKI.
Dialyzability & ESKD dosing
Not appreciably dialyzable—highly protein-bound (~95%), lipophilic, with predominantly fecal/biliary excretion and minimal renal clearance; hemodialysis is not expected to remove meaningful amounts.
Differential diagnosis
Separate diarrhea-driven prerenal AKI (volume depletion, low FE-Na, rapid response to fluids) from intrinsic ATN (muddy-brown casts, slower recovery) and from concurrent nephrotoxins. EGFR-class hypomagnesemia (high FE-Mg) is distinguished from GI magnesium loss (low FE-Mg).
Monitoring
- Serum creatinine/eGFR and electrolytes (including magnesium) during early cycles and any diarrhea
- Stool frequency and volume status at each contact
- Serum magnesium periodically (EGFR-class wasting)
Key trials & series
- LUX-Lung 3 (Sequist JCO 2013) registrational trial; diarrhea the leading AE
- LUX-Lung 2/3/6 pooled uncommon-mutation analysis (Yang Lancet Oncol 2015)
- Crosnier Cancers 2021 VigiBase EGFR renal-safety pharmacovigilance
Clinical pearls
- Afatinib's kidney risk is mostly the gut: aggressive antidiarrheal care and rehydration prevent prerenal AKI.
- Start loperamide at the first loose stool—do not wait for grade 3 diarrhea.
- Reduce the starting dose to 30 mg daily in severe renal impairment.
- Don't forget magnesium: afatinib adds distal-tubule (EGFR/TRPM6) wasting on top of GI losses.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Prerenal / Hemodynamic AKIAcute Tubular NecrosisElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of egfr tkis.
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Acneiform rash, paronychia
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Diarrhea
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Interstitial lung disease (EGFR TKIs)
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkPhase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.Sequist LV et al. · J Clin Oncol 2013 · PMID 23816960LUX-Lung 3 registrational trial; diarrhea the most common adverse event driving dehydration risk.PMIDClinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.Yang JC et al. · Lancet Oncol 2015 · PMID 26051236LUX-Lung pooled analysis documenting afatinib efficacy and its characteristic diarrhea-predominant toxicity profile.PMIDRenal Safety Profile of EGFR Targeted Therapies: A Study from VigiBase, the WHO Global Database of Individual Case Safety Reports.Crosnier A et al. · Cancers (Basel) 2021 · PMID 34885014Pharmacovigilance analysis showing afatinib carries the strongest renal-failure/AKI signal among EGFR agents, often with concurrent diarrhea.PMIDRenal toxicity of anticancer agents targeting HER2 and EGFR.Cosmai L et al. · J Nephrol 2015 · PMID 26341657Onconephrology review of pan-ErbB/EGFR renal and electrolyte toxicity relevant to afatinib.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA · Kidney Int 2015 · PMID 25671763Onconephrology review covering prerenal AKI and electrolyte effects associated with targeted oncology drugs.PMIDOnconephrology: mitigation of renal injury in chemotherapy administration.Selamet U et al. · Curr Opin Nephrol Hypertens 2023 · PMID 38095483Review of renal injury mitigation including volume-related AKI during targeted therapy.
Related agents
Other agents sharing the same signature kidney injury.