Doxorubicin
Adriamycin · Anthracycline
Experimental podocyte model; clinical proteinuria rare.
GLOM
MildOpen →
EGFR TKI
Gefitinib
Iressa · GEF
An EGFR TKI implicated in rare nephrotic syndrome (minimal-change and membranous patterns) and occasional AKI.
MildEGFR TKI · approved 2003
EGFR exon 19 deletion / L858R-mutant metastatic non-small cell lung cancer
Signature kidney injury
Glomerular Injury / Proteinuria
Nephrotic syndrome (minimal-change disease and secondary membranous nephropathy patterns) and rare acute renal failure are reported only as isolated cases; not quantified in clinical-trial datasets.
Source: Maruyama et al., Intern Med 2015
Mechanism of kidney injury
Reported as a drug-associated glomerulopathy/podocytopathy. Biopsy-confirmed cases show either minimal glomerular abnormalities with podocyte foot-process effacement (minimal-change pattern) or secondary membranous nephropathy with subepithelial immune deposits, presumed related to EGFR-pathway effects on podocyte biology and the glomerular filtration barrier; proteinuria characteristically remits after gefitinib withdrawal. Rare acute renal failure has also been described.
Clinical presentation
Nephrotic-range proteinuria with edema and hypoalbuminemia; bland urine and near-normal renal function early. Renal biopsy is needed to distinguish minimal-change versus membranous patterns and to exclude paraneoplastic membranous nephropathy.
Onset
Weeks to months after initiation in reported cases; proteinuria resolves over weeks to months after stopping the drug.
Reversibility
Reversible
Anticancer mechanism
Selective, reversible EGFR tyrosine kinase inhibitor that blocks EGFR autophosphorylation and downstream signaling driving tumor proliferation. Used for EGFR-mutant non-small cell lung cancer.
Management
Discontinue gefitinib for significant nephrotic syndrome, which commonly leads to remission; provide supportive nephrotic-syndrome care (edema management, RAAS blockade, attention to thromboembolic risk). Switching to an alternative EGFR TKI (e.g., erlotinib) has been tolerated in reported cases without recurrence.
Risk factors
- Underlying malignancy (paraneoplastic membranous nephropathy must also be considered)
- Pre-existing kidney disease
Prevention
- Periodic urinalysis/proteinuria monitoring
- Investigate new nephrotic syndrome with biopsy when clinically indicated
Note · Both minimal-change and membranous patterns have been described in single cases; evidence is sparse, so incidence remains unquantified and the signal is idiosyncratic.
Clinical depth
Renal dose adjustment
No defined renal dose adjustment (hepatic CYP3A4 metabolism, biliary excretion; <4% renal elimination); caution in severe impairment given limited data. The intervention for glomerular toxicity is drug discontinuation, not dose titration.
Dialyzability & ESKD dosing
Not appreciably dialyzable—highly protein-bound (~90%), lipophilic, large volume of distribution with predominantly hepatic clearance; hemodialysis is not expected to remove meaningful amounts.
Differential diagnosis
Distinguish drug-associated minimal-change disease (abrupt nephrotic syndrome, remits on withdrawal) from secondary membranous nephropathy and especially from paraneoplastic membranous nephropathy of the underlying lung cancer (where PLA2R is usually negative and the tumor, not the drug, drives disease). Biopsy with immunofluorescence is decisive.
Monitoring
- Urinalysis/urine protein at baseline and periodically
- Serum creatinine/eGFR and serum albumin if proteinuria develops
Key trials & series
- IPASS (Mok NEJM 2009) registrational EGFR-mutant NSCLC trial
- Maruyama Intern Med 2015 minimal-change case; Kaneko CEN Case Rep 2014 membranous case
- Kumasaka JCO 2004 early gefitinib nephrotic-syndrome report
Clinical pearls
- Two glomerular phenotypes are reported—minimal-change disease and secondary membranous nephropathy—so biopsy matters.
- Always weigh paraneoplastic membranous nephropathy from the lung cancer itself before attributing it to gefitinib.
- Proteinuria typically remits after stopping the drug; a switch to another EGFR TKI has been tolerated.
- It is a podocyte/filtration-barrier lesion, not interstitial nephritis—urine is bland aside from protein.
Where it strikes
Nephron segments
Glomerulus
Filtration barrier (podocytes + endothelium)
Injury signatures
Glomerular Injury / Proteinuria
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
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkMinimal change nephrotic syndrome associated with gefitinib and a successful switch to erlotinib.Maruyama K et al. · Intern Med 2015 · PMID 25832950Biopsy-proven minimal-change nephrotic syndrome attributed to gefitinib, remitting on withdrawal.PMIDSide effects of therapy: case 1. Nephrotic syndrome associated with gefitinib therapy.Kumasaka R et al. · J Clin Oncol 2004 · PMID 15197213Early case report establishing gefitinib-associated nephrotic syndrome.PMIDA case of gefitinib-associated membranous nephropathy in treatment for pulmonary adenocarcinoma.Kaneko T et al. · CEN Case Rep 2014 · PMID 28509266Case of gefitinib-associated secondary membranous nephropathy with proteinuria resolving after discontinuation.PMIDAcute renal failure associated with gefitinib therapy.Wan HL et al. · Lung 2006 · PMID 17006753Case documenting gefitinib-associated acute renal failure, broadening the renal phenotype.PMIDGefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.Mok TS et al. · N Engl J Med 2009 · PMID 19692680IPASS registrational trial defining gefitinib's role and overall safety in EGFR-mutant NSCLC.PMIDRenal toxicity of anticancer agents targeting HER2 and EGFR.Cosmai L et al. · J Nephrol 2015 · PMID 26341657Onconephrology review of EGFR-TKI glomerular and renal toxicity, covering gefitinib.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA · Kidney Int 2015 · PMID 25671763Onconephrology review of glomerular and proteinuric effects of targeted anticancer therapies.
Related agents
Other agents sharing the same signature kidney injury.