Cyclophosphamide
Cytoxan · Oxazaphosphorine alkylator
Vasopressin-independent hyponatremia; hemorrhagic cystitis.
SIADHCYST
MildOpen →
EGFR TKI
Osimertinib
Tagrisso · OSI
A third-generation EGFR TKI whose uncommon renal-electrolyte signal is SIADH-type hyponatremia.
MildEGFR TKI · approved 2015
EGFR exon 19 deletion / L858R-mutant non-small cell lung cancer (first-line)EGFR T790M-positive NSCLC after prior EGFR-TKIAdjuvant therapy of resected EGFR-mutant NSCLC
Signature kidney injury
SIADH / Hyponatremia
Syndrome of inappropriate antidiuretic hormone (SIADH)-type hyponatremia is described at the case level; occasional acute kidney injury and rare proteinuria are reported. Not quantified as a discrete renal endpoint in randomized data, where overall renal adverse events are uncommon.
Source: Skribek et al., Lung Cancer 2022
Mechanism of kidney injury
Mechanism is incompletely understood. Reported cases show a euvolemic SIADH pattern—impaired free-water excretion with hypotonic hyponatremia, inappropriately concentrated urine, and natriuresis—that resolves with fluid restriction and drug discontinuation and may recur on rechallenge, implicating drug-associated inappropriate antidiuresis (possibly via EGFR effects on collecting-duct water handling) rather than direct tubular destruction. Distinct, rare AKI/glomerular cases reflect the broader EGFR-TKI nephrotoxicity spectrum.
Clinical presentation
Hyponatremia with low serum osmolality, inappropriately elevated urine osmolality, and urine sodium typically >30-40 mmol/L in a clinically euvolemic patient with normal thyroid/adrenal axes; symptoms range from none to nausea, headache, confusion, or seizures when sodium is severe or falls rapidly. Occasional creatinine rises are reported separately.
Onset
Reported within roughly the first weeks to a few months of therapy (around two months in several published cases).
Reversibility
Reversible
Anticancer mechanism
Third-generation, irreversible EGFR tyrosine kinase inhibitor that covalently binds the C797 residue and is selective for sensitizing EGFR mutations and the T790M resistance mutation while sparing wild-type EGFR. Standard therapy for EGFR-mutant non-small cell lung cancer, including CNS disease.
Management
Confirm the SIADH pattern (serum and urine osmolality, urine sodium, volume status) and exclude adrenal/thyroid and other causes; institute fluid restriction and correct sodium at a safe rate (avoid overcorrection). Hold or discontinue osimertinib for significant or symptomatic hyponatremia; dose-reduced rechallenge or an alternative EGFR TKI may be considered after resolution.
Risk factors
- Concurrent medications that promote hyponatremia (thiazides, SSRIs)
- Older age
- Volume/solute status predisposing to dilutional hyponatremia
Prevention
- Periodic monitoring of serum sodium, particularly early and when symptoms suggest hyponatremia
- Review and minimize concomitant hyponatremia-inducing drugs
Note · The kidney signal is primarily electrolyte (hyponatremia via SIADH) rather than structural nephrotoxicity; evidence is limited to case reports, so incidence is unquantified.
Clinical depth
Renal dose adjustment
No osimertinib dose adjustment is required for mild-to-moderate renal impairment; data in severe impairment/ESKD are limited (hepatic CYP3A metabolism predominates). Management of SIADH is fluid restriction and dose hold, not renal dose modification.
Dialyzability & ESKD dosing
Not appreciably dialyzable—a small but highly lipophilic, extensively protein-bound molecule with a very large volume of distribution; minimal renal excretion of parent drug, so hemodialysis is not expected to remove clinically relevant amounts.
Differential diagnosis
Separate osimertinib-induced SIADH from hypovolemic hyponatremia (prerenal, low urine sodium), thiazide- or SSRI-induced hyponatremia, paraneoplastic SIADH from the underlying lung cancer or brain metastases, and adrenal insufficiency. The temporal link to drug start, euvolemia, and resolution on withdrawal supports drug attribution.
Monitoring
- Serum sodium at baseline and periodically, especially in the first 1-3 months
- Serum and urine osmolality plus urine sodium if hyponatremia develops
- Serum creatinine/eGFR each cycle
Key trials & series
- FLAURA (Soria NEJM 2017) first-line registrational trial
- Skribek Lung Cancer 2022 and Takao Clin Lung Cancer 2021 SIADH case reports
- Crosnier Cancers 2021 VigiBase EGFR renal-safety pharmacovigilance
Clinical pearls
- Osimertinib's renal fingerprint is hyponatremia via SIADH, not AIN or ATN.
- Always exclude paraneoplastic SIADH from the lung cancer itself and from CNS metastases before blaming the drug.
- Fluid restriction plus a drug hold usually fixes it; correct sodium slowly to avoid osmotic demyelination.
- A modest separate AKI/proteinuria signal exists across EGFR TKIs—check creatinine and urinalysis too.
Where it strikes
Nephron segments
Distal Tubule / Collecting Duct
Fine-tuning of Na, K, Mg, acid & water
Injury signatures
SIADH / HyponatremiaElectrolyte 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.
LandmarkOsimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.Soria JC et al. · N Engl J Med 2017 · PMID 29151359FLAURA pivotal first-line trial establishing osimertinib's efficacy and overall safety profile.PMIDOsimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone in oncogene-addicted lung adenocarcinoma: A case report.Skribek M et al. · Lung Cancer 2022 · PMID 35276629Case of osimertinib-induced SIADH resolving with fluid restriction and drug discontinuation.PMIDOsimertinib-induced Syndrome of Inappropriate Secretion of Antidiuretic Hormone.Takao T et al. · Clin Lung Cancer 2021 · PMID 33839042Additional report documenting osimertinib-associated SIADH.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 capturing osimertinib renal and electrolyte adverse-event signals.PMIDRenal toxicity of anticancer agents targeting HER2 and EGFR.Cosmai L et al. · J Nephrol 2015 · PMID 26341657Onconephrology review of EGFR-TKI renal safety, including electrolyte effects.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA · Kidney Int 2015 · PMID 25671763Onconephrology review of electrolyte disturbances and renal effects of targeted anticancer agents.