Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Antibody-drug conjugate (HER2/DXd)
Trastuzumab deruxtecan
Enhertu · T-DXd
A HER2/DXd conjugate with emerging, under-published renal signals — including a reported reversible Fanconi syndrome.
ModerateAntibody-drug conjugate · approved 2019
HER2-positive breast cancerHER2-low breast cancerGastric cancerHER2-expressing solid tumors
Signature kidney injury
Acute Tubular Necrosis
Renal data are emerging and under-published. AKI/proteinuria are reported at case level; a reversible proximal-tubule Fanconi syndrome (glucosuria, phosphate/potassium wasting, non-anion-gap acidosis) has been described and attributed to the deruxtecan payload. Renal-specific incidence is not quantified.
Source: Kalantri & Lomashvili, Cureus 2023 (case)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityVariable
Evidence0 refs
Nephron map
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
Acute Tubular Necrosis
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Mechanism of kidney injury
Proposed proximal tubular injury from off-target uptake of the membrane-permeable DXd payload (the same bystander property that drives anti-tumor activity), producing a tubular/ATN- or Fanconi-pattern picture with impaired proximal reabsorption of glucose, phosphate, potassium and bicarbonate. GI toxicity (diarrhea) can add a prerenal component. The human renal mechanism remains poorly characterized.
Clinical presentation
When renal involvement occurs: tubular electrolyte wasting (hypokalemia, hypophosphatemia, hypomagnesemia), non-anion-gap metabolic acidosis, glucosuria with normoglycemia and proteinuria (Fanconi pattern), or a creatinine rise; the picture is often initially attributed to diarrhea.
Onset
Variable; reported during ongoing therapy, sometimes resolving over months after discontinuation.
Reversibility
Variable
Anticancer mechanism
Antibody-drug conjugate targeting HER2 and delivering deruxtecan (DXd), a topoisomerase I inhibitor, via a cleavable tetrapeptide linker with a high drug-to-antibody ratio (~8) and a membrane-permeable payload that produces a bystander effect on neighboring cells. Approved (including tumor-agnostic) for HER2-positive/HER2-low breast, gastric and other solid tumors.
Management
Electrolyte and bicarbonate repletion, hydration, and hold/discontinue for significant tubulopathy; tubular abnormalities may resolve over months. Supportive care; nephrology input for persistent Fanconi physiology.
Risk factors
- Concurrent GI toxicity/dehydration
- Pre-existing CKD
- Concurrent nephrotoxins
Prevention
- Monitor electrolytes and renal function each cycle
- Maintain hydration and manage diarrhea
- Check urine glucose/electrolytes if wasting is disproportionate
Note · Renal toxicity is emerging and under-published; the high-profile labeled risk for T-DXd is interstitial lung disease/pneumonitis, not the kidney. Renal findings should be interpreted conservatively.
Clinical depth
Renal dose adjustment
No starting-dose adjustment for mild-moderate renal impairment; data are insufficient in severe impairment (CrCl <30) and ESKD, where higher GI/marrow toxicity has been observed and caution is advised. The cytotoxic DXd is hepatically metabolized (CYP3A4).
Dialyzability & ESKD dosing
Intact ADC and protein-bound DXd are not appreciably dialyzed. No supplemental dosing guidance established for HD/PD.
Differential diagnosis
Separate Fanconi-pattern tubulopathy (normoglycemic glucosuria, phosphaturia, non-gap acidosis) from prerenal AKI of diarrhea (volume-responsive, no glucosuria) and from myeloma/light-chain tubulopathy if comorbid. Tubular wasting out of proportion to volume status should prompt urine electrolyte studies.
Monitoring
- Serum electrolytes (K, phosphate, magnesium, bicarbonate) and creatinine each cycle
- Urinalysis for glucosuria/proteinuria if tubular wasting is suspected
- Pulmonary symptoms/imaging for interstitial lung disease (the dominant labeled organ toxicity)
Key trials & series
- DESTINY-Breast03/04 program (registrational efficacy/safety)
- Kalantri Cureus 2023 (reversible Fanconi syndrome case)
Clinical pearls
- Think Fanconi, not just dehydration, when a T-DXd patient has refractory hypokalemia/hypophosphatemia with normoglycemic glucosuria.
- The membrane-permeable bystander payload that makes T-DXd effective is the same property invoked for off-target proximal tubular injury.
- The headline T-DXd toxicity remains interstitial lung disease/pneumonitis — the renal signal is genuinely thin and case-level.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Acute Tubular NecrosisFanconi SyndromeElectrolyte Wasting
Beyond the kidney
Class-level context for the major non-renal toxicities of antibody-drug conjugate (her2/dxd)s.
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression (payload-dependent)
Ophthalmic
Keratopathy, uveitis, retinopathy
- Keratopathy (belantamab, mirvetuximab, tisotumab)
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Interstitial lung disease (deruxtecan ADCs)
Neurologic
Neuropathy, encephalopathy, ICANS, PRES
- Peripheral neuropathy (MMAE payloads)
Evidence
4 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkDeruxtecan-Induced Reversible Fanconi Syndrome.Kalantri P et al. · Cureus 2023 · PMID 37492824Reported reversible proximal-tubule Fanconi syndrome attributed to the deruxtecan component.PMIDEmerging Paradigms in Genitourinary Cancers: Integrating Molecular Imaging, Hypoxia-Inducible Factor-Targeted Therapies, and Antibody-Drug Conjugates in Renal Cell and Urothelial Carcinomas.McKay RR et al. · Am Soc Clin Oncol Educ Book 2025 · PMID 40198857Reviews HER2-directed ADCs including trastuzumab deruxtecan and expanding tumor-agnostic use.PMIDAntibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know.Markides DM et al. · Ann Emerg Med 2024 · PMID 39641680Class review of ADC toxicities and acute management, including payload off-target effects.PMIDAnticancer Drug-Induced Acute Kidney Injury.Izzedine H et al. · Kidney Int Rep 2017 · PMID 29318217Onconephrology reference covering proximal tubulopathy/Fanconi and ATN mechanisms.