Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Antibody-drug conjugate (TROP2/DXd)
Datopotamab deruxtecan (Dato-DXd)
Datroway · DatoDXd
A 2025 TROP2 deruxtecan ADC — proximal-tubular risk extrapolated from the ADC class.
ModerateAntibody-drug conjugate (TROP2/DXd) · approved 2025
HR-positive HER2-negative breast cancerEGFR-mutant non-small-cell lung cancer
Signature kidney injury
Acute Tubular Necrosis
Renal signal is theoretical and not yet quantified, extrapolated from the ADC class. In TROPION-PanTumor01 and the phase III TROPION-Breast01 the dominant toxicities were mucosal (stomatitis ~50%) and ocular events, nausea, and interstitial lung disease; grade ≥3 treatment-related adverse events were actually lower than chemotherapy (~21%), and kidney-specific events were not prominent.
Source: Bardia et al., J Clin Oncol 2024 (TROPION-Breast01)
Mechanism of kidney injury
The class-based concern is proximal-tubular handling of ADC catabolites: filtered or megalin/cubilin-endocytosed conjugate and released membrane-permeable DXd payload could concentrate in proximal tubular epithelial cells and cause topoisomerase-I-mediated tubular injury (acute tubular necrosis). For deruxtecan ADCs specifically, robust human renal data are lacking. Related ADCs provide the precedent for vigilance — e.g., biopsy-proven collapsing FSGS and tubular injury reported with ado-trastuzumab emtansine (T-DM1) — so both a tubular (ATN) and rare glomerular pattern are biologically plausible.
Clinical presentation
If it occurs, a creatinine rise consistent with tubular injury, possibly with low-grade tubular proteinuria, glucosuria or electrolyte wasting; renal events were not a leading toxicity in trials. Watch instead for the characteristic stomatitis, dry eye/keratitis and ILD that dominate the safety profile.
Onset
Not well characterized (recent approval); by class analogy a subacute tubular pattern during cumulative dosing.
Reversibility
Variable
Anticancer mechanism
TROP2 (trophoblast cell-surface antigen 2)-directed antibody-drug conjugate; a humanized anti-TROP2 IgG1 linked via a cleavable tetrapeptide linker to the topoisomerase-I inhibitor payload deruxtecan (DXd, an exatecan derivative). After TROP2 binding and internalization the payload is released and kills the target cell with membrane-permeable bystander activity. Approved for TROP2-expressing HR+/HER2− breast cancer and EGFR-mutant NSCLC.
Management
Supportive care and dose modification/hold per label if renal function declines; nephrology input and consideration of biopsy for unexplained or significant AKI to distinguish ATN from a glomerular ADC lesion.
Risk factors
- Pre-existing CKD
- Concurrent nephrotoxins
- Volume depletion (mucositis-related poor intake)
- Higher cumulative exposure
Prevention
- Baseline and on-treatment renal monitoring
- Avoid concurrent nephrotoxins
- Maintain hydration, especially with stomatitis-related poor intake
- Hold for unexplained AKI and investigate
Note · ASON-flagged, 2025 approval; the proximal-tubular ATN signature is conservative class extrapolation, not established drug-specific data. The clinically dominant toxicities are mucosal, ocular and pulmonary (ILD), not renal.
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment established; not studied in severe renal impairment/ESKD. Modify dose/hold for toxicity per label. The antibody component is not renally cleared; small-molecule payload exposure in advanced CKD is not well defined.
Dialyzability & ESKD dosing
The IgG–ADC is not dialyzable; the released small-molecule DXd payload's dialyzability is not characterized. No ESKD dosing guidance — use clinical judgment and close monitoring.
Differential diagnosis
Distinguish potential ADC tubular injury (ATN, bland-to-tubular sediment) from pre-renal AKI driven by mucositis/poor intake, from a glomerular ADC lesion (proteinuria, by analogy to T-DM1 collapsing FSGS), and from concurrent nephrotoxins; biopsy resolves ambiguous significant AKI.
Monitoring
- Serum creatinine/eGFR each cycle
- Urinalysis (proteinuria/glucosuria) if creatinine rises
- Vigilance for ILD (the priority class toxicity), stomatitis and ocular symptoms
- Hydration/intake status
Key trials & series
- TROPION-PanTumor01 (Shimizu JCO 2023) first-in-human
- TROPION-Breast01 (Bardia JCO 2024) phase III HR+/HER2−
- TROPION-Breast02 (TNBC) and TROPION-Lung program
Clinical pearls
- The renal signature is class extrapolation — published kidney events with Dato-DXd are not prominent; the real toxicities to watch are ILD, stomatitis and ocular surface disease.
- Precedent for ADC renal injury comes from T-DM1 (collapsing FSGS, tubular injury) — keep biopsy on the table for unexplained AKI.
- Stomatitis-driven dehydration can cause pre-renal AKI that mimics intrinsic toxicity — assess volume first.
- Antibody is not dialyzed; ESKD dosing is undefined — monitor closely.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Acute Tubular NecrosisGlomerular Injury / Proteinuria
Beyond the kidney
Class-level context for the major non-renal toxicities of antibody-drug conjugate (trop2/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
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkDatopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive HER2-Negative Breast Cancer: Primary Results From TROPION-Breast01.Bardia A et al. · J Clin Oncol 2024 · PMID 39265124Phase III registrational safety/efficacy: stomatitis/nausea dominate, grade ≥3 TRAEs lower than chemotherapy, renal events not prominent.PMIDFirst-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of TROP2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.Shimizu T et al. · J Clin Oncol 2023 · PMID 37327461First-in-human safety: dominant mucosal/ocular and ILD toxicities; kidney events not prominent.PMIDTROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer.Dent RA et al. · Future Oncol 2023 · PMID 37526149Describes Dato-DXd construct (anti-TROP2 IgG1, cleavable linker, topo-I payload) and trial design for TNBC.PMIDCase Report: Collapsing Focal Segmental Glomerulosclerosis After Initiation of Ado-Trastuzumab Emtansine Therapy.Hakroush S et al. · Front Oncol 2021 · PMID 34912725Biopsy-proven ADC-associated renal injury (collapsing FSGS, tubular injury) supporting class-based renal vigilance.PMIDRecent advances in therapeutic strategies for non-small cell lung cancer.Su PL et al. · J Hematol Oncol 2025 · PMID 40140911Review situating TROP2 ADCs (including Dato-DXd) among emerging NSCLC therapies.PMIDRenal Side Effects of Novel Molecular Targeted Oncologic Agents.Fenoglio R et al. · G Ital Nefrol 2023 · PMID 38007829Onconephrology overview noting delayed/under-recognized renal toxicity of novel agents (including ADCs) and the role of biopsy.