Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Antibody-drug conjugate (Nectin-4/MMAE)
Enfortumab vedotin
Padcev · EV
A Nectin-4/MMAE conjugate for bladder cancer — usable in renal impairment, with a hyperglycemia-AKI spectrum and case-level tubular injury.
ModerateAntibody-drug conjugate · approved 2019
Urothelial carcinomaBladder cancer
Signature kidney injury
Acute Tubular Necrosis
Renal injury is not a prominent or well-quantified trial signal, and EV is notably usable across the spectrum of renal function (including eGFR <30). When AKI occurs it spans prerenal (GI-toxicity dehydration), hyperglycemia/DKA-associated, and case-level tubular (ATN) patterns. In EV-201 cohort 2, three of 89 patients had treatment-related deaths within 30 days (one each from AKI, metabolic acidosis and multi-organ dysfunction), underscoring a real but uncommon acute renal-metabolic risk.
Source: Yu et al., Lancet Oncol 2021 (EV-201 cohort 2)
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityVariable
Evidence0 refs
Nephron map
Vasculature / Endothelium
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
MMAE-based ADCs can be taken up off-target by proximal tubular cells and disrupt microtubules, giving a tubular/ATN-pattern picture. Clinically, two added drivers dominate: (1) volume depletion from diarrhea/nausea producing prerenal and ischemic tubular injury, and (2) EV-associated hyperglycemia/diabetic ketoacidosis (a labeled, sometimes fatal effect, disproportionate in patients with elevated BMI) that can drive osmotic diuresis, volume loss and oliguric AKI. The direct human renal mechanism remains incompletely characterized.
Clinical presentation
Often preserved renal function. When AKI occurs: tubular-pattern injury with bland-to-granular sediment, sometimes with electrolyte disturbances; or abrupt hyperglycemia/DKA (severe hyperglycemia, high insulin requirement, ketoacidosis) with oliguric AKI that may require continuous renal replacement therapy. The reported DKA cases progressed rapidly.
Onset
Variable; tubular/prerenal AKI tracks with intercurrent GI toxicity, and hyperglycemic-AKI events are often reported after the second or third dose.
Reversibility
Variable
Anticancer mechanism
Antibody-drug conjugate targeting Nectin-4 and delivering the microtubule inhibitor monomethyl auristatin E (MMAE) via a protease-cleavable linker. Approved for locally advanced/metastatic urothelial carcinoma (as monotherapy and with pembrolizumab).
Management
Hold for significant AKI or hyperglycemia; rehydrate, correct electrolytes, and treat hyperglycemia/DKA aggressively (insulin, fluids, ICU-level care for ketoacidosis); continuous renal replacement therapy for severe oliguric AKI. The ~3-4 day terminal half-life of EV informs the duration of supportive measures. Resume per tolerance.
Risk factors
- Volume depletion from diarrhea/nausea
- Hyperglycemia, pre-existing diabetes or elevated BMI
- Pre-existing CKD
- Concurrent nephrotoxins
Prevention
- Baseline and on-treatment glucose monitoring (screen for/optimize diabetes before starting)
- Maintain hydration and manage GI toxicity promptly
- Monitor renal function and electrolytes each cycle
Note · EV can be given across the spectrum of renal function, including eGFR <30; a direct nephrotoxic signal is emerging and not well quantified. Skin reactions, neuropathy and hyperglycemia dominate the labeled toxicity profile, and the hyperglycemia-AKI axis is the highest-stakes renal-metabolic risk.
Clinical depth
Renal dose adjustment
No starting-dose adjustment for mild-moderate renal impairment; per label, the recommended dose has been administered to patients with CrCl >=15 mL/min, and the drug is used in real-world practice at eGFR <30. Limited data in ESKD/dialysis. The cytotoxic exposure is the released MMAE (hepatically metabolized via CYP3A4), not renally cleared parent ADC.
Dialyzability & ESKD dosing
The intact ADC and protein-bound MMAE are not meaningfully dialyzed; HD is used to support AKI/metabolic complications, not to remove the drug. Terminal half-life ~3.4 days guides how long toxicity (e.g., refractory hyperglycemia) may persist.
Differential diagnosis
Separate prerenal AKI (GI losses, fluid-responsive) from hyperglycemia/DKA-driven AKI (check glucose, ketones, anion gap in every EV patient with new AKI) and from intrinsic MMAE tubular injury (granular casts, persistent after volume repletion). New AKI on EV should prompt an immediate glucose/ketone check — DKA can be occult and lethal.
Monitoring
- Blood glucose before each dose and during treatment (DKA risk)
- Serum creatinine and electrolytes every cycle
- Skin exam and neurologic exam (dominant labeled toxicities) alongside renal review
Key trials & series
- EV-301 (Rosenberg, phase III vs chemotherapy)
- EV-201 cohort 2 (Yu, Lancet Oncol 2021 — treatment-related AKI/metabolic-acidosis deaths)
- UNITE real-world cohort (use at eGFR <30)
Clinical pearls
- Always check glucose and ketones when an EV patient presents with AKI — EV-associated DKA can be fulminant and fatal within days, even without known diabetes.
- EV is one of the few cytotoxics genuinely usable at eGFR <30, because the active payload is hepatically (not renally) cleared.
- Most EV AKI is prerenal/metabolic and reversible; true MMAE tubular injury is a case-level diagnosis.
- Skin, neuropathy and hyperglycemia dominate the label — keep the kidney in context.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Acute Tubular NecrosisElectrolyte WastingPrerenal / Hemodynamic AKI
Beyond the kidney
Class-level context for the major non-renal toxicities of antibody-drug conjugate (nectin-4/mmae)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
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma.Rosenberg JE et al. · Ann Oncol 2023 · PMID 37678672Pivotal phase III safety: skin reactions, neuropathy and hyperglycemia dominate; no new tubular renal signal.PMIDEnfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial.Yu EY et al. · Lancet Oncol 2021 · PMID 33991512Cohort 2: three treatment-related deaths within 30 days including AKI and metabolic acidosis - documents the acute renal-metabolic risk.PMIDDiabetic Ketoacidosis and Acute Kidney Injury Associated With Enfortumab Vedotin for Urothelial Carcinoma: A Case Report.Atemnkeng F et al. · Kidney Med 2023 · PMID 38028029Fulminant EV-associated DKA with oliguric AKI requiring CVVHD - the hyperglycemia-AKI spectrum.PMIDEnfortumab Vedotin-Induced Febrile Neutropenia and Hyperglycemia Successfully Treated with Multidisciplinary Treatment Including Continuous Hemodialysis Filtration and Insulin Injection in a Patient with Chemo-Resistant Metastatic Urothelial Carcinoma: A Case Report.Otsuka A et al. · Case Rep Oncol 2024 · PMID 39144238EV hyperglycemia and sepsis-associated AKI managed with CHDF; notes EV elimination half-life of ~3.4 days guiding support duration.PMIDEfficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.Koshkin VS et al. · Cancer 2021 · PMID 34882781Real-world use including patients with eGFR <30 mL/min, supporting tolerability in renal impairment.PMIDEnfortumab Vedotin in urothelial cancer.Alt M et al. · Ther Adv Urol 2020 · PMID 33447264Review of mechanism (Nectin-4/MMAE) and tolerability, including administration in renal dysfunction.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 relevant to acute renal/metabolic presentations.