Busulfan
Myleran · Alkylator
Conditioning-regimen TMA risk.
TMA
ModerateOpen →
Antibody-drug conjugate (HER2/DM1)
Trastuzumab emtansine (T-DM1)
Kadcyla · T-DM1
A HER2/DM1 conjugate with rare vascular-pattern renal injury — case reports of TMA and collapsing glomerulopathy.
ModerateAntibody-drug conjugate · approved 2013
HER2-positive breast cancer
Signature kidney injury
Thrombotic Microangiopathy
Renal toxicity is rare and case-level. FDA adverse-event analyses flagged renal events with trastuzumab-based therapy, and biopsy-proven cases (collapsing focal segmental glomerulosclerosis; TMA-like microvascular injury) have been reported. Incidence is not quantified.
Source: Hakroush et al., Front Oncol 2021 (case)
Mechanism of kidney injury
Anti-HER2 therapy can perturb glomerular endothelial/podocyte homeostasis (HER2 and VEGF-related signaling), producing rare thrombotic microangiopathy with microvascular thrombosis or a collapsing glomerulopathy with podocyte injury on biopsy. Thrombocytopenia and hepatic (nodular regenerative hyperplasia) changes are recognized class effects of DM1-based therapy; the renal mechanism remains case-level and incompletely defined.
Clinical presentation
Proteinuria (sometimes nephrotic-range), AKI, and — with TMA — microangiopathic hemolytic anemia (schistocytes, elevated LDH, low haptoglobin) with thrombocytopenia; biopsy may show collapsing FSGS or microangiopathic vascular injury.
Onset
Variable; reported after initiation, over weeks to months of therapy.
Reversibility
Variable
Anticancer mechanism
Antibody-drug conjugate linking trastuzumab to the maytansinoid microtubule inhibitor DM1 (emtansine) via a non-cleavable thioether linker. Approved for HER2-positive breast cancer, including adjuvant therapy for residual invasive disease after neoadjuvant treatment.
Management
Hold/discontinue for significant renal injury; supportive care, manage TMA per cause (stop the offending agent; plasma exchange/complement inhibition have been used in proteasome-inhibitor TMA but evidence in ADC-TMA is anecdotal); nephrology evaluation and kidney biopsy for unexplained proteinuria or AKI.
Risk factors
- Pre-existing CKD or glomerular disease
- Concurrent nephrotoxins
- Treatment-emergent thrombocytopenia
Prevention
- Monitor renal function, urine protein and platelet count
- Evaluate new proteinuria/AKI promptly, with a low threshold for nephrology referral and biopsy
Note · Renal injury is a rare, case-level signal. Dominant labeled toxicities are thrombocytopenia and hepatotoxicity; interpret renal findings conservatively.
Clinical depth
Renal dose adjustment
No starting-dose adjustment for mild-moderate renal impairment; data are lacking in severe impairment/ESKD. DM1 is hepatically metabolized; thrombocytopenia and hepatotoxicity (not renal clearance) drive most dose modifications.
Dialyzability & ESKD dosing
Not appreciably dialyzed (large ADC; non-cleavable linker, hepatically handled payload).
Differential diagnosis
Distinguish drug-associated TMA (MAHA, thrombocytopenia, schistocytes) from collapsing glomerulopathy (heavy proteinuria, podocyte collapse without systemic MAHA) and from unrelated diabetic/hypertensive glomerular disease. Biopsy is often required to separate these.
Monitoring
- Platelet count and LFTs each cycle (dominant labeled toxicities; thrombocytopenia can accompany TMA)
- Serum creatinine and urine protein periodically
- Hemolysis labs (LDH, haptoglobin, schistocytes) if cytopenias plus AKI raise suspicion for TMA
Key trials & series
- EMILIA/KATHERINE registrational program (safety backbone)
- Hakroush Front Oncol 2021 (biopsy-proven collapsing FSGS)
Clinical pearls
- T-DM1 thrombocytopenia is common and benign in most patients, but cytopenias plus AKI and hemolysis should trigger a TMA workup.
- The renal lesions reported are vascular/glomerular (TMA, collapsing FSGS), not tubular — proteinuria, not tubular wasting, is the clue.
- Hepatotoxicity and thrombocytopenia, not nephrotoxicity, govern routine dose decisions.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Thrombotic MicroangiopathyGlomerular Injury / Proteinuria
Beyond the kidney
Class-level context for the major non-renal toxicities of antibody-drug conjugate (her2/dm1)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.
LandmarkCase Report: Collapsing Focal Segmental Glomerulosclerosis After Initiation of Ado-Trastuzumab Emtansine Therapy.Hakroush S et al. · Front Oncol 2021 · PMID 34912725Biopsy-proven collapsing FSGS after T-DM1; notes FDA-reported renal adverse events for trastuzumab.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 including T-DM1.PMIDThrombotic microangiopathy associated with proteasome inhibitors.Lodhi A et al. · Clin Kidney J 2015 · PMID 26413293Frames drug-associated TMA pathophysiology and management relevant to ADC-associated microangiopathy.PMIDAnticancer Drug-Induced Acute Kidney Injury.Izzedine H et al. · Kidney Int Rep 2017 · PMID 29318217Onconephrology reference covering glomerular/vascular (TMA) drug-induced injury.
Related agents
Other agents sharing the same signature kidney injury.