TMA

Thrombotic Microangiopathy

Endothelial injury with microvascular thrombi, hemolysis and thrombocytopenia — gemcitabine, mitomycin C, anti-VEGF.

25agents

Where it strikes

Vasculature / Endothelium

Glomerular & peritubular capillaries

Glomerulus

Filtration barrier (podocytes + endothelium)

See it on the nephron

Severity mix

Severe· 5Moderate· 14Mild· 6

Reversibility

Often irreversible· 3Partially reversible· 2Variable· 9Reversible· 11

Signature offenders

Agents for which thrombotic microangiopathy is the defining renal lesion.

GemcitabineDelayed — months of cumulative exposure.~0.015–2.2%; best single estimate ~0.31% cumulative. Historically high mortality.Severe Mitomycin CDelayed — after cumulative dosing, sometimes after therapy ends.Dose-dependent, generally 4–15%; risk rises sharply at cumulative dose ≥30 mg/m². >50% historical mortality.Severe CarfilzomibVariable — frequently early (first cycles), but TMA can also appear later, sometimes after a treatment break and re-escalation.Renal complications are common and a recognized class concern: in a 114-patient real-world cohort, ~17% had carfilzomib-attributable renal events (TMA ~5%, albuminuria >1 g/day ~6%, otherwise-unexplained grade >=3 AKI ~5%), occurring mostly early and unpredictably. On the prospective CARDAMON trial, TMA occurred at ~1.6-4.2 events per 1,000 patient-cycles, with most patients hypertensive and almost all developing AKI. Pharmacovigilance (FAERS) shows carfilzomib carries by far the strongest TMA signal among proteasome inhibitors.Severe Moxetumomab pasudotoxCycle-related: CLS within the first days of a cycle; HUS often during/after cycles 2-3.Boxed warning for capillary-leak syndrome (CLS) and hemolytic-uremic syndrome (HUS)/TMA. In the pivotal phase 3 trial HUS occurred in ~7.5% and CLS in ~5%; reviews cite roughly 9% each. Fatal CLS has been reported (in a pediatric ALL case).Severe Tegafur-uracil (UFT)Variable; TMA/HUS typically emerges after weeks to months of cumulative exposure.Direct renal injury from UFT is rare and largely class-level. Fluoropyrimidine-associated thrombotic microangiopathy / hemolytic-uremic syndrome is a rare, mostly case-report-level event, frequently in combination regimens (e.g., with mitomycin C). No reliable drug-specific incidence rate is established.Severe BusulfanWeeks after conditioning/transplant.Transplant-associated thrombotic microangiopathy (TA-TMA) with renal involvement complicates a subset of conditioning regimens; high-dose busulfan (e.g., 16 mg/kg) has been identified as an independent risk factor for post-transplant TMA, and high busulfan exposure also drives sinusoidal obstruction syndrome/VOD.Moderate Trastuzumab emtansine (T-DM1)Variable; reported after initiation, over weeks to months of therapy.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.Moderate BortezomibRare adverse renal events occur during therapy (days to weeks); the beneficial light-chain reduction is often rapid.Bortezomib is generally renal-friendly and often improves renal function in myeloma by rapidly reducing light-chain-driven cast nephropathy; it requires no renal dose adjustment. Thrombotic microangiopathy and glomerular microangiopathy are rare, case-level events, and pharmacovigilance shows a far weaker TMA signal than carfilzomib.Moderate IxazomibVariable; reported after weeks to months of therapy, including with cumulative exposure. Class median time to TMA onset ~8 days from a triggering cycle.Drug-induced thrombotic microangiopathy (TMA) is a rare, case-level event for ixazomib and is not reliably quantified. In a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS, 2004-2023), proteasome inhibitors as a class were significantly associated with TMA (213 cases; ROR 1.71), but carfilzomib accounted for the overwhelming majority of the signal (58.7% of cases; ROR ~18), with bortezomib and ixazomib contributing far fewer reports. The ixazomib signal is therefore extrapolated largely from the class.Moderate DoxifluridineVariable; class-level TMA typically after prolonged cumulative exposure.No drug-specific nephrotoxicity incidence is established. Renal risk is inferred at the fluoropyrimidine-class level (rare TMA/HUS); direct doxifluridine renal injury reports are sparse.Moderate Carmofur (HCFU)Variable; class-level TMA after cumulative exposure.No established drug-specific renal incidence. Renal risk is class-level (rare fluoropyrimidine TMA/HUS). Carmofur's characteristic serious toxicity is leukoencephalopathy, not nephrotoxicity.Moderate 5-FluorouracilTMA often delayed (weeks to months); prerenal effects acute with GI toxicity.Intrinsic nephrotoxicity is low; the recognized vascular renal complication is thrombotic microangiopathy/hemolytic-uremic syndrome, classically with mitomycin C, with 5-FU as a frequent co-agent. In TTP/HUS series the most common antecedent chemotherapy is mitomycin C plus 5-FU.Mild

Also associated

Agents that cause thrombotic microangiopathy as a secondary pattern alongside a different signature lesion.

BevacizumabWeeks to months; dose-dependent.All-grade proteinuria ~20–40%; high-grade ~2.2%. Hypertension RR 3–7.5. Nephrotic syndrome RR 7.78.Moderate VEGFR Tyrosine Kinase InhibitorsHypertension within days–weeks; proteinuria over weeks–months.Hypertension ~17–50%; proteinuria 8–73% across agents (all-grade ~18.7%, high-grade ~2.4%).Moderate Carmustine (BCNU)Delayed - months to years after cumulative exposure; conditioning-associated TMA appears within weeks.Insidious, cumulative-dose chronic nephrotoxicity; in classic high-cumulative-dose series the majority of long-term survivors develop reduced renal function, with small scarred kidneys. Acute injury is uncommon except via infusion hypotension or as part of conditioning-associated TMA/HUS.Moderate BendamustineTLS within hours to days of the first cycle; TMA delayed and rare.Direct nephrotoxicity is uncommon; the principal renal risk is acute kidney injury from tumor lysis syndrome in high-burden disease, classically during the first cycle. TLS with renal failure is documented from the first reported case onward; TMA is rare and case-level.Moderate RamucirumabWithin the first one to two cycles (weeks).Hypertension and proteinuria are common class effects; nephrotic syndrome is a less frequent but reported event, sometimes after only 1-2 doses and typically accompanied by hypertension.Moderate Ziv-afliberceptWithin weeks to a few months of therapy.Hypertension and proteinuria are common class effects; in the registrational VELOUR trial, grade 3-4 hypertension and proteinuria were notably more frequent with aflibercept plus FOLFIRI than with FOLFIRI alone. Nephrotic-range proteinuria and renal thrombotic microangiopathy are documented, including with the ophthalmic formulation, indicating a direct VEGF-trap mechanism.Moderate LenalidomideVariable; azotemia reported from weeks to several months after initiation.AKI/azotemia is uncommon but recognized, described mainly in case series of plasma-cell dyscrasias with underlying renal insufficiency; not reliably quantified as an incidence. Rare Fanconi syndrome and TMA are reported. Because ~80% of lenalidomide is renally cleared as unchanged drug, accumulation in renal impairment is the dominant driver of toxicity, including myelosuppression.Moderate Lutetium-177 DotatateDelayed — radiation nephropathy evolves over months to years after treatment; the amino-acid-related hyperkalemia is acute (during infusion).Clinically significant nephrotoxicity is uncommon when amino-acid renoprotection is used: in the NETTER-1 and large Erasmus/Rotterdam cohorts, no therapy-related long-term renal failure was attributed to lutetium-177 dotatate, and the typical long-term GFR decline is modest (~2 mL/min/year). A precise incidence of grade >=3 nephrotoxicity is not well quantified and is low; the more feared long-term toxicity is delayed MDS/AML (~1-2%).Moderate OxaliplatinAcute if immune-mediated (often on re-challenge).Lowest nephrotoxic potential of the platinums; AKI is rare and case-level, often immune-mediated.Mild CapecitabineAcute, during cycles with GI toxicity; TMA delayed and rare.Intrinsic nephrotoxicity is uncommon; the main renal issue is prerenal AKI from drug-induced diarrhea and volume depletion. Renal impairment increases toxicity - in the PK study, all patients with severe impairment (CrCl <30) had grade 3-4 adverse events - so labeling mandates dose adjustment by creatinine clearance and contraindicates severe impairment.Mild DecitabineEarly after a treatment cycle (days) for tumor lysis; TMA over weeks.Tumor lysis syndrome with AKI is a recognized but uncommon complication when bulky/proliferative disease responds; renal incidence specific to decitabine is not well quantified (case-level). Rare biopsy-proven renal thrombotic microangiopathy has been reported.Mild NintedanibOver months of therapy in reported cases.Renal effects are uncommon; proteinuria and rare biopsy-proven renal thrombotic microangiopathy have been reported, consistent with VEGF-pathway inhibition. Renal incidence is not well quantified (case-level), and much of the published renal experience comes from pulmonary-fibrosis rather than oncology cohorts.Mild OlaparibCreatinine rise within weeks of starting therapy; reverses on discontinuation.Olaparib commonly causes a reversible, dose-dependent rise in serum creatinine. In a 66-patient study, median creatinine rose ~14% (and creatinine-based eGFR fell ~13%) on treatment, while cystatin C and cystatin C-based eGFR were unchanged - indicating no true GFR decline. Thrombotic microangiopathy is a rare, case-level event for the PARP-inhibitor class.Mild

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