Chemotherapy-Associated Thrombotic Microangiopathy

Kidney360 · 2 authors, 1 centre

AI SUMMARY

FIDELITY 76%

POPULATIONPatients with cancer receiving chemotherapy who develop thrombotic microangiopathy

INTERVENTIONDrug discontinuation, therapeutic plasma exchange, corticosteroids, rituximab, eculizumab, protein-A immunoadsorption

COMPARISONSupportive care alone versus various treatment modalities

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

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TL;DR

Chemotherapy-associated thrombotic microangiopathy (TMA) is a rare but serious kidney complication of antineoplastic drugs, most commonly mitomycin-C and gemcitabine, presenting with hypertension, proteinuria, microangiopathic hemolytic anemia, and thrombocytopenia. Diagnosis requires excluding primary TMA subtypes (TTP, aHUS) via ADAMTS13 testing and kidney biopsy, while management centers on drug discontinuation and supportive care, as therapeutic plasma exchange has not shown benefit. The condition carries high mortality (15%–90%) and incomplete renal recovery, though complement inhibition with eculizumab shows promise in severe or refractory cases.

Full summary

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**Background:** Chemotherapy-associated thrombotic microangiopathy (TMA) is an underdiagnosed cause of kidney injury in cancer patients, characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and end-organ damage. First recognized in 1971 with mitomycin-C, the condition is now associated with multiple antineoplastics including gemcitabine, platinum agents, bleomycin, VEGF inhibitors, and proteasome inhibitors. The incidence of TMA among cancer patients ranges from 6%–15%, reaching approximately 40% in hematopoietic stem cell transplant settings. In a French registry of 564 hospitalized TMA patients, 94% were attributed to secondary causes, with malignancies accounting for 19% and drugs for 26% (calcineurin inhibitors 68%, gemcitabine 8%, VEGF inhibitors 3%).

**Methods:** This is a narrative review synthesizing case reports, case series, systematic reviews, and registry data on chemotherapy-associated TMA. The authors present a detailed case of a 63-year-old woman with stage IIIB ovarian carcinoma who developed TMA after gemcitabine/bevacizumab therapy, with creatinine rising from 0.8 to 2.2 mg/dl, proteinuria of 8.6 g/g creatinine, hemoglobin dropping from 12 to 8.4 g/dl, platelets falling to 144×1000/µL, undetectable haptoglobin, and LDH of 705 U/L. Kidney biopsy showed chronic TMA with 10% interstitial fibrosis and tubular atrophy. After gemcitabine discontinuation, creatinine improved to 1.0 mg/dl and proteinuria decreased to 0.22 g/g creatinine at 6 months.

**Key Results:** Mitomycin-C carries a 4%–15% TMA incidence with mortality up to 75%; cumulative doses exceeding 40–60 mg are a major risk factor. Noncardiogenic pulmonary edema occurred in 65% of 84 patients. Gemcitabine-associated TMA incidence ranges from 0.015%–1.4%, with cumulative dosing >20,000 mg/m² increasing risk. In a French registry of 120 gemcitabine-TMA patients, 97% had AKI, 62% hypertension, 96% anemia, and 75% thrombocytopenia; 65% achieved complete hematologic response after drug discontinuation, while 42% had some renal remission. TPE did not improve outcomes compared with corticosteroids or eculizumab. For bleomycin-associated TMA, only 1 of 11 TPE-treated patients versus 3 of 4 untreated patients had hematologic and kidney recovery. Eculizumab showed rapid response in case reports of carfilzomib- and bleomycin-associated TMA. Rituximab demonstrated renal recovery in gemcitabine-TMA cases refractory to TPE and corticosteroids. Protein-A immunoadsorption achieved 30-day remission in 25 of 55 patients (45%) with mitomycin-C-associated TMA.

**Clinical Implications:** Prompt discontinuation of the suspected causative agent remains the cornerstone of management. TPE is not recommended for chemotherapy-associated TMA (category IV, Grade 2C per ASFA guidelines) but may be initiated while awaiting ADAMTS13 results if TTP is suspected. Complement inhibition with eculizumab may benefit severe or refractory cases, with median four infusions reported. Rechallenge with gemcitabine has been successful in select cases, including with concomitant eculizumab. Poor prognostic factors include older age, underlying kidney disease, severe hypertension, higher chronicity on biopsy, and advanced malignancy. The condition carries mortality rates of 15%–90% depending on cancer stage, and renal recovery is often incomplete. Future directions include endothelial biomarkers for early diagnosis, genetic complement testing, and randomized trials of complement inhibitors such as ravulizumab (ongoing phase III trial NCT04743804).

PICO

PPOPULATION

Patients with cancer receiving chemotherapy who develop thrombotic microangiopathy

IINTERVENTION

Drug discontinuation, therapeutic plasma exchange, corticosteroids, rituximab, eculizumab, protein-A immunoadsorption

OOUTCOME

Hematologic remission, renal recovery (partial or complete), progression to CKD/ESKD, overall survival

STUDY TYPE

narrative_review

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

76% · B

ORIGINAL PAPER

PMC10103319

Chemotherapy-Associated Thrombotic Microangiopathy

Kidney360

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ABSTRACT

Abstract Thrombotic microangiopathy (TMA) is a syndrome of microangiopathic hemolytic anemia and thrombocytopenia with end-organ dysfunction. Although the advent of plasma exchange, immunosuppression, and complement inhibition has improved morbidity and mortality for primary TMAs, the management of secondary TMAs, particularly drug-induced TMA, remains less clear. TMA related to cancer drugs disrupts the antineoplastic treatment course, increasing the risk of cancer progression. Chemotherapeutic agents such as mitomycin-C, gemcitabine, and platinum-based drugs as well as targeted therapies such as antiangiogenesis agents and proteasome inhibitors have been implicated in oncotherapy-associated TMA. Among TMA subtypes, drug-induced TMA is less well-understood. Treatment generally involves withdrawal of the offending agent and supportive care targeting blood pressure and proteinuria reduction. Immunosuppression and therapeutic plasma exchange have not shown clear benefit. The terminal complement inhibitor, eculizumab, has shown promising results in some cases of chemotherapy-associated TMA including in re-exposure. However, the data are limited, and unlike in primary atypical hemolytic uremic syndrome, the role of complement in the pathogenesis of drug-induced TMA is unclear. Larger multicenter studies and unified definitions are needed to elucidate the extent of the problem and potential treatment strategies. Keywords: chemotherapy, thrombotic microangiopathy, TMA, drug-induced TMA, DITMA, antineoplastics, cancer-associated TMA, gemcitabine-induced TMA, mitomycin-C-associated TMA, cisplatin induced TMA

CITATION EXPORT

Abinet M Aklilu, Anushree C Shirali. Chemotherapy-Associated Thrombotic Microangiopathy. Kidney360. (2023). https://doi.org/10.34067/KID.0000000000000061

AUTHORS

2 · 1 CENTRES

Abinet M Aklilu, Anushree C Shirali

1Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut