Prevention and Treatment of Acute Kidney Injury Associated with High-Dose Methotrexate.

AKI is a rare but life-threatening complication of the administration of methotrexate (MTX) at high doses (≥1 g/m 2 ) for the treatment of solid or hematological malignancies. MTX overexposure can lead to MTX-AKI and subsequent higher risk of extrakidney toxicities, morbidity, and mortality. MTX-AKI can also lead to secondary CKD requiring a reduced dose or contraindication for subsequent MTX infusions, thus worsening the cancer-related prognosis. Treatment of MTX-AKI is mainly preventive, combining alkaline hyperhydration, withdrawal of all nephrotoxic agents and drugs that modulate the metabolism of MTX, metabolic salvage using leucovorin (folinic acid), and close monitoring of serum MTX and creatinine concentrations. Glucarpidase (carboxypeptidase-G2), a recombinant bacterial enzyme that hydrolyzes MTX into two noncytotoxic metabolites, should be considered for patients with MTX overexposure to prevent and lessen AKI and other potential toxicities. This article provides a comprehensive review of MTX metabolism, mechanisms and prevention of MTX-AKI, and its management.

Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.