{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:05:57Z","timestamp":1790654757092,"version":"4.1.0"},"reference-count":55,"publisher":"S. Karger AG","issue":"2","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"},{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am J Nephrol"],"abstract":"<jats:p>Background: Methotrexate (MTX) is an antimetabolite anticancer agent that has been used at doses ranging from 20 mg\/m2 of body surface area to 33,000 mg\/m2. High-dose methotrexate (HDMTX), defined as doses higher than 500 mg\/m2, is used to treat acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, brain cancers, leptomeningeal spread of carcinomas, and other cancers. Depending on the dose and other factors, acute kidney injury occurs in 2%\u201339% of HDMTX courses and severe (Acute Kidney Injury Network grade 2 or higher) nephrotoxicity in approximately 2%, though incidence varies widely. Prompt recognition and treatment of delayed MTX elimination and renal dysfunction which includes increased hydration, high-dose leucovorin, and sometimes glucarpidase, is crucial to prevent life-threatening toxicities such as myelosuppression, mucositis, renal failure, and dermatitis. Summary: In this article, we emphasize the importance of MTX pharmacokinetics and pharmacodynamics, highlight the cellular mechanisms of MTX anticancer activity, review the pathophysiology of MTX-induced renal injury, and explore strategies to prevent and manage MTX nephrotoxicity. Key Messages: Prompt recognition and effective treatment of renal and non-renal toxicities of HDMTX can improve outcomes, cancer prognosis, and survival.<\/jats:p>","DOI":"10.1159\/000549144","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T16:01:16Z","timestamp":1761321676000},"page":"209-222","source":"Crossref","is-referenced-by-count":4,"title":["High-Dose Methotrexate Nephrotoxicity"],"prefix":"10.1159","volume":"57","author":[{"given":"Jaya","family":"Kala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott 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