title: Preventing and Managing Toxicities of High-Dose Methotrexate.
abstract: : High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.
  
  
  
  High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
authors: School of Health Studies, University of Memphis, Memphis, Tennessee, USA Scott.howard@worldchildcancer.us.
authors: Scott C
authors: SC
authors: Howard
authors: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, New York, New York, USA.
authors: John
authors: J
authors: McCormick
authors: Department of Oncology, St. Jude Children's Research Hospital, New York, New York, USA.
authors: Ching-Hon
authors: CH
authors: Pui
authors: School of Health Studies, University of Memphis, Memphis, Tennessee, USA.
authors: Randall K
authors: RK
authors: Buddington
authors: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors: R Donald
authors: RD
authors: Harvey
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000188:drug therapy; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001853:Bone Marrow / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003460:Crystallization; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008727:Methotrexate / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics; D052016:Mucositis / Q000139:chemically induced; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D011623:gamma-Glutamyl Hydrolase; D002955:Leucovorin; D008727:Methotrexate
keywords: Acute kidney injury; Glucarpidase; High-dose methotrexate; Leucovorin; Methotrexate; Pharmacokinetics