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2016 ; 21
(12
): 1471-1482
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Preventing and Managing Toxicities of High-Dose Methotrexate
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Oncologist
2016[Dec]; 21
(12
): 1471-1482
PMID27496039
show ga
: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m(2), 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. IMPLICATIONS FOR PRACTICE: High-dose methotrexate (HDMTX),
defined as a dose higher than 500 mg/m(2), 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.
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