High-dose methotrexate–induced nephrotoxicity is a medical emergency. Renal methotrexate excretion, which typically accounts for 90% of the drug's elimination, is delayed, resulting in prolonged exposure to high methotrexate concentrations. The duration of exposure is the primary determinant of the drug's toxic effects, and early recognition and prompt efforts to lower methotrexate concentrations are critical to preventing severe systemic toxicity. High-dose methotrexate–induced renal dysfunction is heralded by an increasing serum creatinine concentration during or shortly after the methotrexate infusion. Urine output is usually maintained despite a rapid decline in glomerular filtration. Daily monitoring of serum creatinine and methotrexate concentrations is essential to early detection of this complication.
Leucovorin provides a source of the tetrahydrofolates that are depleted by methotrexate's inhibition of dihydrofolate reductase, but methotrexate competes with leucovorin for cell uptake. Therefore, leucovorin rescue is less effective at methotrexate concentrations that exceed 10 μmol/L for 48 h. The leucovorin dose must be increased in proportion to the serum methotrexate concentration when methotrexate clearance is delayed (e.g., 1000 mg/m2 every 6 h for a methotrexate concentration ≥10 μmol/L at 48 h). High leucovorin doses (250 mg/m2 every 6 h) should also be continued for 48 h after glucarpidase administration because the enzyme hydrolyzes leucovorin and its active circulating metabolite, 5-methyltetrahydrofolate, to inactive forms.
Glucarpidase rapidly and efficiently lowers the serum methotrexate concentration by providing an alternative route of elimination and, when administered as soon as possible after the recognition of nephrotoxicity, can effectively prevent methotrexate toxicity. Patients who receive inadequate leucovorin rescue or receive glucarpidase >96 h after the start of the methotrexate infusion are at greater risk for developing life-threatening methotrexate toxicity (1).
As illustrated by the case study, commercial methotrexate assays will underestimate the impact of glucarpidase on serum methotrexate concentrations because of the interference by the inactive byproduct, DAMPA. DAMPA is subsequently metabolized by hydroxylation and glucuronide conjugation and is cleared more rapidly than residual methotrexate.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
- Received for publication September 17, 2010.
- Accepted for publication September 20, 2010.
- © 2010 The American Association for Clinical Chemistry