Commentary

Abstract

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 mol/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/m every 6 h for a methotrexate concentration 10 mol/L at 48 h). High leucovorin doses (250 mg/m 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 lifethreatening 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.