Figure 57

Methotrexate (MTX) nephrotoxicity. Renal biopsy specimen from a patient treated with 3 g/m2 of MTX followed by leucovorin who became dehydrated and developed acute renal failure. Precipitated material in the tubules (arrow) strongly reacted with a fluorescinated rabbit anti-MTX antibody [23]. MTX nephrotoxicity may occur with high-dose therapy (1 to 15 g/m2); at conventional doses, MTX does not produce nephrotoxicity. Before the importance of maintaining a high urinary volume and pH was realized, renal toxicity was noted in approximately 30% of treatment courses and was responsible for 20% of drug-related deaths during high-dose MTX-leucov-orin rescue therapy [24]. MTX is excreted primarily by the kidneys by means of glomerular filtration and tubular secretion; more than 90% of an intravenous dose appears unchanged in the urine following conventional doses [25]. During high-dose infusions, urinary MTX levels exceed solubility and therefore drug precipitation occurs, as illustrated previously. At physiologic systemic pH, MTX is completely ionized; however, the un-ionized moiety predominates at the more acidic pH usually encountered within the distal nephron, with solubility being markedly reduced. Thus, patients receiving high-dose MTX therapy may be more prone to development of nephrotoxicity if they are dehydrated and excreting an acidic urine. The 7-OH metabolite of MTX also may precipitate within the nephrons. This metabolite may account for as much as 7% to 33% of the MTX appearing in the urine 24 to 48 hours after intravenous administration; its solubility is only 25% of that observed for MTX [26]. (From Rieselbach and Garnick [1]; with permission.)

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