Enhancement of methotrexate nephrotoxicity after cisplatin therapy.

We measured urinary levels of total protein, N-acetyl-beta-D-glucosaminidase (NAG), alanine aminopeptidase, and adenosine deaminase-binding protein in ten children with osteogenic sarcoma who were receiving combination chemotherapy that included 12 doses of methotrexate (12 g/m2). Analysis of the changes in these sensitive markers of renal tubular damage permitted detection of subclinical methotrexate-induced nephrotoxicity. In the absence of cisplatin, methotrexate therapy was associated with significant but transient increases in each of the four markers. Irreversible nephrotoxicity, indicated by persistent rises in NAG and alanine aminopeptidase as well as increased serum creatinine levels, was associated with doses of methotrexate that followed the administration of cisplatin (400 mg/m2). The biphasic pattern of total protein and NAG excretion observed in all patients suggests more than one mechanism of methotrexate-induced nephrotoxicity. Monitoring renal tubular damage in patients who are receiving methotrexate in combined-drug regimens would provide useful information for scheduling nephrotoxic drugs in clinical trials.