A pharmacologically-based approach to high dose methotrexate administration to investigate nephrotoxicity and acute kidney injury biomarkers in children and adolescents with newly diagnosed osteosarcoma.

Abstract

High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed. Patients were randomized by cycle to 4h or 12h HDMTX (12g/m2) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFRCr or GFRcysC) were obtained. Serum and urine methotrexate concentrations [MTX] were measured. Patients (n = 12), median (range) age 12.4 (5.7-19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine [MTX] were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4)mM at the end of 4h infusion and 557 (493, 586)µM and 11.1 (9.9, 21.1)mM at the end of 12h infusion. Time to serum [MTX] < 0.1µM was 83 (80.7, 90.7)h and 87 (82.8, 92.4)h for 4 and 12h infusions. GFRCr was highly variable, increased after cisplatin, and exceeded 150ml/min/1.73m2. GFRcysC was less variable and decreased at the end of therapy. AKI biomarkers were elevated indicating acute tubular dysfunction, however, did not differ between 4 and 12h infusions. Radiographic and histological response were similar for patients receiving 4h or 12h infusions; the median percent tumor necrosis was > 95%. Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFRcysC was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity. NCT01848457.