Purpose
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.
Methods
Patients were randomized by cycle to 4 h or 12 h HDMTX (12 g/m
2
) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFR
Cr
or GFR
cysC
) were obtained. Serum and urine methotrexate concentrations MTX were measured.
Results
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 4 h infusion and 557 (493, 586) µM and 11.1 (9.9, 21.1) mM at the end of 12 h infusion. Time to serum MTX < 0.1 µM was 83 (80.7, 90.7) h and 87 (82.8, 92.4) h for 4 and 12 h infusions. GFR
Cr
was highly variable, increased after cisplatin, and exceeded 150 ml/min/1.73 m
2
. GFR
cysC
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 12 h infusions. Radiographic and histological response were similar for patients receiving 4 h or 12 h infusions; the median percent tumor necrosis was > 95%.
Conclusions
Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFR
cysC
was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity.
Clinical Trial
NCT01848457.
