Renal Function and Methotrexate Clearance in Children With Newly Diagnosed Leukemia

Abstract

Study Objectives. To determine whether glomerular filtration rate (GFR) changes during induction chemotherapy in children with leukemia, and to examine GFR as a determinant of pharmacokinetic variability of methotrexate clearance.Design. Prospective, unblinded observational study in consecutive patients.Setting. A research hospital.Patients. Thirty‐eight children newly diagnosed with acute lymphoblastic leukemia.Interventions. The patients received either high‐dose methotrexate 1 g/m2 intravenously over 24 hours or low‐dose methotrexate 30 mg/m2 orally every 6 hours for six doses; both regimens were followed by an intensive six‐drug chemotherapy regimen given over 6 weeks. Glomerular filtration rate was determined in each subject before and at the conclusion of induction therapy.Measurements and Main Results. The GFR was determined from 99mTc‐DTPA serum clearance in all patients, and methotrexate clearance was estimated from serial serum concentrations in 18 of these children who received high‐dose methotrexate. Median values for GFR at diagnosis (131 ml/min/1.73 m2) and after induction therapy (120 ml/min/1.73 m2) were not significantly different (p=0.26) but were highly variable (range 49–274 ml/min/1.73 m2). Body size, age, and serum creatinine were correlated significantly with GFR at diagnosis. Amphotericin B therapy (6 patients) significantly decreased GFR (p=0.046) without a corresponding increase in serum creatinine. Methotrexate clearance (58–155 ml/min/m2) was significantly (p=0.007) correlated with GFR, but GFR accounted for only 37% of the variability of methotrexate clearance.Conclusions. The GFR was normal but highly variable in these children with leukemia and was significantly altered by amphotericin. Our results explain little of the intersubject variability in methotrexate clearance.