Effective Clearance of Methotrexate Using High-Flux Hemodialysis Membranes Susan M. Wall, MD, Mary d. Johansen, PharmD, Donald A. Molony, MD, Thomas D. DuBose, Jr, MD, Norman Jaffe, MD, and Timothy Madden, PharmD • We report the first series demonstrating effective clearance of methotrexate using acute intermittent hemodialy- sis with a high-flux dialyzer. The study was performed on six patients, two females and four males aged 13 to 72 years. All were patients at M.D. Anderson Cancer Center. Patients were dialyzed for 4 to 6 hours daily using a Fresenius F-80 membrane (Fresenius Inc, Walnut Creek, CA). Following the initiation of dialysis, there was a reduction in arterial and venous serum concentration of methotrexate with time. Mean plasma clearance of methotrexate during dialysis in these six patients was 92.1 ± 10.3 mL/min. One patient who was nearly functionally anephric was studied in detail. In this patient, following a high dose of methotrexate (7.2 g/m2), approximately 63% of this dose was cleared with 6 hours of hemodialysis. With subsequent dialysis performed daily for 6 hours, the drug was cleared completely in 5.6 ± 0.3 days (n = 7 separate methotrexate treatments). A reduction in plasma methotrexate concentration from 1,733 ± 40/~mol/L 1 hour postinfusion to less than 0.3/~mol/L in 5 to 6 days was observed for these seven separate treatments. We conclude that significant clearance of methotrexate can be achieved with high-flux dialyzers, making methotrexate therapy a viable treatment option in patients with responsive malignancies despite the presence of renal failure. © 1996 by the National Kidney Foundation, Inc. INDEX WORDS: Dialysis; methotrexate; renal failure; toxic nephropathy; chemotherapy. M 'ETHOTREXATE is a nephrotoxic che- .motherapeutic agent of which 85% to 100% is excreted unchanged in the urine. 1~3 The use of high-dose methotrexate protocols for the treatment of malignancy often results in the de- velopment of high transient plasma levels of the drug. 3 Such therapy can result in renal tubule injury and renal failure, which impairs excretion of the drug and amplifies adverse side effects. 3'4 Thus, rnethotrexate administration is often con- sidered inappropriate for patients with mild to moderate renal insufficiency due to prolonged exposure to concentrations of the drug in excess of 0.3/.tmol/L. Increased toxicity in humans has been found at plasma concentrations above 0.9 #mol/L 48 hours after drug administration. 4'5 In addition, studies in the mouse have demonstrated that leucovorin, a reduced folate used to "res- cue" patients from methotrexate toxicity, may not adequately reverse methotrexate toxicity when plasma methotrexate concentrations are above 100 ~mol]L. 6 One approach used to reduce plasma methotrexate concentrations and the asso- From the Division of Renal Diseases and Hypertension, University of Texas Medical School, Houston, TX; and the Divisions of Pharmacy and Pediatrics, M.D. Anderson Can- cer Center, Houston, TX. Address reprint requests to Susan M. Wall, MD, Division of Renal Diseases and Hypertension, University of Texas, Medical School at Houston, 6431 Fannin, MSB 4.148, Hous- ton, TX 77030. © 1996 by the National Kidney Foundation, Inc. 0272-6386/96/2806-000853.00/0 ciated toxicity of prolonged methotrexate expo- sure is acute intermittent hemodialysis with or without leucovorin rescue. 3 However, previous reports have shown that the clearance of metho- trexate achieved with hemodialysis 7 or acute peritoneal dialysis 8 is poor. One case report de- scribed a reduction in serum methotrexate con- centrations in a single patient undergoing two dialysis treatments using an Ultraflow II coil dia- lyzer. 9 Isolated case reports have suggested ac- ceptable clearance rates with combined hemodi- alysis and charcoal hemoperfusion 1° or charcoal hemoperfusion alone. 11 We report the first series in which effective clearance of methotrexate was achieved with acute intermittent hemodialysis with a high-flux dialyzer. MATERIALS AND METHODS Criteria for Entry Into the Study Patients entered into the study fell into two groups. Group 1 comprised those patients with acute renal failure that re- sulted from methotrexate administration and group 2 com- prised those patients with end-stage renal disease unrelated to methotrexate exposure who required chronic hemodialysis. These patients were dialysis dependent prior to methotrexate administration. Patients were eligible for inclusion in this study if they met the criteria described below. Group 1 (acute renal failure) patients were included if, in the absence of evidence of improvement in renal function, plasma methotrexate concentrations did not reach target lev- els at defined intervals postinfusion. Previous reports have indicated that toxicity can be predicted in patients who re- ceived intravenous methotrexate (> 1 g/m2), based on serum concentrations of the drug measured 48 to 72 hours after the infusion.4,~2 Target levels used in this study were based on 846 American Journal of Kidney Diseases, Vol 28, No 6 (December), 1996: pp 846-854