Treatment consisted of HDMTX (1g/m²; total dose 1600mg) administered as an intravenous (IV) infusion over 2 hours every two weeks, followed by extended hours high-flux hemodialysis (Figure 1). At each dialysis session a Fresenius FX80 synthetic high-flux membrane (Fresenius Inc., Walnut Creek, CA) was used with a blood flow rate of 250 ml/min and a dialysate flow rate of 500 ml/min. Plasma MTX concentrations were measured using a Fluorescence Polarization Radioimmunoassay (Abbott Laboratories, Abbott Park, IL) according to manufacturer's instructions (Figure 1). Leucovorin rescue commenced with a dose of 60mg IV 12 hours after completion of the MTX infusion followed by 50mg IV q6h × 2, then 200mg IV q4h × 12 doses after the first dose of HDMTX and 50mg IV q6h × 15, then 200mg IV q6h × 10 doses after the second dose. In addition to HDMTX, the patient's treatment included dexamethasone, rituximab 375mg/m² IV weekly × 8 and intrathecal cytarabine 100mg. Subsequently, when further myelosuppressive chemotherapy was precluded by infection, EBV specific T-cell therapy and whole brain irradiation (30Gy in 10 fractions) was administered [3].

Both standard intermittent hemodialysis and peritoneal dialysis have limited effectiveness in reducing plasma MTX concentrations due to its moderate (50%) plasma protein binding and large volume of distribution (0.76 L/kg), such that rebound increases of MTX concentrations post-dialysis have been reported, particularly following shorter dialysis sessions [6,14,15]. The effective use of repeated prolonged hemodialysis and charcoal hemoperfusion in the management of a patient who developed ARF and very high MTX concentrations following HDMTX has been described, with the patient avoiding significant toxicity [13]. High-flux hemodialysis has been successfully used to avoid toxicity in the management of three pediatric patients who developed post-HDMTX ARF, two of whom also received carboxypeptidase G2 (glucarpidase) [16]. Two previous reports have described the effective use of high-flux hemodialysis in patients with pre-existing ESRD. Murashima et al describe the case of a patient with cerebral lymphoma who received HDMTX without significant toxicity with the support of high-flux hemodialysis [17]. In the same patient, the use of continuous multiple exchange peritoneal dialysis achieved lower clearance of MTX, but also prevented toxicity. A report from the M.D. Anderson described the effective clearance of MTX in six patients with high-flux hemodialysis [18].

Alternative approaches to dialysis in the management of high MTX concentrations complicating HDMTX induced ARF have been investigated, the most promising of which is glucarpidase, which rapidly metabolises circulating MTX to an inactive metabolite. Glucarpidase is not commercially available, but has been used on a compassionate basis. Reported case series of these patients indicate that the administration of glucarpidase rapidly reduces MTX concentrations, although does not completely prevent toxicity and deaths still occur, especially if administration is delayed [6,19]. There have been no reports of its use to facilitate the delivery of HDMTX in patients with pre-existing ESRD.

With the support of high-flux hemodialysis, our patient was able to receive two doses of HDMTX. The toxicities directly attributable to MTX were limited, easily managed and reversible. More toxicity was observed following the second dose than the first. While the frequency and severity of abnormal transaminases relates to number of doses received [20], no such trend has been observed for mucositis or hematological toxicity [21]. Possible reasons for the greater mucositis and hematological toxicity observed following the second dose include the lower dose of leucovorin given in the first 48 hours, longer time to complete clearance of MTX, more severe hypoalbuminemia and the presence of infection [22,23]. The infectious complications seen in the second cycle preceded, and may have contributed to, the brief episode of neutropenia. They occurred in the context of a patient who had substantial co-morbidities and multiple other risk factors for infection, including post-transplant immunosuppressive therapy, ESRD, dexamethasone, rituximab and the presence of a central venous catheter and ateriovenous fistula. The patient's immunosuppressive state also substantially contributed to her cause of death. It is likely that the use of HDMTX played a role in the achievement of the complete pathologic response observed at autopsy.