This case discusses the use of HDMTX in a patient with ESRD with the support of high-flux hemodialysis, MTX concentration monitoring and leucovorin rescue. The use of MTX in ESRD is controversial with the literature describing prolonged severe toxicity and increased mortality following low dose MTX [1
]. While HDMTX has traditionally been avoided in patients with ESRD, it is documented that patients with delayed MTX excretion due to HDMTX induced acute renal failure (ARF) experience substantial morbidity and mortality [4
]. However, HDMTX has a critical role in the management of PCNSL with several studies demonstrating the superiority of HDMTX over radiation alone and of chemotherapy regimens containing HDMTX over those which do not [7
]. Therefore, in order to treat the described patient optimally, HDMTX needed to be included in the regimen. HDMTX is also used in the curative treatment of acute lymphoblastic leukemia, Burkitt's lymphoma and childhood osteosarcoma. Furthermore, while the use of intensive hydration and alkalinisation of the urine has substantially reduced the risk of ARF following HDMTX, it still occasionally occurs [4
]. The use of optimal techniques to clear MTX in this scenario is essential to avoid a fatal outcome.
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
]. 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
]. 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
]. 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.
This case adds to the limited literature showing that intensive high-flux hemodialysis can effectively clear MTX in patients with ESRD. While these patients may have other co-morbidities which limit their tolerance of aggressive therapy, ESRD is not an absolute contraindication to the use of HDMTX when required for curative therapy of malignancy.