Effective clearance of methotrexate using high-flux hemodialysis membranes

doi:10.1016/S0272-6386(96)90384-4

American Journal of Kidney Diseases

Volume 28, Issue 6, December 1996, Pages 846-854

https://doi.org/10.1016/S0272-6386(96)90384-4 Get rights and content

Abstract

We report the first series demonstrating effective clearance of methotrexate using acute intermittent hemodialysis 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 μmol/L 1 hour postinfusion to less than 0.3 μmol/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.

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Cited by (96)

Successful treatment with adapted high dose methotrexate in a hemodialysis patient with primary central nervous system lymphoma: 100 mg/m<sup>2</sup> seems sufficient
2022, Nefrologia
High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX.
We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100 mg/m², instead of the usual dose of 3500 mg/m², and daily hemodialysis started 24 h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment.
We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100 mg/m² as a viable therapeutic modality in ESRD patients.
La quimioinmunoterapia basada en una dosis elevada de metotrexato (HD-MTX) es una parte central del enfoque terapéutico estándar del linfoma primario del sistema nervioso central (PCNSL). La insuficiencia renal causa la demora de la eliminación completa de MTX, así como la concentración crítica del mismo. A pesar de las recomendaciones, el estatus de hemodiálisis no debería excluir la HD-MTX.
Reportamos el caso de una mujer de 64 años con PCNSL y tratamiento de hemodiálisis crónica que fue exitosamente tratada con quimioinmunoterapia basada en HD-MTX con una dosis ajustada de 100 mg/m², en lugar de la dosis habitual de 3.500 mg/m², iniciándose la hemodiálisis diaria al cabo de 24 h. La paciente no reflejó toxicidad significativa y experimentó remisión completa al cabo de un año desde la finalización del tratamiento.
Nosotros argumentamos que la enfermedad renal en etapa terminal (ESRD) no constituye un escollo en absoluto para utilizar la HD-MTX para neoplasias hematológicas. Los expertos deberían considerar el uso de una dosis ajustada a 100 mg/m² como modalidad terapéutica viable en los pacientes de ESRD.
Fixed-Dose Glucarpidase for Toxic Methotrexate Levels and Acute Kidney Injury in Adult Lymphoma Patients: Case Series
2021, Clinical Lymphoma, Myeloma and Leukemia
Dose recommendations for anticancer drugs in patients with renal or hepatic impairment
2019, The Lancet Oncology
Citation Excerpt :
This scenario is illustrated by a case describing the administration of a high dose of methotrexate (7·2 g/m2) in a patient who was functionally anephric.31 Daily intermittent high-flux haemodialysis yielded a total body clearance comparable to those patients who had unimpaired renal function.31 Most reviewed anticancer drugs are highly protein bound, and therefore unlikely to be dialysed by conventional haemodialysis.
Renal or hepatic impairment is a common comorbidity for patients with cancer either because of the disease itself, toxicity of previous anticancer treatments, or because of other factors affecting organ function, such as increased age. Because renal and hepatic function are among the main determinants of drug exposure, the pharmacokinetic profile might be altered for patients with cancer who have renal or hepatic impairment, necessitating dose adjustments. Most anticancer drugs are dosed near their maximum tolerated dose and are characterised by a narrow therapeutic index. Consequently, selecting an adequate dose for patients who have either hepatic or renal impairment, or both, is challenging and definitive recommendations on dose adjustments are scarce. In this Review, we discuss the effect of renal and hepatic impairment on the pharmacokinetics of anticancer drugs. To guide clinicians in selecting appropriate dose adjustments, information from available drug labels and from the published literature were combined to provide a practical set of recommendations for dose adjustments of 160 anticancer drugs for patients with hepatic and renal impairment.
Chemotherapy in chronic kidney disease and dialysis
2019, Onco-Nephrology
Poisoning: Kinetics to Therapeutics
2019, Critical Care Nephrology: Third Edition
Renal toxicity of high-dose methotrexate
2018, Nephrologie et Therapeutique
Le méthotrexate à haute dose (supérieure ou égale à 1 g/m²) est utilisé pour traiter certaines hémopathies malignes et ostéosarcomes. La survenue d’une insuffisance rénale aiguë est une complication classique qui favorise le retard d’élimination du méthotrexate et ses diverses toxicités. Au-delà des mesures thérapeutiques classiques (hyperhydratation alcaline, acide folinique, épuration extrarénale), une enzymothérapie spécifique onéreuse est disponible (glucarpidase) mais son impact clinique est mal évalué.
Nous avons analysé les prescriptions de hautes doses de méthotrexate dans 11 centres au cours des 15 dernières années, afin d’identifier et décrire les patients adultes ayant développé une insuffisance rénale aiguë (classification selon Kidney Disease : Improving Global Outcomes [KDIGO]). Nous avons référencé un usage éventuel de glucarpidase (autorisation temporaire d’utilisation officielle : méthotrexatémie supérieure ou égale à 10 μmol/L après 48 h, ou supérieure ou égale à 3 μmol/L après 48 h avec insuffisance rénale aiguë).
Soixante-seize cas d’insuffisance rénale aiguë ont été étudiés. En moyenne, le pic de créatinine était de 206 μmol/L, observé après 5,6 jours ; il y avait 19 cas d’insuffisance rénale aiguë de stade 1 (25 %), 29 de stade 2 (38 %) et 27 de stade 3 (36 %). L’anurie (un cas) et le recours à la dialyse (quatre cas) étaient rares, la surcharge hydrosodée fréquente (29 % des patients). À 3 mois, 17 % des patients étaient décédés 12 % présentaient des séquelles rénales.
Lors de l’épisode d’insuffisance rénale aiguë, 61 % des patients ont reçu de la glucarpidase. Malgré un effet spectaculaire sur la méthotrexatémie, la glucarpidase (comparativement à un traitement conservateur) ne modifiait ni le profil évolutif de l’insuffisance rénale aiguë (sévérité, délai de récupération, recours à l’épuration extrarénale) ni l’incidence des toxicités extrarénales. L’absence de bénéfice persistait après stratification pour le respect ou non du libellé d’autorisation temporaire d’utilisation. La glucarpidase a probablement peu d’effet sur le méthotrexate déjà présent au niveau de la lumière tubulaire ou dans la cellule tubulaire rénale, ce qui pourrait expliquer l’absence d’effet néphroprotecteur observé.
High-dose methotrexate (at least 1 g/m²) is used to treat haematologic malignancies and osteosarcomas. Acute kidney injury is a well-known adverse-event after high-dose methotrexate and may lead to delayed drug elimination. Besides usual therapeutics (hyperhydration, urine alkalinisation, leucovorin rescue, renal replacement therapy), a costly specific enzymatic treatment (glucarpidase) is now available but its clinical impact remains elusive.
We analysed high-dose methotrexate prescription charts in 11 clinical centres during the last 15 years to identify and describe adult patients who developed acute kidney injury (according to KDIGO classification). Glucarpidase use was recorded (French temporary regulatory approval criteria: methotrexate at least 10 μmol/L at 48 h or at least 3 μmol/L at 48 h associated with acute kidney injury).
Seventy-six acute kidney injury cases have been studied. Mean peak creatinine was 206 μmol/L after a mean delay of 5.6 days, with 19 cases of stage 1 acute kidney injury (25%), 29 cases of stage 2 (38%) and 27 cases of stage 3 (36%). Anuria (one case) and need for renal replacement therapy (four cases) were unusual whereas fluid overload was often observed (29%). Three months after high-dose methotrexate treatment, mortality-rate was 17%, and 12% of surviving patients developed renal sequelae.
Sixty-one percent of patients received a glucarpidase perfusion during acute kidney injury. Despite a dramatic decrease of methotrexate serum levels, glucarpidase as compared with conservative treatment did not modify acute kidney injury stage, recovery delay, need for renal replacement therapy or the incidence of extrarenal toxicities. Net clinical benefit was not observed even after stratification according to eligibility criteria for glucarpidase use. Glucarpidase has probably no or little effects on methotrexate localized into tubular lumen or proximal tubular cells and that may account for the absence of nephroprotective effect for enzymatic treatment.

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Original investigationEffective clearance of methotrexate using high-flux hemodialysis membranes

Abstract

Eur J Cancer

Biochem Pharmacol

Blood

The clinical pharmacology of methotrexate

Cancer

The metabolic fate of tritiated methotrexate II. Absorption and excretion in man

Cancer Res

Acute renal failure associated with cancer treatment

Pharmacokinetics of high-dose methotrexate (NSC-740)

Cancer Chemother Rep

Will hemoperfusion be useful for cancer chemotherapeutic drug removal?

Clin Toxicol

The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides

Cancer Res

Methotrexate-induced renal failure and ineffectiveness of peritoneal dialysis

Arch Intern Med

Successful treatment of methotrexate-induced renal failure by haemodialysis

Aust N Z J Med

Removal of methotrexate, leucovorin and their metabolites by combined hemodialysis and hemoperfusion

Cancer

Original investigation
Effective clearance of methotrexate using high-flux hemodialysis membranes