Hugo Garcia1, Véronique Leblond2, François Goldwasser3, Didier Bouscary4, Emmanuel Raffoux5, Nicolas Boissel5, Sophie Broutin6, Dominique Joly7. 1. Service de néphrologie, hôpital universitaire Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75013 Paris, France; Université Pierre-et-Marie-Curie Paris 6, Sorbonne universités, 47, boulevard de l'Hôpital, 75013 Paris, France. Electronic address: hugo.garcia@aphp.fr. 2. Université Pierre-et-Marie-Curie Paris 6, Sorbonne universités, 47, boulevard de l'Hôpital, 75013 Paris, France; Service d'hématologie clinique, hôpital universitaire Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75013 Paris, France. 3. Service de cancérologie, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France. 4. Service d'hématologie clinique, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France. 5. Service des maladies du sang, hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France. 6. Service de pharmacologie, institut Gustave-Roussy, 114, rue Édouard-Vaillant, 94800 Villejuif, France. 7. Service de néphrologie, hôpital Necker-Enfants-Malade, 149, rue de Sèvres, 75015 Paris, France.
Abstract
INTRODUCTION: High-dose methotrexate (at least 1g/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. PATIENTS AND METHODS: 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 10μmol/L at 48h or at least 3μmol/L at 48h associated with acute kidney injury). RESULTS: Seventy-six acute kidney injury cases have been studied. Mean peak creatinine was 206μmol/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. CONCLUSION: 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.
INTRODUCTION: High-dose methotrexate (at least 1g/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. PATIENTS AND METHODS: 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 10μmol/L at 48h or at least 3μmol/L at 48h associated with acute kidney injury). RESULTS: Seventy-six acute kidney injury cases have been studied. Mean peak creatinine was 206μmol/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. CONCLUSION: 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.
Authors: Marc Ghannoum; Darren M Roberts; David S Goldfarb; Jesper Heldrup; Kurt Anseeuw; Tais F Galvao; Thomas D Nolin; Robert S Hoffman; Valery Lavergne; Paul Meyers; Sophie Gosselin; Tudor Botnaru; Karine Mardini; David M Wood Journal: Clin J Am Soc Nephrol Date: 2022-03-02 Impact factor: 10.614