Garcia Hugo, Leblond Véronique, Goldwasser François, Bouscary Didier, Raffoux Emmanuel, Boissel Nicolas, Broutin Sophie, Joly Dominique
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.
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.
Nephrol Ther. 2018 Apr;14 Suppl 1:S103-S113. doi: 10.1016/j.nephro.2018.02.015.
High-dose methotrexate (at least 1g/m) 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 10μmol/L at 48h or at least 3μmol/L at 48h associated with acute kidney injury).
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.
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.
高剂量甲氨蝶呤（至少1g/m²）用于治疗血液系统恶性肿瘤和骨肉瘤。急性肾损伤是高剂量甲氨蝶呤治疗后一种众所周知的不良事件，可能导致药物清除延迟。除了常规治疗（水化、尿液碱化、亚叶酸钙解救、肾脏替代治疗）外，现在有一种昂贵的特异性酶促治疗（羧肽酶G2）可用，但其临床影响仍不明确。
我们分析了过去15年中11个临床中心的高剂量甲氨蝶呤处方记录，以识别和描述发生急性肾损伤的成年患者（根据KDIGO分类）。记录羧肽酶G2的使用情况（法国临时监管批准标准：48小时时甲氨蝶呤至少10μmol/L或48小时时至少3μmol/L且伴有急性肾损伤）。
共研究了76例急性肾损伤病例。平均肌酐峰值在平均延迟5.6天后为206μmol/L，其中19例为1期急性肾损伤（25%），29例为2期（38%），27例为3期（36%）。无尿（1例）和需要肾脏替代治疗（4例）不常见，而液体超负荷经常出现（29%）。高剂量甲氨蝶呤治疗三个月后，死亡率为17%，12%的存活患者出现肾脏后遗症。
61%的患者在急性肾损伤期间接受了羧肽酶G2灌注。尽管甲氨蝶呤血清水平显著下降，但与保守治疗相比，羧肽酶G2并未改变急性肾损伤分期、恢复延迟、肾脏替代治疗需求或肾外毒性发生率。即使根据羧肽酶G2使用的 eligibility criteria进行分层，也未观察到净临床益处。羧肽酶G2可能对肾小管管腔或近端肾小管细胞中的甲氨蝶呤没有或几乎没有影响，这可能解释了酶促治疗缺乏肾保护作用的原因。
