Hempel Lutz, Misselwitz Joachim, Fleck Christian, Kentouche Karim, Leder Christiane, Appenroth Dorothea, Rost Michael, Zintl Felix
Department of Pediatric Hematology and Oncology, Friedrich Schiller University, Jena, Germany.
Med Pediatr Oncol. 2003 Jun;40(6):348-54. doi: 10.1002/mpo.10293.
The present investigation was intended to further clarify the mechanisms involved in renal dysfunction following high-dose methotrexate (HD-MTX) treatment.
Fifty eight predominately pediatric patients [39 male, 19 female; mean age 12.3 years (range 2.2-34.1)] suffering from acute lymphoblastic leukemia (ALL, n = 28), Non Hodgkins lymphoma (NHL, n = 13), osteosarcoma (n = 8), malignant brain tumor (n = 6), or an ALL relapse (n = 3), were prospectively examined. In the course of 220 infusions of HD-MTX, glomerular and tubular renal function was determined by measuring proteinuria and glomerular filtration rate (GFR), as well as renal excretion of alpha-1-microglobulin (AMG) and N-acetyl-beta-D-glucosaminidase (NAG). It was investigated whether there were differences in MTX toxicity in dependence on the administered dose (1, 5, or 12 g/m(2) BSA), on the combination with other cytostatic agents (ifosfamide or cyclophosphamide), on the metabolism of MTX into 7-OH-MTX, and on pre-treatment with MTX.
The administration of HD-MTX has no direct tubulotoxic effect. The disturbance in glomerular function was dose dependently and indicated by an increase in proteinuria as well as by a decrease in GFR; all changes were completely reversible and did not correlate to the metabolism of MTX to 7-OH-MTX. Increasing the number of MTX therapeutic cycles did not increase the nephrotoxicity of MTX.
MTX is not directly tubulotoxic. Its side effects on glomeruli are usually without clinical relevance.
本研究旨在进一步阐明大剂量甲氨蝶呤（HD-MTX）治疗后肾功能障碍的相关机制。
前瞻性检查了58例主要为儿科的患者[39例男性，19例女性；平均年龄12.3岁（范围2.2 - 34.1岁）]，他们患有急性淋巴细胞白血病（ALL，n = 28）、非霍奇金淋巴瘤（NHL，n = 13）、骨肉瘤（n = 8）、恶性脑肿瘤（n = 6）或ALL复发（n = 3）。在220次HD-MTX输注过程中，通过测量蛋白尿、肾小球滤过率（GFR）以及α-1-微球蛋白（AMG）和N-乙酰-β-D-氨基葡萄糖苷酶（NAG）的肾排泄来测定肾小球和肾小管的肾功能。研究了MTX毒性是否因给药剂量（1、5或12 g/m²体表面积）、与其他细胞毒性药物（异环磷酰胺或环磷酰胺）联合使用、MTX代谢为7-羟基甲氨蝶呤（7-OH-MTX）以及MTX预处理而存在差异。
HD-MTX的给药没有直接的肾小管毒性作用。肾小球功能障碍呈剂量依赖性，表现为蛋白尿增加以及GFR降低；所有变化都是完全可逆的，且与MTX代谢为7-OH-MTX无关。增加MTX治疗周期数并未增加MTX的肾毒性。
MTX没有直接的肾小管毒性。其对肾小球的副作用通常无临床意义。
