Caught in the crossfire: cancer, cisplatin therapy, and kidney injury.
Caught in the crossfire: cancer, cisplatin therapy, and kidney injury.
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陷入交火：癌症、顺铂治疗和肾损伤。
DOI：
10.1152/ajprenal.00037.2023
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Humphreys,BenjaminD
中科院分区：
文献类型：
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作者：
Humphreys,BenjaminD
顺铂于1978年首次被批准用于治疗睾丸癌，目前仍是广泛的实体瘤治疗的主要药物（1）。尽管在这几十年中有数百万患者受益于顺铂治疗，但即使是最早的临床试验也显示顺铂具有显著肾毒性的风险。尽管优化剂量和将顺铂作为联合治疗的一部分降低了顺铂诱导的急性肾损伤（阿基）的发生率，但肾毒性仍然是剂量限制性副作用，并且还与未来慢性肾脏疾病（CKD）的风险相关（2）。大量的临床前研究已经阐明了顺铂引起阿基的机制。近端小管上皮细胞通过SLC 22 A2有机阴离子转运蛋白优先吸收滤过的顺铂，导致细胞内浓度高于其他肾细胞类型。这种细胞内顺铂激活多种应激反应，包括自噬、炎症、内质网应激、衰老、凋亡和程序性坏死（3）。多年来，研究人员一直使用顺铂在啮齿动物中建立阿基模型，最近Siskind实验室和其他人已经表征了重复低剂量顺铂（RLDC）模型，该模型可重复诱导阿基向CKD转变，包括晚期肾纤维化和炎症（4-7）。
First approved for the treatment of testicular cancer in 1978, cisplatin remains a mainstay of therapy for a broad range of solid tumors (1). Although millions of patients have benefitted from cisplatin therapy in the intervening decades, even the earliest clinical trials revealed that cisplatin carries with it the risk of significant nephrotoxicity. Although optimization of dosing and inclusion of cisplatin as part of combination therapy has reduced the incidence of cisplatin-induced acute kidney injury (AKI), nephrotoxicity remains the doselimiting side effect and is also associated with the risk of future chronic kidney disease (CKD)(2). A large body of investigation in preclinical studies has clarified the mechanisms by which cisplatin causes AKI. Proximal tubule epithelial cells preferentially absorb filtered cisplatin through the SLC22A2 organic anion transporter, leading to high intracellular concentrations compared with other kidney cell types. This intracellular cisplatin activates a variety of stress responses including autophagy, inflammation, endoplasmic reticulum stress, senescence, apoptosis, and programmed necrosis (3). For many years, investigators have used cisplatin to model AKI in rodents, and recently the Siskind laboratory and others have characterized a repeated low-dose cisplatin (RLDC) model that reproducibly induces the AKI to CKD transition, including late renal fibrosis and inflammation (4–7).