Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention
Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention
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DOI：
10.1002/phar.2388
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发表时间：
2020-05-04
期刊：
影响因子：
4.1
通讯作者：
Scheetz, Marc H.
中科院分区：
文献类型：
--
作者：
Pais, Gwendolyn M.;Liu, Jiajun;Scheetz, Marc H.
万古霉素是多个国家指南中推荐的治疗方法。尽管万古霉素的使用很普遍，但对万古霉素介导的肾损伤的机制驱动因素和潜在的修饰物了解很少。本文综述了万古霉素所致肾损伤(VIKI)的历史和现代发生率，并对临床前研究中的毒物动力学模型和毒性机制进行了综述。除了已知的导致VIKI恶化的临床协变量外，临床前模型已经证明了各种因素对VIKI的影响，包括剂量、给药途径和药代动力学参数的阈值。静脉给药的急性肾损伤(AKI)程度最大，剂量越大，最大浓度越大，浓度曲线下的面积越大。低谷(即最低浓度)的影响较小。从机制上讲，临床前研究已经证实VIKI是药物在近端小管细胞积聚的结果，它触发细胞氧化应激和细胞凋亡。然而，在可能代表使万古霉素疗法毒性较低的可行靶点的知识方面存在几个空白。可能的策略包括延长输液时间和降低最大浓度，使用抗氧化剂，使用减少细胞积聚的药物，以及重新配制万古霉素以改变肾脏清除机制。基于临床前模型和毒性机制，我们提出了减轻VIKI的潜在策略。
Vancomycin is a recommended therapy in multiple national guidelines. Despite the common use, there is a poor understanding of the mechanistic drivers and potential modifiers of vancomycin-mediated kidney injury. In this review, historic and contemporary rates of vancomycin-induced kidney injury (VIKI) are described, and toxicodynamic models and mechanisms of toxicity from preclinical studies are reviewed. Aside from known clinical covariates that worsen VIKI, preclinical models have demonstrated that various factors impact VIKI, including dose, route of administration, and thresholds for pharmacokinetic parameters. The degree of acute kidney injury (AKI) is greatest with the intravenous route and higher doses that produce larger maximal concentrations and areas under the concentration curve. Troughs (i.e., minimum concentrations) have less of an impact. Mechanistically, preclinical studies have identified that VIKI is a result of drug accumulation in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. Yet, there are several gaps in the knowledge that may represent viable targets to make vancomycin therapy less toxic. Potential strategies include prolonging infusions and lowering maximal concentrations, administration of antioxidants, administering agents that decrease cellular accumulation, and reformulating vancomycin to alter the renal clearance mechanism. Based on preclinical models and mechanisms of toxicity, we propose potential strategies to lessen VIKI.