Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States.
Department of Medicine, University of Louisville, Louisville, Kentucky, United States.
Am J Physiol Renal Physiol. 2023 Mar 1;324(3):F287-F300. doi: 10.1152/ajprenal.00317.2022. Epub 2023 Feb 2.
Patients with cancer represent a unique patient population with increased susceptibility to kidney disease. Drug-induced acute kidney injury (AKI) in patients with cancer is a common problem. Cisplatin is a highly effective treatment used in many solid-organ cancers and causes AKI in 30% of patients, increasing the risk of chronic kidney disease development. Most preclinical cisplatin toxicity studies have been completed in mice without cancer. We believe that the physiology of patients with cancer is not adequately represented in preclinical models, and the objective of this study was to determine how lung cancer will alter the nephrotoxicity of cisplatin. A genetically engineered mouse model and a syngeneic xenograft model of lung cancer were used. Mice were divided into the following four groups: ) noncancer/vehicle, ) noncancer/cisplatin, ) cancer/vehicle, and ) cancer/cisplatin. Mice were administered cisplatin via intraperitoneal injection once a week for 4 wk. Animals were euthanized 72 h following their final cisplatin injection. Mice with lung cancer had increased renal toxicity, injury, and fibrosis following repeated low doses of cisplatin. In addition, lung cancer alone induced kidney injury and fibrosis in the kidney before cisplatin treatment. In conclusion, this is the first study that we are aware of that assesses the impact of cancer on the kidney in conjunction with the nephrotoxicity of cisplatin. We believe that cancer is providing the first hit to the kidney and the subsequent damage from repeated doses of cisplatin becomes unsurmountable, leading to AKI and progression to chronic kidney disease. Patients with cancer have impaired kidney function and increased susceptibility to nephrotoxic agents. Cisplatin is a commonly used chemotherapeutic with nephrotoxicity as the dose-limiting side effect. Cisplatin nephrotoxicity is almost exclusively studied in mice without cancer. Our current preclinical models do not adequately represent the complexity of patients with cancer. This study demonstrates increased renal toxicity, injury, and fibrosis in mice with lung cancer, which is exacerbated with cisplatin treatment. These results highlight the necessity of using preclinical models that more accurately capture the altered physiology of patients with cancer treated with cisplatin.
癌症患者是一类具有更高易感性的特殊患者群体，易患肾脏疾病。癌症患者的药物诱导急性肾损伤（AKI）是一个常见问题。顺铂是一种广泛应用于多种实体瘤的高效治疗药物，可导致 30%的患者发生 AKI，增加了慢性肾脏病发展的风险。大多数顺铂毒性的临床前研究都是在没有癌症的小鼠中完成的。我们认为，癌症患者的生理学在临床前模型中没有得到充分体现，本研究的目的是确定肺癌将如何改变顺铂的肾毒性。本研究使用了一种基因工程小鼠模型和一种肺癌的同源异种移植模型。将小鼠分为以下四组：)非癌症/载体组、)非癌症/顺铂组、)癌症/载体组和)癌症/顺铂组。每周通过腹腔注射顺铂一次，共 4 周。在最后一次顺铂注射后 72 小时处死动物。接受重复低剂量顺铂治疗的肺癌小鼠出现了更严重的肾毒性、损伤和纤维化。此外，肺癌本身在顺铂治疗前就导致了肾脏损伤和纤维化。总之，这是我们所知的首次评估癌症与顺铂肾毒性共同作用对肾脏的影响的研究。我们认为，癌症是对肾脏的首次打击，随后重复剂量的顺铂造成的损害变得不可逾越，导致 AKI 并进展为慢性肾脏病。癌症患者的肾功能受损，对肾毒性药物的易感性增加。顺铂是一种常用的化疗药物，其肾毒性是剂量限制的副作用。顺铂肾毒性几乎完全在没有癌症的小鼠中进行研究。我们目前的临床前模型不能充分代表癌症患者的复杂性。本研究表明，肺癌小鼠的肾脏毒性、损伤和纤维化增加，顺铂治疗进一步加重了这种情况。这些结果强调了使用更准确地捕捉接受顺铂治疗的癌症患者改变的生理学的临床前模型的必要性。
