Lung cancer-kidney cross talk induces kidney injury, interstitial fibrosis, and enhances cisplatin-induced nephrotoxicity.

Abstract

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: 1) noncancer/vehicle, 2) noncancer/cisplatin, 3) cancer/vehicle, and 4) 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.NEW & NOTEWORTHY 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.