Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis.

Abstract

The effectiveness of cisplatin, a mainstay in treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes acute kidney injury (AKI) in 30% of patients. Patients who do not develop AKI by clinical standards during the course of treatment are still at risk for long-term decline in kidney function and the development of chronic kidney disease (CKD). The connection between AKI and CKD has become increasingly studied, with renal fibrosis being a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. Use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.