Gene

Kidney

Cisplatin

Biology

Epigenetics

Kidney disease

Apoptosis

Autophagy

Acute kidney injury

Cancer research

Biochemistry

Bioinformatics

Oxidative stress

Internal medicine

Pharmacology

Chemotherapy

Nephrotoxicity

Medicine

Pathology

Nature Reviews Nephrology

Cisplatin is an effective chemotherapeutic agent for various solid tumours, but its use is limited by adverse effects in normal tissues. In particular, cisplatin is nephrotoxic and can cause acute kidney injury and chronic kidney disease. Preclinical studies have provided insights into the cellular and molecular mechanisms of cisplatin nephrotoxicity, which involve intracellular stresses including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress. Stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation have key roles in the pathogenesis of cisplatin nephrotoxicity. In addition, emerging evidence suggests a contribution of epigenetic changes to cisplatin-induced acute kidney injury and chronic kidney disease. Further research is needed to determine how these pathways are integrated and to identify the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity. A number of potential therapeutic targets for cisplatin nephrotoxicity have been identified. However, the effects of renoprotective strategies on the efficacy of cisplatin chemotherapy needs to be thoroughly evaluated. Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding of the complex cellular and molecular mechanisms of cisplatin nephrotoxicity and potentially lead to the identification of specific targets to protect the kidney without compromising the chemotherapeutic efficacy of cisplatin. Here, the authors review the mechanisms that underlie cisplatin-induced acute kidney injury and chronic kidney disease. They also discuss the challenges of developing renoprotective approaches for patients receiving cisplatin-based chemotherapy and potential targets for renoprotection.

Cisplatin nephrotoxicity: new insights and therapeutic implications