New Insights in the Pathogenesis of Cisplatin-Induced Nephrotoxicity

Cisplatin (cis-diamminedichloroplatinum II) is a widely used chemotherapeutic agent. However, efficacy and clinical utility of this drug is significantly limited by severe side effects such as nephrotoxicity which develops due to renal accumulation and bio-transformation in proximal tubular epithelial cells. Cisplatin-induced nephrotoxicity can be manifested as acute kidney injury (AKI), or as different types of tubulopathies, salt wasting, loss of urinary concentrating ability, and magnesium wasting. The attenuation of cisplatin-caused AKI is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis. However, mannitol treatment causes over-diuresis and consequent dehydration, indicating an urgent need for the clinical use of newly designed, safe and efficacious renoprotective drug, as an additive therapy for high dose cisplatin-treated patients. Accordingly, we emphasized current knowledge regarding molecular mechanisms responsible for cisplatin-caused nephrotoxicity and we described in detail the main clinical manifestations of cisplatin-induced renal dysfunction in order to pave the way for the design of new therapeutic approaches that can minimize detrimental effects of cisplatin in the kidneys. Having in mind that most of cisplatin-induced cytotoxic effects against renal cells are, at the same time, involved in anti-tumor activity of cisplatin, new nephroprotective therapeutic strategies have to prevent renal injury and inflammation without affecting cisplatin-induced toxicity against malignant cells.