13 1 Outline of this thesis Part One: Cisplatin-induced acute kidney injury Cisplatin, or cis-diamminedichloroplatinum II [CDDP], is a potent and valuable chemotherapy agent used to treat a broad spectrum of malignancies. Cisplatin exerts anticancer activity through multiple mechanisms, but its most prominent (and best understood) mode of action involves the generation of DNA lesions through interaction with purine bases on DNA, followed by activation of several signal transduction pathways that ultimately lead to apoptosis in cancer cells [26]. Side effects, such as nausea and vomiting, myelosuppression, neurotoxicity and ototoxicity, often limit the use and effectiveness of cisplatin [27]. The major dose-limiting side effect of cisplatin, however, is nephrotoxicity [28, 29]. The most common and severe presentation of cisplatin-induced nephrotoxicity is acute kidney injury (AKI) [30, 31]. Multiple mechanisms contribute to cisplatin-induced kidney damage [32, 33]. Cisplatin accumulates in theproximal tubular cells during glomerular filtration and tubular secretion, and a cascade of intracellular injury pathways occurs (Figure 1). These pathways include caspase activation, cyclin-dependent kinases, mitogen-activated protein kinase activation, and p53 signaling. Along with additional inflammation, oxidative stress, and vascular injury, this results in apoptosis and necrosis of the renal tubules, ultimately leading to AKI and/ or tubulopathy. Figure 1. Cisplatin enters proximal tubular cells through organic cation transporters (OCTs), and when it accumulates within cells, it causes cell injury through multiple mechanisms. Apoptosis and necrosis of tubular cells result and cause clinical AKI and tubulopathy. Abbreviations: CDKs, cyclin-dependent kinases; Cis, cisplatin; MAPK, mitogen-activated protein kinase; MRP, multidrug-resisitant protein; NaDC, sodium dicarboxylate; OAT, organic anion transporter; P53, protein 53; Pgp, P glycoprotein; ROS, reactive oxygen species. From Clin J Am Soc Nephrol 2012;7:1713-21. Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents. Reprinted with permission.
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