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Cisplatin nephrotoxicity

INTRODUCTION

Cisplatin is a potent and valuable chemotherapy agent used to treat a broad spectrum of malignancies. Renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the glomerular filtration rate (GFR), can be dose limiting. The laboratory observation that forced hydration and diuresis may prevent nephrotoxicity facilitated the subsequent clinical development of cisplatin [1-3].

Cisplatin-induced renal toxicity is reviewed here. The use of cisplatin in patients with pre-existing renal dysfunction and the renal effects of the platinum analogs, carboplatin and oxaliplatin, are discussed elsewhere. (See "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency".)

PATHOGENESIS

Multiple mechanisms contribute to renal dysfunction following exposure to cisplatin. These include tubular epithelial cell toxicity, vasoconstriction in the renal microvasculature, and proinflammatory effects.

Cellular toxicity — Cisplatin is a potent cellular toxin, particularly in a low-chloride environment. In the interior of cells, chloride atoms in cisplatin are replaced by water molecules. This hydrolysis product is believed to be the active species, reacting with glutathione in the cytoplasm and DNA in the nucleus [4]. In tumors and other dividing cells, cisplatin-DNA intrastrand crosslinks result in cytotoxicity [5]. These molecular events are thought to be responsible for arresting cancer cell proliferation. More than 50 percent of the drug is excreted in the urine in the first 24 hours following cisplatin administration, and the concentration of platinum achieved in the renal cortex is several-fold greater than that in plasma and other organs [6,7]. Cisplatin primarily injures the S3 segment of the proximal tubule, causing a decrease in the glomerular filtration rate (GFR) [8].

Experimental studies suggest that basolateral drug transporters play a role in cisplatin uptake [9]. Changes in expression of proximal tubule organic cation transporter-2 (OCT2) have been shown to mediate the accumulation of cisplatin in proximal tubular epithelial cells, which suggests a key role for OCT2 in the development of cisplatin-mediated nephrotoxicity [10-12].

                             

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Literature review current through: Nov 2014. | This topic last updated: Sep 20, 2013.
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