Abstract
Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and γ-glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI.
Highlights
While effective as a chemotherapeutic agent for various solid tumors [1,2,3,4,5,6,7], cisplatin has been limited by its toxicities
The allelic frequencies were in Hardy-Weinberg Equilibrium (HWE) (Table 2)
The expected frequencies of minor and major alleles used in the HWE determinations were for the Caucasian (EUR) population in HapMap, which reflected the majority (92%) of patients enrolled in the study
Summary
While effective as a chemotherapeutic agent for various solid tumors [1,2,3,4,5,6,7], cisplatin has been limited by its toxicities. Cisplatin treatment can result in nephrotoxicity, ototoxicity, neurotoxicity, infections, and gastrointestinal toxicity secondary to its high emetogenic potential. Of these adverse events, acute kidney injury (AKI) is a prominent toxicity. It is known that cisplatin selectively accumulates in the proximal tubule, leading to oxidative stress, inflammation, and vascular injury, and subsequent renal pathology [10]. The degree to which cisplatin and its metabolites accumulate and induce injury can be influenced by the coordinated activity of uptake and efflux transport proteins on the basolateral and apical membranes of the kidney proximal tubules [11]. Cisplatin metabolism is important in governing proximal tubule exposure to the parent drug and its conjugates [12]
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