Background: Nephrotoxicity is a notable adverse effect in cisplatin treated patients characterized by tubular injury and/or increased serum creatinine (SCr) with incidence varying from 20 to 70%. Pharmacogenomics has been shown to identify strongly predictive genetic markers to help determine which patients are more likely to experience, for example, a serious adverse drug reaction or receive optimal benefit through enhanced efficacy. Genetic variations have been reported to influence the risk of cisplatin nephrotoxicity; however, a comprehensive overview is lacking. Methods: A systematic review was performed using Pubmed, Embase and Web of Science on clinical studies that used cisplatin-based chemotherapy as treatment, had available genotyping data, and evaluated nephrotoxicity as an outcome. The quality of reporting was assessed using the STrengthening the REporting of Genetic Association Studies (STREGA) checklist. Results: Twenty-eight eligible studies were included; all were candidate gene studies. Over 300 SNPs across 135 genes were studied; 29 SNPs in 14 genes were significantly associated with cisplatin-induced nephrotoxicity. A variation in SLC22A2 rs316019, a gene involved in platinum uptake by the kidney, was associated with different measures of nephrotoxicity in four independent studies. Further, variants of ERCC1 (rs11615 and rs3212986) and ERCC2 (rs13181), two genes involved in DNA repair, were found to be positively associated with increased risks of nephrotoxicity in two independent studies. Conclusion: Three genes consistently associated with cisplatin-induced nephrotoxicity. Further research is needed to assess the biological mechanism and the clinical value of modifying treatment based on SLCC22A2 and ERCC1/2 genotypes.

A considerable number of drugs and/or their metabolites are excreted by the kidneys through glomerular filtration and active renal tubule secretion via transporter proteins. Uptake transporters in the proximal tubule are part of the solute carrier (SLC) superfamily, and include the organic cation transporters (OCTs). Several studies have shown that specific genetic polymorphisms in OCTs alter drug disposition and may lead to nephrotoxicity. Multiple single nucleotide polymorphisms (SNPs) have been reported for the OCT genes (SLC22A1, SLC22A2 and SLC22A3), which can influence the proteins’ structure and expression levels and affect their transport function. A gain-in-function mutation may lead to accumulation of drugs in renal proximal tubule cells, eventually leading to nephrotoxicity. This review illustrates the impact of genetic polymorphisms in OCTs on renal drug disposition and kidney injury, the clinical significances and how to personalize therapies to minimize the risk of drug toxicity.

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009–2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (OR_adj = 0.24; 95% CI: 0.08–0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (OR_adj = 4.41; 95% CI: 1.96–9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (OR_adj = 5.06; 95% CI: 1.69–15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.

The imbalance in the production of reactive oxygen species (ROS) with endogenous antioxidant capacity leads to oxidative stress, which drives many disorders, especially in the skin. In such conditions, supplementing exogenous antioxidants may help the body prevent the negative effect of ROS. However, the skin, as the outermost barrier of the body, provides a perfect barricade, making the antioxidant delivery complicated. Several strategies have been developed to enhance the penetration of antioxidants through the skin, one of which is nanotechnology. This review focuses on utilizing several nanocarrier systems, including nanoemulsions, liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and polymeric nanoparticles, for transporting antioxidants into the skin. We also reveal ROS formation in the skin and the role of antioxidant therapy, as well as the natural sources of antioxidants. Furthermore, we discuss the clinical application of topical antioxidant therapy concomitantly with the current status of using nanotechnology to deliver topical antioxidants. This review will accelerate the advancement of topical antioxidant therapy.