title: Aging increases the susceptibility of cisplatin-induced nephrotoxicity.
abstract: Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100% to baseline) in CDDP-treated patients was -9.2%, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (≥50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35% of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity.
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Jiagen
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Meizi
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Zhaoqian
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.|Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China. yjsd2003@163.com.|Hunan Key Laboratory of Pharmacogenetics, Changsha, China. yjsd2003@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers / Q000032:analysis; D016190:Carboplatin / Q000633:toxicity; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced*; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D016190:Carboplatin; D002945:Cisplatin
keywords: Cisplatin; Inflammatory response; Nephrotoxicity; Nrf2; Transporters; eGFR