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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11357-015-9844-3) contains supplementary material, which is available to authorized users.

The aging kidney and the nephrotoxic effects of mercury

“…Such exposure may enhance morbidity and mortality as these patients may be more sensitive to the adverse effects of Hg. While an association between age, exposure to Hg, and CKD has not been established with certainty, there are a number of studies showing that exposure to nephrotoxic metals, such as lead (Pb), cadmium(Cd) and cisplatin, exacerbate renal insufficiency in older individuals (Ferraro et al 2010; Noonan et al 2002; Roels et al 1991; Sommar et al 2013; Kim et al 2015b; Wen et al 2015). Since exposure to Cd or Pb were found to exert adverse effects on renal function of older individuals, it may be postulated that exposure of these individuals to Hg may also exacerbate renal disease.…”

A clinically relevant mouse model of cisplatin-induced kidney injury.

“…These physiological changes ultimately culminate in decreased GFR, the inability to properly conserve and secrete sodium, and difficulties in proper concentration or dilution of urine (53,95). In the context of cisplatin-induced nephrotoxicity, Wen et al found that lung cancer patients receiving one dose of cisplatin had a 9.2% decrease in GFR, and that age was the only risk factor examined to have a significant relationship with decline in kidney function after the first round of cisplatin treatment (96). However, these patients had also received other chemotherapeutics known to cause kidney injury.…”

“…However, these patients had also received other chemotherapeutics known to cause kidney injury. Of note, 83 patients that received cisplatin also received gemcitabine, a well-known inducer of nephrotoxicity (96,97). Studies such as this highlight the need to better understand the true contribution of cisplatin to worsened kidney injury with aging.…”

“…Furthermore, most experimental studies that examine the effects of aging in regards to increased injury are performed in very old animals, making it difficult to translate these findings into the clinical setting where the median age of all cancer diagnoses is 65 years old (52). Wen et al demonstrated that 18 month old C57BL/6J mice developed more severe kidney injury when treated with 15 mg/kg cisplatin compared to 3 month old mice (96). These aged mice had increased BUN levels when treated with cisplatin, an increase in TLR4 mediated signaling, increased cisplatin accumulation in the kidney, and a 35% decrease in protein levels of MATE1, an efflux transporter that is responsible for removal of cisplatin from the kidney (96).…”

“…Wen et al demonstrated that 18 month old C57BL/6J mice developed more severe kidney injury when treated with 15 mg/kg cisplatin compared to 3 month old mice (96). These aged mice had increased BUN levels when treated with cisplatin, an increase in TLR4 mediated signaling, increased cisplatin accumulation in the kidney, and a 35% decrease in protein levels of MATE1, an efflux transporter that is responsible for removal of cisplatin from the kidney (96).…”