Age-dependent changes in vancomycin-induced nephrotoxicity in mice

• Published in: Journal of Toxicologic Pathology Vol. 32; no. 1; pp. 57 - 66
• Main Authors: Takigawa, Masaki, Masutomi, Hirofumi, Shimazaki, Yoshitomo, Arai, Tomio, Lee, Jaewon, Ishii, Toshihiro, Mori, Yoshiko, Ishigami, Akihito
• Format: Journal Article
• Language: English
• Published: Japan JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY 01.01.2019; Japan Science and Technology Agency; Japanese Society of Toxicologic Pathology
• Subjects: Aging; Antibiotics; Antibodies; Apoptosis; Atrophy; Body weight; Cocci; Creatinine; Degeneration; Drug resistance; Epithelial cells; Epithelium; Geriatrics; Gram-positive cocci; kidney; Kidneys; Methicillin; Mice; mouse; Necrosis; nephrotoxicity; Older people; Original; Proximal tubules; Side effects; Single-stranded DNA; Stretching; Vancomycin; kidney; mouse; apoptosis; vancomycin; aging; nephrotoxicity
• ISSN: 0914-9198; 1881-915X; 1347-7404
• DOI: 10.1293/tox.2018-0036

Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic that is commonly used to eradicate methicillin-resistant gram-positive cocci, despite its nephrotoxic side effects. Elderly people are particularly susceptible to developing VCM-induced nephrotoxicity. However, the precise mechanism by which VCM induces nephrotoxicity in elderly people is not completely understood. Therefore, we investigated VCM-induced nephrotoxicity in mice of different ages. VCM was injected intraperitoneally into mice at 1, 3, 6, 12, and 24 months of age at a dosage of 400 mg/kg body weight for 3 and 14 days. Twenty-four hours after the last injection, we examined plasma creatinine levels and histopathological alterations in the kidneys. VCM administration increased plasma creatinine levels, and these values gradually increased to higher levels with aging. The histological examination revealed renal tubular degeneration, such as brush-border atrophy, apoptosis/necrosis of the tubular epithelium, and epithelial desquamation, that gradually became more severe with aging. Furthermore, immunohistochemical staining with anti-CD10 and anti-single-stranded DNA antibodies revealed damaged renal proximal tubules with marked dilatation, as well as numerous apoptotic cells, and these features increased in severity in 12- and 24-month-old mice receiving VCM. Based on these results, aged mice were highly susceptible to kidney damage induced by VCM administration. In addition, proximal tubular epithelial cells likely underwent apoptosis after the administration of VCM. This report is the first to document VCM-induced nephrotoxicity in mice of different ages. Thus, this mouse model could be useful for understanding the mechanisms of VCM-induced nephrotoxicity in the elderly.