Investigation of treatment-time differences in colistin-induced nephrotoxicity in Wistar rats

ABSTRACT

Colistin-induced nephrotoxicity (CIN) occurs in up to 60% of patients, and this has restricted its clinical use. In view of its efficacy amidst the rising challenge of infections caused by multidrug-resistant bacteria, current studies are focusing on ways to ameliorate colistin-induced nephrotoxicity. This study investigated treatment-time differences in colistin-induced nephrotoxicity in Wistar rats. A dose of 600,000 IU/Kg/day of colistimethate sodium (CMS) was administered to male Wistar rats to induce nephrotoxicity; the rats tolerated the higher dose for the treatment duration with higher mean values of serum creatinine, urea, and malondialdehyde compared to the group that received 450,000 IU/Kg/day CMS (p ≤ 0.05). Four groups (n = 8/group) of rats received intraperitoneal (i.p.) injections of 600,000 IU/Kg/day CMS each at four equally spaced circadian times (00:00, 06:00, 12:00, and 18:00 h) to determine the time of administration with least renal toxicity. Biomarkers of oxidative stress and renal toxicity were measured and kidney histology studied after the treatments. The results showed a 24-h pattern in nephrotoxicity from CIN, and that treatment during the activity time period (dark phase) caused lowest CIN. Histological findings supported this finding, with photomicrographs consistently showing more pronounced features of CIN in the groups treated during time frame that coincided with the rest phase in rats (12:00 and 18:00).

KEYWORDS:

• Chronotoxicology
• circadian rhythmicity
• colistin
• colistin-induced nephrotoxicity
• oxidative stress
• Wistar rats