Abstract
Polymyxins have a long history of dose-limiting toxicity, but the underlying mechanism of polymyxin B-induced nephrotoxicity is unclear. This study investigated the link between the nephrotoxic effects of polymyxin B on renal metabolic functions and mitochondrial morphology in rats and on the structural integrity of LLC-PK1 cells. Fifteen Wistar rats were divided into two groups: Saline group, rats received 3 mL/kg of 0.9% NaCl intraperitoneally (i.p.) once a day for 5 days; Polymyxin B group, rats received 4 mg/kg/day of polymyxin B i.p. once a day for 5 days. Renal function, renal hemodynamics, oxidative stress, mitochondrial injury and histological characteristics were assessed. Cell membrane damage was evaluated via lactate dehydrogenase and nitric oxide levels, cell viability, and apoptosis in cells exposed to 12.5 μM, 75 μM and 375 μM polymyxin B. Polymyxin B was immunolocated using Lissamine rhodamine-polymyxin B in LLC-PK1 cells. Polymyxin B administration in rats reduced creatinine clearance and increased renal vascular resistance and oxidative damage. Mitochondrial damage was confirmed by electron microscopy and cytosolic localization of cytochrome c. Histological analysis revealed tubular dilatation and necrosis in the renal cortex. The reduction in cell viability and the increase in apoptosis, lactate dehydrogenase levels and nitric oxide levels confirmed the cytotoxicity of polymyxin B. The incubation of LLC-PK1 cells resulted in mitochondrial localization of polymyxin B. This study demonstrates that polymyxin B nephrotoxicity is characterized by mitochondrial dysfunction and free radical generation in both LLC-PK1 cells and rat kidneys. These data also provide support for clinical studies on the side effects of polymyxin B.
Highlights
Polymyxins were discovered late in 1947, but their toxicity has limited their use
Polymyxins have been reintroduced to clinical practice due to the prevalence of infections caused by gram-negative bacteria such as multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae [1, 2, 3]
Animals exposed to 4 mg/kg/day of polymyxin B for 5 days exhibited no changes in urinary output, but a significant elevation in serum creatinine compared with that of the Saline group (p
Summary
Polymyxins were discovered late in 1947, but their toxicity has limited their use. Polymyxins have been reintroduced to clinical practice due to the prevalence of infections caused by gram-negative bacteria such as multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae [1, 2, 3]. Nephrotoxicity is the major dose-limiting factor restricting its use in clinical practice, occurring in up to 60% of all patients treated with polymyxins [4, 5, 6]. The elucidation of the mechanisms of action, the concentration-dependent capacity to kill bacterial, and the dose-limiting adverse effects of polymyxins would contribute to the management of their use in patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
