Imaging the distribution of polymyxins in the kidney

Bo Yun, Mohammad Abul Kalam Azad, Jiping Wang, Roger Leigh Nation, Philip Thompson, Kade Douglas Roberts, Tony Velkov, Jian Li

Research output: Contribution to journalArticleResearchpeer-review

47 Citations (Scopus)

Abstract

Objectives: Dose-limiting nephrotoxicity remains the Achilles heel of polymyxin B and polymyxin E (also known as colistin), which are important last-line antibiotics used against infections caused by MDR Gram-negative superbugs . An understanding of the mechanisms of nephrotoxicity, including renal tissue distribution, is crucial for the development of safer polymyxin lipopeptide antibiotics. This is the first study to visualize the kidney distribution of polymyxin B using a mouse nephrotoxicity model and in situ immunostaining of kidney sections. Methods: Polymyxin B nephrotoxicity in mice was induced over the course of 3 days (accumulated intravenous dose 175 mg/kg) and kidneys were harvested and frozen sectioned. The sectionswere fixed in cold acetone, dried and treated with 1 hydrogen peroxide. Endogenous mouse immunoglobulins were blocked and the tissue sections were treated with anti-polymyxin B mouse IgM antibody. The sections were incubated with a biotinylated anti-mouse secondary antibody conjugate followed by an Alexa Fluor 647-streptavidin conjugate. Polymyxin B distribution in the kidney sections was then visualized using a fluorescence scanning microscope. Kidney sections were also subjected to haematoxylin and eosin staining to assess pathological damage from the polymyxininduced nephrotoxicity. Results: Immunostaining of kidney sections from a mouse with polymyxin B-induced nephrotoxicity revealed that polymyxin B distributed predominantly within the renal cortex. More specifically, polymyxin B accumulated within the proximal tubular cells. Conclusions: The observed accumulation of polymyxin B within proximal tubular cells is consistent with the extensive renal reabsorption of polymyxins and the likely cause of the associated nephrotoxicity.
Original languageEnglish
Pages (from-to)827 - 829
Number of pages3
JournalJournal of Antimicrobial Chemotherapy
Volume70
Issue number3
DOIs
Publication statusPublished - 2015

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