Mechanisms of Polymyxin-Induced Nephrotoxicity

Mohammad A. K. Azad, Roger L. Nation, Tony Velkov, Jian Li

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Otherpeer-review

25 Citations (Scopus)


Polymyxin-induced nephrotoxicity is the major dose-limiting factor and can occur in up to 60% of patients after intravenous administration. This chapter reviews the latest literature on the mechanisms of polymyxin-induced nephrotoxicity and its amelioration. After filtration by glomeruli, polymyxins substantially accumulate in renal proximal tubules via receptor-mediated endocytosis mainly by megalin and PEPT2. It is believed that subsequently, a cascade of interconnected events occur, including the activation of death receptor and mitochondrial apoptotic pathways, mitochondrial damage, endoplasmic reticulum stress, oxidative stress and cell cycle arrest. The current literature shows that oxidative stress plays a key role in polymyxin-induced kidney damage. Use of antioxidants have a potential in the attenuation of polymyxin-induced nephrotoxicity, thereby widening the therapeutic window. Mechanistic findings on polymyxin-induced nephrotoxicity are critical for the optimization of their use in the clinic and the discovery of safer polymyxin-like antibiotics.

Original languageEnglish
Title of host publicationPolymyxin Antibiotics
Subtitle of host publicationFrom Laboratory Bench to Bedside
EditorsJian Li, Keith S. Kaye, Roger L. Nation
Place of PublicationSwitzerland
Number of pages15
ISBN (Electronic)9783030163730
ISBN (Print)9783030163716
Publication statusPublished - 2019

Publication series

NameAdvances in Experimental Medicine and Biology
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019


  • Apoptosis
  • Cell cycle
  • Nephrotoxicity
  • Oxidative stress
  • Polymyxin

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