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Molecules 2019, 24(3), 653; https://doi.org/10.3390/molecules24030653

Molecular Mechanisms of Colistin-Induced Nephrotoxicity

1
Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8006 Zurich, Switzerland
2
Key Laboratory of Traditional Chinese Medicine for Classical Theory, Ministry of Education, Shandong University, Jinan 250355, China
3
Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, 4056 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Received: 12 December 2018 / Revised: 7 February 2019 / Accepted: 8 February 2019 / Published: 12 February 2019
(This article belongs to the Special Issue Polymyxins)
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Abstract

The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected. For years, the renal damage induced by colistin was considered a mere consequence of the detergent activity of this drug on the cell membrane of proximal tubule cells. Lately, it has been proposed that the intracellular accumulation is a precondition for colistin-mediated renal damage, and that mitochondria might be a primary site of damage. Antioxidant approaches (e.g., ascorbic acid) have shown promising results in protecting the kidney of rodents exposed to colistin, yet none of these strategies have yet reached the bedside. Here we provide a critical overview of the possible mechanisms that may contribute to colistin-induced renal damage and the potential protective strategies under investigation. View Full-Text
Keywords: acute kidney injury; colistin; mitochondria; nephrotoxicity; polymyxins; proximal tubule acute kidney injury; colistin; mitochondria; nephrotoxicity; polymyxins; proximal tubule
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Gai, Z.; Samodelov, S.L.; Kullak-Ublick, G.A.; Visentin, M. Molecular Mechanisms of Colistin-Induced Nephrotoxicity. Molecules 2019, 24, 653.

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