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Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice


Samodelov, Sophia L; Visentin, Michele; Gai, Zhibo; Häusler, Stephanie; Kullak-Ublick, Gerd A (2019). Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice. Antimicrobial Agents and Chemotherapy, 63(12):e01650-19.

Abstract

The polymyxin colistin represents a last-resort antibiotic for multidrug-resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimize long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule-1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a <jats:italic>cis</jats:italic>-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by Western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to that in control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in <jats:italic>ex vivo</jats:italic> glucose uptake compared to that in BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy.

Abstract

The polymyxin colistin represents a last-resort antibiotic for multidrug-resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimize long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule-1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a <jats:italic>cis</jats:italic>-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by Western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to that in control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in <jats:italic>ex vivo</jats:italic> glucose uptake compared to that in BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Pharmacology
Health Sciences > Pharmacology (medical)
Health Sciences > Infectious Diseases
Uncontrolled Keywords:Pharmacology (medical), Pharmacology, Infectious Diseases
Language:English
Date:7 October 2019
Deposited On:14 Feb 2020 12:51
Last Modified:29 Jul 2020 13:01
Publisher:American Society for Microbiology
ISSN:0066-4804
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/aac.01650-19
PubMed ID:31591120
Project Information:
  • : FunderSNSF
  • : Grant ID310030_175639
  • : Project TitleRole of drug transporters and nuclear receptors in drug-induced liver and kidney injury

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