Urinary Metabolomics From a Dose-Fractionated Polymyxin B Rat Model of Acute Kidney Injury

Emanuela Locci; Jiajun Liu; Gwendolyn M Pais; Alberto Chighine; Dariusc Andrea Kahnamoei; Theodoros Xanthos; Athanasios Chalkias; Andrew Lee; Alan R Hauser; Jack Chang; Nathaniel J Rhodes; Ernesto d'Aloja; Marc H Scheetz

doi:10.1016/j.ijantimicag.2022.106593

Urinary Metabolomics From a Dose-Fractionated Polymyxin B Rat Model of Acute Kidney Injury

Int J Antimicrob Agents. 2022 Jul;60(1):106593. doi: 10.1016/j.ijantimicag.2022.106593. Epub 2022 Apr 20.

Affiliations

¹ Department of Medical Sciences and Public Health, Section of Legal Medicine, University of Cagliari, Cagliari, Italy.
² Midwestern University, Downers Grove, IL, USA; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA; Northwestern Memorial Hospital, Chicago, IL, USA.
³ Midwestern University, Downers Grove, IL, USA; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA.
⁴ School of Medicine, European University Cyprus, Cyprus.
⁵ University of Thessaly, Faculty of Medicine, Department of Anesthesiology, Larisa, Greece; Outcomes Research Consortium, Cleveland, OH, USA.
⁶ Northwestern University, Chicago, IL, USA.
⁷ Midwestern University, Downers Grove, IL, USA; Midwestern University Chicago College of Pharmacy Pharmacometrics Center of Excellence, Downers Grove, IL, USA; Northwestern Memorial Hospital, Chicago, IL, USA. Electronic address: mschee@midwestern.edu.

PMID: 35460851
DOI: 10.1016/j.ijantimicag.2022.106593

Abstract

Background: Polymyxin B treatment is limited by kidney injury. This study sought to identify Polymyxin B-related urinary metabolomic profile modifications for early detection of polymyxin-associated nephrotoxicity.

Methods: Samples were obtained from a previously conducted study. Male Sprague-Dawley rats received dose-fractionated polymyxin B (12 mg/kg/day) once daily (QD), twice daily (BID), and thrice daily (TID) for three days, with urinary biomarkers and kidney histopathology scores determined. Daily urine was analysed for metabolites via 1H nuclear magnetic resonance (NMR). Principal components analyses identified spectral data trends with orthogonal partial least square discriminant analysis applied to classify metabolic differences. Metabolomes were compared across groups (i.e., those receiving QD, BID, TID, and control) using a mixed-effects models. Spearman correlation was performed for injury biomarkers and the metabolome.

Results: A total of 25 rats were treated with Polymyxin B, and n = 2 received saline, contributing 77 urinary samples. Pre-dosing samples clustered well, characterised by higher amounts of citrate, 2-oxoglutarate, and hippurate. Day 1 samples showed higher taurine; day 3 samples had higher lactate, acetate and creatine. Taurine was the only metabolite that significantly increased in both BID and TID compared with the QD group. Day 1 taurine correlated with increasing histopathology scores (rho = 0.4167, P = 0.038) and kidney injury molecule-1 (KIM-1) (rho = 0.4052, P = 0.036), whereas KIM-1 on day 1 and day 3 did not reach significance with histopathology (rho = 0.3248, P = 0.11 and rho = 0.3739, P = 0.066).

Conclusions: Polymyxin B causes increased amounts of urinary taurine on day 1, which then normalizes to baseline concentrations. Taurine may provide one of the earlier signals of acute kidney damage caused by polymyxin B.

Keywords: Acute kidney injury; Animal model; Metabolomics; Polymyxin B; Polymyxins; Urinary biomarker.

MeSH terms

Acute Kidney Injury* / chemically induced
Acute Kidney Injury* / pathology
Animals
Biomarkers / metabolism
Kidney
Male
Metabolomics
Polymyxin B* / adverse effects
Rats
Rats, Sprague-Dawley
Taurine / metabolism
Taurine / pharmacology

Substances

Biomarkers
Taurine
Polymyxin B