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Locci E, Liu J, Pais GM, Chighine A, Kahnamoei DA, Xanthos T, Chalkias A, Lee A, Hauser AR, Chang J, Rhodes NJ, d’Aloja E, Scheetz MH: Urinary metabolomics from a dose-fractionated polymyxin B rat model of acute kidney injury. Int J Antimicrob Agents 2022; 60: 106593

July 26, 2022

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 nephro- toxicity.
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 iden- tified 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.
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, ac- etate and creatine. Taurine was the only metabolite that significantly increased in both BID and TID com- pared 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. © 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.