Abstract
Background: Vancomycin is commonly used as a first line therapy for gram positive organisms such as methicillin resistant Staphylococcus aureus. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. The precise mechanism of injury in humans remains elusive, with recent evidence directed towards proximal tubule cell apoptosis. In this study, we investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. Methods: Urine samples from patients with V-AKI who were enrolled in the DIRECT study and matched healthy controls from the UAB-UCSD O’Brien Center Biorepository were included in the analysis. Exosomes were extracted using solvent exclusion principle and polyethylene glycol induced precipitation. Protein identity and quantification was determined by label-free liquid chromatography mass spectrometry (LC/MS). The mean peak serum creatinine was 3.7 ± 1.4 mg/dL and time to kidney injury was 4.0 ± 3.0 days. At discharge, 90% of patients demonstrated partial recovery; 33% experienced full recovery by day 28. Proteomic analyses on five V-AKI and 7 control samples revealed 2009 proteins in all samples and 251 proteins significantly associated with V-AKI (Pi-score > 1). The top discriminatory proteins were complement C3, complement C4, galectin-3-binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin. Conclusion: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers.
Highlights
Vancomycin is a glycopeptide antibiotic used for treatment of methicillin-resistant Staphylococcus aureus infections in critically ill patients
Two hundred and fifty-one proteins were dysregulated in Vancomycin-induced acute kidney injury (V-AKI), and these appeared to be predominantly involved in the inflammatory and coagulation pathways. Among these 251 proteins, our analysis demonstrated that C3 complement, C4 complement, galectin-3binding protein, fibrinogen, alpha-2 macroglobulin, immunoglobulin heavy constant mu and serotransferrin were significantly associated with V-AKI cases
Based on our results that C3 and C4 were among the top discriminating V-AKI exosome proteins, we propose that activation of a complement system is involved in vancomycin-induced renal tubular injury
Summary
Vancomycin is a glycopeptide antibiotic used for treatment of methicillin-resistant Staphylococcus aureus infections in critically ill patients. Vancomycin associated acute kidney injury (V-AKI) is dose-related and with an onset of 4–17 days therapy initiation. V-AKI has long been recognized as a major side effect of vancomycin, the mechanisms of nephrotoxicity have remained poorly understood. Vancomycin-induced acute kidney injury (V-AKI) has been reported in up to 43% of patients, especially in those with higher targeted trough concentrations. We investigated the protein contents of urinary exosomes in patients with V-AKI to further elucidate biomarkers of mechanisms of injury and potential responses. Conclusion: Urinary exosomes reveal up-regulation of inflammatory proteins after nephrotoxic injury in V-AKI. Further studies are necessary in a large patient sample to confirm these findings for elucidation of pathophysiologic mechanisms and validation of potential injury biomarkers
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