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Kidney Week

Abstract: PO0213

Identification of Predictive Biomarkers Associated with Antibiotic Associated Nephrotoxicity from Polymyxin and Tobramycin Antibiotics Using a Kidney Microphysiological Device

Session Information

  • AKI Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Van Ness, Kirk Peter, University of Washington, Seattle, Washington, United States
Background

With the emergence of multi-drug resistant gram-negative infections, polymyxin and aminoglycoside antibiotics are ever more important for effective bacterial treatment. However, the use of these antibiotics is limited due to concerns of acute kidney injury (AKI). We have employed a kidney microphysiological device system (MPS) with cultured human primary proximal tubule epithelial cells (PTECs) to identify potential sensitive renal biomarkers arising from exposure to aminoglycosides and polymyxins.

Methods

We exposed human PTECs to various concentrations of Polymyxin B (PMB), Polymyxin E (colistin) and tobramycin for 72 hours and collected daily effluents for biomarker discovery. In addition, we evaluated PTEC mRNA transcripts (RNAseq) from control and antibiotic treated MPS devices after 72 hours of antibiotic exposure. Biomarkers associated with epithelial cell injury [kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)], inflammation/apoptosis [soluble Fas Receptor (sFAS), Fas Ligand and tumor necrosis factor receptor 1 (TNFR-1)] were measured in the MPS effluents using ELISA.

Results

In MPS devices, we observed with PMB and colistin, elevations of KIM-1 at 24 and 48 hours, sFAS at 24 hours and NGAL at 48 hours. In contrast, tobramycin exposures up to 100 mg/mL (5 times clinical Cmax) showed no evidence of toxicity either through lack of elevation of nephrotoxicity biomarkers in effluents or by changes in differentially expressed genes compared to controls. In discovery RNAseq analyses, 7641 genes were differentially regulated between colistin and control MPS. Specific pathways included upregulation of metallothionein and cholesterol biosynthesis genes with colistin exposure. With tobramycin exposure, no genes were differentially regulated compared to controls.

Conclusion

We found that different biomarkers have variable kinetics after PTEC injury. sFas and KIM-1 concentrations rose the earliest after antibiotic exposure. In RNAseq analyses, we found that pathways of metallothionein and cholesterol biosynthesis were dysregulated after colistin exposure. Finally, we found minimal PTEC injury with tobramycin, suggesting that this antibiotic may be less toxic than previously believed. Future work seeks to test these candidate biomarkers in human urine samples.