Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis

Andrew Hart; Francine Cesar; Leila R Zelnick; Nick O'Connor; Zoie Bailey; Jordan Lo; Kirk Van Ness; Ian B Stanaway; Theo K Bammler; James W MacDonald; Matthew R Thau; Jonathan Himmelfarb; Christopher H Goss; Moira Aitken; Edward J Kelly; Pavan K Bhatraju

doi:10.1016/j.jcf.2023.10.021

Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis

J Cyst Fibros. 2023 Nov 8:S1569-1993(23)01671-5. doi: 10.1016/j.jcf.2023.10.021. Online ahead of print.

Authors

Affiliations

¹ University of Washington School of Medicine, Seattle, USA.
² Department of Pharmaceutics, University of Washington, Seattle, USA.
³ Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, USA.
⁴ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, USA.
⁵ Division of Pediatric Pulmonary Medicine, University of Washington, Seattle, USA.
⁶ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, USA.
⁷ Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, USA; Division of Pediatric Pulmonary Medicine, University of Washington, Seattle, USA.
⁸ Kidney Research Institute and Division of Nephrology, Department of Medicine, University of Washington, Seattle, USA; Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, USA. Electronic address: bhatraju@uw.edu.

PMID: 37949747
DOI: 10.1016/j.jcf.2023.10.021

Abstract

Background: Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation.

Methods: We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents. We translated candidate biomarkers to a CF cohort via analysis of urine collected prior to, during and two weeks after antibiotics and patients were followed for a median of 3 years after antibiotic use.

Results: Polymyxin E treatment resulted in a statistically significant increase in the pro-apoptotic Fas gene relative to control in RNAseq of MPS: fold-change = 1.63, FDR q-value = 7.29 × 10^-5. Effluent analysis demonstrated an acute rise of soluble Fas (sFas) concentrations that correlated with cellular injury. In 16 patients with CF, urinary sFas concentrations were significantly elevated during antibiotic treatment, regardless of development of AKI. Over a median of three years of follow up, we identified seven cases of incident chronic kidney disease (CKD). Urinary sFas concentrations during antibiotic treatment were significantly associated with subsequent development of incident CKD (unadjusted relative risk = 2.02 per doubling of urinary sFas, 95 % CI = 1.40, 2.90, p < 0.001).

Conclusions: Using an ex-vivo MPS, we identified a novel biomarker of proximal tubule epithelial cell injury, sFas, and translated these findings to a clinical cohort of patients with CF.

Keywords: Chronic kidney injury; Nephrotoxicity; Urinary biomarkers.

Abstract

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