Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity
Elijah J. Weber, … , Jonathan Himmelfarb, Edward J. Kelly
Elijah J. Weber, … , Jonathan Himmelfarb, Edward J. Kelly
Published December 20, 2018
Citation Information: JCI Insight. 2018;3(24):e123673. https://doi.org/10.1172/jci.insight.123673.
View: Text | PDF
Research Article Nephrology

Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity

  • Text
  • PDF
Abstract

Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques — including human microphysiological systems, or “organs on chips” — are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.22 ×10–16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)–like 2 pathway, despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as a potentially novel pathway for PMB-induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule.

Authors

Elijah J. Weber, Kevin A. Lidberg, Lu Wang, Theo K. Bammler, James W. MacDonald, Mavis J. Li, Michelle Redhair, William M. Atkins, Cecilia Tran, Kelly M. Hines, Josi Herron, Libin Xu, Maria Beatriz Monteiro, Susanne Ramm, Vishal Vaidya, Martti Vaara, Timo Vaara, Jonathan Himmelfarb, Edward J. Kelly

×

Figure 1

Kidney microphysiological system, PMB/analog structural variants, and PMB dosimetry in the microphysiological system.

Options: View larger image (or click on image) Download as PowerPoint
Kidney microphysiological system, PMB/analog structural variants, and PM...
(A) Single-channel Nortis microphysiological system (MPS). (B) Structural comparisons of PMB and polymyxin analogs (NAB739 and NAB741). (C) PMB dosimetry in the MPS after 48 hours of treatment with increasing PMB concentrations. Cell survival was assessed for differences in viability (green) and toxicity (red) with increasing concentrations of PMB. Devices exposed to 250 μM or higher resulted in severe cell death and loss of tubule integrity while 50 μM PMB caused detectable but modest injury (n = 1).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts