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Kidney Library

University of Washington and Nortis publish first organ-on-chip study modeling human liver-kidney interactions for preclinical pharmacology and toxicology studies

Posted by Matthew Hayes on

Liver-kidney, 3D organ-on-chip model run on Nortis ParVivo™ system elucidates absorption, distribution and metabolism ex vivo for the first time using human cells   Seattle, WA — November 28, 2017 — Nortis today announced the publication of the first study to show microfludically-linked, 3D organ-on-chip human models for liver and kidney can be used to identify organ-organ interactions in response to known chemical toxicants. The University of Washington used the Nortis ParVivo system in this study that was published in JCI Insights and highlighted as its cover article.  It is often difficult to study toxicological mechanisms in human subjects due...

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Microphysiological Systems to Assess Nonclinical Toxicity

Posted by Matthew Hayes on

Abstract

The liver and the kidney are key toxicity target organs during drug development campaigns, as they typically carry the burden of drug transport and metabolism. Primary hepatocytes and proximal tubule epithelial cells grown in traditional in vitro 2-D culture systems do not maintain transporter and metabolic functions, thus limiting their utility for nonclinical toxicology investigations. We have developed a renal and hepatic microphysiological system (MPS) platform that uses a commercially available MPS device as the core cell culture platform for our methodologies. We describe protocols for isolating and propagating human proximal epithelial cells and how to seed and culture a renal MPS to recapitulate the human proximal tubule. We present two methods to culture hepatocytes within an MPS and the steps required to connect a renal MPS to a liver MPS. © 2017 by John Wiley & Sons, Inc.

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Concise review: Current and emerging biomarkers of nephrotoxicity

Posted by Matthew Hayes on

Abstract

The kidney is a primary organ for filtration of the blood and elimination of drugs and xenobiotics. These active reabsorptive and secretory processes can result in acute kidney injury as a result of these concentrative properties. Classic measures of acute kidney injury are hampered by their ability to accurately assess function before irreversible damage has occurred. This review will discuss efforts to refine the clinical utility of standard biomarkers as well as the development of novel biomarkers of nephrotoxicity.

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Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.

Posted by Matthew Hayes on

Abstract

Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.

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Development of a microphysiological model of human kidney proximal tubule function

Posted by Matthew Hayes on

The kidney proximal tubule is the primary site in the nephron for excretion of waste products through a combination of active uptake and secretory processes and is also a primary target of drug-induced nephrotoxicity. Here, we describe the development and functional characterization of a 3-dimensional flow-directed human kidney proximal tubule microphysiological system. The system replicates the polarity of the proximal tubule, expresses appropriate marker proteins, exhibits biochemical and synthetic activities, as well as secretory and reabsorptive processes associated with proximal tubule function in vivo. This microphysiological system can serve as an ideal platform for ex vivomodeling of renal drug clearance and drug-induced nephrotoxicity. Additionally, this novel system can be used for preclinical screening of new chemical compounds prior to initiating human clinical trials.

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