Emerging Kidney Models to Investigate Metabolism, Transport, and Toxicity of Drugs and Xenobiotics

Abstract

The kidney is a major clearance organ of the body and is responsible for the elimination of many xenobiotics and prescription drugs. With its multitude of uptake and efflux transporters and metabolizing enzymes, the proximal tubule cell (PTC) in the nephron plays a key role in the disposition of xenobiotics and is also a primary site for toxicity. In this minireview, we first provide an overview of the major transporters and metabolizing enzymes in the PTCs responsible for biotransformation and disposition of drugs. Next, we discuss different cell sources that have been used to model PTCs in vitro, their pros and cons, and their characterization. As current technology is inadequate to evaluate reliably drug disposition and toxicity in the kidney, we then discuss recent advancements in kidney microphysiological systems (MPS) and the need to develop robust in vitro platforms that could be routinely used by pharmaceutical companies to screen compounds. Finally, we discuss the new and exciting field of stem cell-derived kidney models as potential cell sources for future kidney MPS. Given the push from both regulatory agencies and pharmaceutical companies to use more predictive "human-like" in vitro systems in the early stages of drug development to reduce attrition, these emerging models have the potential to be a game changer and may revolutionize how renal disposition and kidney toxicity in drug discovery are evaluated in the future.

Fig. 1.

Morphologic comparisons of commonly used kidney cell lines and primary cells derived from induced pluripotent stems cells or human tissue. (A) LLC-PK1, (B) MDCK, (C) HK-2, (D) iPSC-derived tubule epithelial cells, (E) proximal tubule epithelial cells grown from human kidney biopsy (scale bar = 100 µm).

Fig. 2.

Examples of kidney microfluidic devices (A–C) and bioprinted device (D). (A) Bilayer PDMS device with a sandwiched porous ECM-coated polyester membrane creating two compartments: top compartment for cell seeding with physiologic flow and bottom compartment serves as a reservoir. Reproduced with permission from the Royal Society of Chemistry and Jang et al. (2013). (B-1) Single-channel 3D MPS platform showing phase contrast and live/dead image of PTCs at day 28 within the microfluidic channel. Reproduced with permission from Elsevier and Weber et al. (2016) (B-2) Three-channel device of the 3D MPS platfrom shown in (B-1). Image provided by Nortis Bio (C-1) Overview of the platform for epithelium and endothelial tubule coculture. The three-lane OrganoPlate contains 40 microfluidic chips in a 384-well plate. Photos show top and bottom of the three-lane plate with zoom of a single chip. An ECM is patterned by two PhaseGuides. (C-2) A 3D reconstruction of a confocal stack shows the tubular morphology of the RPTEC and human umbilical cord endothelial cell cultures (HUVEC) alongside the ECM gel. The HUVEC cells express RFP (purple), and the tubes are stained for ZO-1 (green), ezrin (red), and DNA (blue). Scale bar, 100 µm. Image provided by Mimetas (D-1). Schematics and images showing the different steps of fabricating a 3D convoluted PTC channel. (D-2) A confocal 3D rendering of PTCs in the channel: actin (red) and nuclei (blue). Reproduced with permission from Homan et al. (2016). The work was published under a CC BY license (Creative Commons Attribution 4.0 International License; https://creativecommons.org/licenses/by/4.0/). No changes were made to the original figure.