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Updated: Jun 26, 2026
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Advanced in vitro evaluation of drug-induced kidney injury using microphysiological systems in drug discovery and
Hiroshi Arakawa1, Kohei Matsushita2, Naoki Ishiguro3
1Faculty of Pharmaceutical Sciences, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Abstract:
Drug-induced kidney injury (DIKI) is a major cause of acute kidney injury (AKI). Given concerns about animal welfare and the need for more accurate prediction of human events, there is an urgent need to develop an in vitro evaluation method for DIKI using human cells. Renal proximal tubular epithelial cells (RPTECs) are the main targets of DIKI in drug discovery and development because of their abundant expression of drug transporters that contribute to renal-specific drug distribution. In general, physiological kidney function is significantly reduced in primary cell monolayer culture systems. However, with recent advances in cell engineering and regenerative medicine, human kidney-derived cell culture systems, with higher kidney function compared to conventional systems, have been established. For example, three-dimensional cultured RPTECs show enhanced expression of drug transporters and higher predictive performance than monolayer culture systems. The use of organs-on-a-chip with liver and kidney co-cultures also allows the detection of drug metabolite-induced nephrotoxicity. Kidney organoids differentiated from induced pluripotent stem cells (iPS) have also been established. In this review, we introduce a recently established renal cell culture system that includes a microphysiological system, and review the in vitro methods used to evaluate DIKI in RPTECs.
Insights
Developing novel in vitro methods using human renal proximal tubular epithelial cells (RPTECs) is crucial for accurately predicting drug-induced kidney injury (DIKI) and improving drug safety.
Area of Science:
- Nephrology
- Toxicology
- Regenerative Medicine
Background:
- Drug-induced kidney injury (DIKI) is a significant cause of acute kidney injury (AKI).
- Current in vitro models often fail to accurately predict human DIKI due to reduced physiological function.
- Renal proximal tubular epithelial cells (RPTECs) are key targets for DIKI due to high drug transporter expression.
Purpose of the Study:
- To review advanced in vitro methods for evaluating DIKI using human RPTECs.
- To highlight the importance of improved cell culture systems for DIKI prediction.
- To discuss the role of cell engineering and regenerative medicine in DIKI assessment.
Main Methods:
- Review of advanced renal cell culture systems, including microphysiological systems and organs-on-a-chip.
- Discussion of three-dimensional (3D) cultured RPTECs and kidney organoids derived from induced pluripotent stem cells (iPS).
- Focus on systems enhancing drug transporter expression and predictive performance.
Main Results:
- 3D cultured RPTECs demonstrate enhanced drug transporter expression and improved predictive capacity over traditional monolayer cultures.
- Co-culture systems, such as liver-kidney organs-on-a-chip, enable detection of drug metabolite-induced nephrotoxicity.
- Established kidney organoid systems offer a more physiologically relevant model for DIKI studies.
Conclusions:
- Advanced in vitro systems, particularly those utilizing 3D RPTECs, microphysiological systems, and kidney organoids, show significant promise for accurate DIKI evaluation.
- These novel methods address limitations of traditional cell cultures and animal testing, aligning with welfare concerns and the need for human-relevant predictions.
- Further development and implementation of these systems are essential for safer drug discovery and development.
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