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Published on: July 17, 2016
Drug-induced nephrotoxicity: clinical impact and preclinical in vitro models
Ho Yee Tiong1, Peng Huang, Sijing Xiong
1Yong Loo Lin School of Medicine, National University Health System , 1E Kent Ridge Road, NUHS Tower Block, Singapore 119228, Singapore.
Abstract:
The kidney is a major target for drug-induced toxicity. Drug-induced nephrotoxicity remains a major problem in the clinical setting, where the use of nephrotoxic drugs is often unavoidable. This leads frequently to acute kidney injury, and current problems are discussed. One strategy to avoid such problems would be the development of drugs with decreased nephrotoxic potential. However, the prediction of nephrotoxicity during preclinical drug development is difficult and nephrotoxicity is typically detected only late. Also, the nephrotoxic potential of newly approved drugs is often underestimated. Regulatory approved or validated in vitro models for the prediction of nephrotoxicity are currently not available. Here, we will review current approaches on the development of such models. This includes a discussion of three-dimensional and microfluidic models and recently developed stem cell based approaches. Most in vitro models have been tested with a limited number of compounds and are of unclear predictivity. However, some studies have tested larger numbers of compounds and the predictivity of the respective in vitro model had been determined. The results showed that high predictivity can be obtained by using primary or stem cell derived human renal cells in combination with appropriate end points.
Insights
Predicting drug-induced kidney injury is challenging. New in vitro models using human renal cells show high accuracy for forecasting nephrotoxicity during drug development.
Area of Science:
- Nephrology
- Toxicology
- Drug Development
Background:
- Drug-induced nephrotoxicity frequently causes acute kidney injury.
- Predicting kidney toxicity during preclinical drug development is difficult.
- Validated in vitro models for predicting nephrotoxicity are currently unavailable.
Purpose of the Study:
- To review current approaches for developing predictive in vitro models of nephrotoxicity.
- To discuss the potential of advanced models like 3D, microfluidic, and stem cell-based systems.
- To assess the predictivity of existing in vitro models for drug-induced kidney injury.
Main Methods:
- Review of current literature on in vitro models for nephrotoxicity prediction.
- Discussion of three-dimensional (3D) and microfluidic models.
- Evaluation of stem cell-based approaches using human renal cells.
Main Results:
- Many in vitro models have limited compound testing and unclear predictivity.
- Some models tested with larger compound sets demonstrate high predictivity.
- Combining primary or stem cell-derived human renal cells with specific endpoints enhances prediction accuracy.
Conclusions:
- Developing predictive in vitro models is crucial for mitigating drug-induced nephrotoxicity.
- Human renal cells, particularly stem cell-derived ones, are promising for accurate nephrotoxicity assessment.
- Further validation and development of these models are needed for regulatory use.
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