Emerging In Vitro Systems to Screen and Predict Drug-Induced Kidney Toxicity

Drug attrition related to kidney toxicity remains a challenge in drug discovery and development. In vitro models established over the past 2 decades to supplement in vivo studies have improved the throughput capacity of toxicity evaluation, but usually suffer from low predictive value. To achieve a paradigm shift in the prediction of drug-induced kidney toxicity, two aspects are fundamental: increased physiological relevance of the kidney model, and use of appropriate toxicity end points. Recent studies have suggested that increasing the physiological relevance of kidney models can improve their sensitivity to drug-induced damage. Here, we discuss how advanced culture models, including modified cell lines, induced pluripotent stem cells, kidney organoid cultures, and microfluidic devices enhance in vivo similarity. To this end, culture models aim to increase the proximal tubule epithelial phenotype, reconstitute multiple tissue compartments and extracellular matrix, allow exposure to fluid shear stress, and enable interaction between multiple cell types. Applying computation-aided end points and novel biomarkers to advanced culture models will further improve sensitivity and clinical relevance of in vitro drug-induced toxicity prediction. Implemented at the right stage of drug discovery and development and coupled to high-content evaluation techniques, these models have the potential to reduce attrition and aid the selection of candidate drugs with an appropriate safety profile.