Characterization of human induced pluripotent stem cell (hiPSC)- derived Kidney Organoids as a Platform to Assess Drug-Induced Nephrotoxicity

Drug inducted nephrotoxicity is a major cause of withdrawal of Food and Drug Administration (FDA) approved drugs. Animal models and 2D cell culture approaches do not faithfully replicate the structure and drug response associated with human renal tissues. Therefore, the goal of this study is to develop 3D organoid-based models of the kidney to provide a physiologically relevant platform to screen drugs for potential nephrotoxicity. In this study, kidney organoids were created using a process that involves mesodermal induction, organoid , and kidney differentiation. Immunofluorescence imaging was used to profile and quantitatively assess the presence of cells associated with the kidney including endothelial cells and renal tubular cells. Multicellular kidney organoids were then exposed to increasing concentrations (25-800 µM) of four nephrotoxic agents of varying levels of toxicity: cisplatin, gentamicin, dexamethasone, and probenecid. Cisplatin and gentamicin represent high toxicity drugs whereas, dexamethasone and probenecid represent low toxicity drugs. Cellular injury was assessed via evaluation of cell death. Our results show that drug-treated organoids exhibit dose-dependent increases in cell death with significant cell death associated with high toxicity drugs. These findings provide preliminary support for kidney organoids as valuable platforms to study nephrotoxic injury. Further optimization of both organoid maturation and toxicity assays can potentially enhance the reliability and physiological relevance of kidney organoid-based in-vitro platforms for nephrotoxicity testing.