title: Prediction of drug-induced nephrotoxicity and injury mechanisms with human induced pluripotent stem cell-derived cells and machine learning methods.
abstract: The renal proximal tubule is a main target for drug-induced toxicity. The prediction of proximal tubular toxicity during drug development remains difficult. Any in vitro methods based on induced pluripotent stem cell-derived renal cells had not been developed, so far. Here, we developed a rapid 1-step protocol for the differentiation of human induced pluripotent stem cells (hiPSC) into proximal tubular-like cells. These proximal tubular-like cells had a purity of >90% after 8 days of differentiation and could be directly applied for compound screening. The nephrotoxicity prediction performance of the cells was determined by evaluating their responses to 30 compounds. The results were automatically determined using a machine learning algorithm called random forest. In this way, proximal tubular toxicity in humans could be predicted with 99.8% training accuracy and 87.0% test accuracy. Further, we studied the underlying mechanisms of injury and drug-induced cellular pathways in these hiPSC-derived renal cells, and the results were in agreement with human and animal data. Our methods will enable the development of personalized or disease-specific hiPSC-based renal in vitro models for compound screening and nephrotoxicity prediction.
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Kandasamy
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Jacqueline Kai Chin
authors.initials: JK
authors.lastname: Chuah
authors.affiliation: Bioinformatics Institute, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
authors.forename: Ran
authors.initials: R
authors.lastname: Su
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Kim Guan
authors.initials: KG
authors.lastname: Eng
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Sijing
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Chun Siang
authors.initials: CS
authors.lastname: Chia
authors.affiliation: 1] Bioinformatics Institute, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore [2] Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
authors.forename: Lit-Hsin
authors.initials: LH
authors.lastname: Loo
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore.
authors.forename: Daniele
authors.initials: D
authors.lastname: Zink
mesh_terms: D058186:Acute Kidney Injury; D001681:Biological Assay / Q000379:methods; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology*; D000069550:Machine Learning; D010363:Pattern Recognition, Automated / Q000379:methods; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D018675:Toxicity Tests / Q000379:methods*