Trajectory-resolved human kidney organoid model defines OPFR developmental toxicity linked to adult CKD

Human kidneys are highly vulnerable to environmental insults from gestation into adulthood, yet causal links between fetal chemical exposure and adult chronic kidney disease (CKD) remain difficult to establish because of decades-long latency and pervasive confounding in epidemiological study. As nephrogenesis establishes nephron endowment underlying fetal-origin adult-onset CKD, we developed a scalable, nephron-enriched, and trajectory-resolved human kidney organoid model using simple suspension culture approach. Using this model, we took organophosphate flame retardants (OPFRs), ubiquitous environmental contaminants in human embryos, as a representative class of chemical that disrupt nephrogenesis by specifically impairing the critical developmental transition underlying pre-tubular aggregation. We modeled our findings in organoids by treating pregnant mice with OPFR and followed the CKD-like phenotypes of their progeny later in adulthood. Together, this study establishes a kidney organoid model for assessing toxicity of an environmental chemical or a drug in nephrogenesis through mechanistically anchored “in-a-dish” testing.