Experimental models of acute kidney injury for translational research

Preclinical models of human disease provide powerful tools for therapeutic discovery but have limitations. This problem is especially apparent in the field of acute kidney injury (AKI), in which clinical trial failures have been attributed to inaccurate modelling performed largely in rodents. Multidisciplinary efforts such as the Kidney Precision Medicine Project are now starting to identify molecular subtypes of human AKI. In addition, over the past decade, there have been developments in human pluripotent stem cell-derived kidney organoids as well as zebrafish, rodent and large animal models of AKI. These organoid and AKI models are being deployed at different stages of preclinical therapeutic development. However, the traditionally siloed, preclinical investigator-driven approaches that have been used to evaluate AKI therapeutics to date rarely account for the limitations of the model systems used and have given rise to false expectations of clinical efficacy in patients with different AKI pathophysiologies. To address this problem, there is a need to develop more flexible and integrated approaches, involving teams of investigators with expertise in a range of different model systems, working closely with clinical investigators, to develop robust preclinical evidence to support more focused interventions in patients with AKI. This Review summarizes the state of the art of acute kidney injury model development, focusing on the translatability of discoveries using human kidney organoid, zebrafish, rodent and large animal models. The authors recommend a multidisciplinary approach to optimize the development of effective therapies for acute kidney injury. Key points Human induced pluripotent stem cell-derived kidney organoid models of toxin-induced acute kidney injury (AKI) are amenable to high-throughput drug discovery and may provide insight into inter-individual variations in responses to therapeutic interventions. Zebrafish models of toxin-induced AKI can be used for high-throughput, rapid therapeutic discovery before translation into mammalian systems. Ischaemic, cardiac, toxin and sepsis-associated rodent models of AKI can be used to reflect diverse pathophysiologies in human AKI, validate therapeutic targets using genetic studies and explore distant organ effects of AKI. Large animal models provide opportunities to more closely model human AKI pathophysiology and pharmacology, with increasingly complex, layered models of injury. The discovery of mole