Nontraditional Models for Acute Kidney Injury Research: Organoids, Zebrafish, and More.

Acute kidney injury (AKI) is a condition that is associated with increased mortality in the clinic and currently has no Food and Drug Administration-approved drug intervention that prevents progression to chronic kidney disease. To address the lack of therapy, it is imperative to use multiple model systems that can recapitulate the complex pathophysiology of AKI. Rodent AKI models are the gold standard and are widely used, but their genetic, metabolic, and circadian cycle divergence from humans can create hurdles in translational research. Similarly, well-established two-dimensional cell lines lack the complexity necessary to model heterogeneous injury occurring in multiple distinct renal cell types during AKI events. Advances in three-dimensional kidney organoids and microfluidic model systems are increasingly bridging the gap by improving structural and functional similarities to human renal tissue. Zebrafish and Drosophila models also provide functionally relevant systems that allow for high-content screening capabilities in whole organisms. In this review, we summarize three-dimensional in vitro and nonmammalian model systems and discuss how these systems have provided researchers with valuable platforms for furthering AKI drug discovery efforts.