Modeling podocytopathies with kidney organoids

Kidney organoids have emerged as powerful in vitro models for investigating normal kidney physiology, disease development, and drug screening, offering unique advantages over traditional cell culture and animal-based systems. By recapitulating glomerular podocyte-like structures, these models have provided unique opportunities to study the pathophysiology of podocytopathies. While prior reviews have summarized novel applications of kidney organoids to kidney disease research in general, these have largely focused on renal tubular physiology and injury mechanisms, for which a greater body of data currently exists. In this review, however, we solely consider kidney organoid-based studies to date that have modeled diverse forms of podocyte injury. We first discuss investigations of drug-induced podocyte injury via kidney organoids, with consideration of their potential future role as high-throughput platforms for preclinical drug screening. We then examine how organoids have furthered research into the genetics of kidney disease, particularly monogenic forms of focal segmental glomerulosclerosis and collagenopathies, and their potential use to assess variants of uncertain significance and mutation-specific therapeutic responses. We additionally highlight how organoid systems have been employed to model complex glomerular disorders, including APOL1-mediated kidney disease, virus-induced podocyte injury, diabetic nephropathy, and podocyte senescence. We further consider the application of kidney organoids to the study of autoantibody-mediated podocytopathies, an area of emerging research. Finally, we provide an overall critique of the strengths and limitations of kidney organoids models specifically in the context of podocytopathy research, emphasizing unmet research needs and opportunities to enhance their fidelity, maturity, and functional integration as precision medicine tools.