Patient-Derived Kidney Organoids For Modeling Kidney Injury

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Dr. Sutha’s long-term career goal is to be a physician-scientist who improves the lives of his patients through basic science and translational research directed at developing novel therapies for kidney disease, including acute kidney injury and allograft rejection. A detailed understanding of both acute and chronic kidney disease pathogenesis and advancement of targeted therapies to treat them remains limited. Development of novel therapeutics has been hampered by lack of holistic, in vitro experimental models that fully preserve the complex interactions between epithelial, stromal, and immune components of the kidney. In this work, Ken Sutha, MD, PhD, a pediatric nephrology physician-scientist, builds upon his expertise establishing a patient-derived, adult kidney organoid culture preserving endogenous stroma and immune cells, in addition to his primary mentor Dr. Calvin Kuo’s experience with organoids from other tissues for studying immune processes and diseases. First, using his established adult kidney organoids as a platform, Aim 1 will delineate interactions occurring between kidney epithelia and accompanying stroma in the setting of nephrotoxic injury induced by cisplatin. These studies will yield insights into epithelial and fibroblast activation and interactions after injury and will further identify protective versus maladaptive signals in the progression of acute kidney injury to chronic kidney disease. This knowledge will enable the development of novel strategies to disrupt fibrosis while promoting repair, which will subsequently be further tested within adult kidney organoids. Aim 2 will then translate the use of his adult kidney organoids to kidney transplant, using organoids to model the allograft immune microenvironment, critically while preserving host immune cells within allograft tissue. These organoids will then be applied to model transplant rejection and treatment response, including functional assessments of immune activation. Initial feasibility studies will serve as proof of principle for future prospective studies using transplant organoid treatment response to inform patient therapeutic decisions. Dr. Sutha will benefit from the interdisciplinary environment at Stanford University, along with resources and support available to him through the Department of Pediatrics. With mentorship from Drs. Kuo, Vivek Bhalla, and Jonathan Maltzman, Dr. Sutha will expand upon his expertise in nephrology and adult kidney organoid models by developing new, complementary skills in bioinformatic analysis and transplant immunology, critical to successful advancement of his project. This training will enable the novel application of his established kidney organoid model to study kidney injury and the transplant immune microenvironment, eventually enabling him to develop and test new, targeted kidney disease therapies. This approach will be further applied to model other kidney diseases and treatments using biopsy samples, and results generated from the completion of his K08 Aims will serve as preliminary data for Dr. Sutha’s future R01 investigating cellular interactions and crosstalk in the progression of chronic kidney disease.