ABSTRACT - MPS Resources Section Predicting the safety and efficacy of candidate therapeutics, including their mechanisms of action and likelihood of success in patients, requires fundamentally new strategies, assays, and models of the kidney that better replicate human pathophysiology. Recently, human cellular models in vitro have emerged that can recapitulate critical aspects of kidney physiology, mimic the unique complexities of specific nephron segments, model disease heterogeneity, and assess injury-repair mechanisms, with great potential to accelerate and enable therapy development. Induced pluripotent stem (iPS) cells are a powerful source for such models, as they are self- renewing (immortal), can change into diverse cell types, and are amenable to gene editing. Human models endogenously express species-specific target genes and have unique advantages for mechanistic analysis and throughput. The FDA Modernization Act 2.0 “allows an applicant for market approval for a new drug to use methods other than animal testing to establish the drug's safety and effectiveness.” However, the complexity and limited availability of human microphysiological models, their lack of standardization, and questions regarding their appropriateness and clinically-relevant interpretation, need to be addressed in order for these to be brought into widespread use. Qualification of these systems as drug development tools will be helpful for achieving this and enabling use to provide clinical guidance. To bridge this gap, the overarching goal of the Kidney MPS Resources Section is, in collaboration with commercial partners to manufacture and share qualification-grade kidney-on-chip platforms for two innovative human cellular models: the proximal tubule kidney chip microphysiological system (PTEC-MPS), and the human kidney organoid-on-chip. These two systems are complementary, enabling (respectively) apical and basolateral tubular perfusion and heterocellular modeling of genetic disease. Each model will be improved to produce more biomimetic qualities. We will further cross-translate these two cellular models by constructing PTEC-MPS using organoid-derived tubular epithelial cells for the first time. We will achieve these goals with two complementary Specific Aims: (1) Establish reference standard kidney MPS by detailing operating procedures, quality controls, validation datasets, and longevity characteristics. (2) Iteratively optimize kidney MPS to incorporate features relevant for qualification. These Aims will establish rigorous kidney chips appropriate for qualification by regulatory agencies and advance their transfer from academic laboratories to commercial industry. Each Aim will be accompanied by specific Milestones that track the major steps necessary to accomplish this bench-to-business effort.