Organ-on-chip based assays for personalized assessment of renal resilience in aging patients

Project Summary Age related kidney diseasesincluding chronic kidney diseaseCKDand acute kidney injuryAKIare major health problems and an economic burden worldwideIn the U Salonemillion people are affected by CKD diseasealthough the vast majority of these individuals are unaware of their conditionA coexisting diseasea new medicationor a surgical procedure can overstress the already compromised kidney resilience and result in AKIwith risk for end stage renal disease and deathAge affects the regenerative capacity of the kidney and is a major risk factor for developing renal diseaseHoweverthe degree of kidney resilience in the aged population varies significantly among individualsThereforea diagnostic test that screens for reduced kidney resiliencespecifically in older patientscould aid the physician in selecting therapies that are not only efficacious but tolerable by the patient s kidneysCurrentlysuch a test does not existThe proposed project aims to develop a test for assessing the resilience status of a patient s kidneysThe test involves collecting living urine derived renal progenitor cellsUPCsfrom a patient s urine samplegrowing them into functional kidney tubules in a microfluidic chipand subjecting the tubules to conditions that challenge kidney resilienceThe response of the tubules grown from the patient s own UPCs provide information about that patient s kidney resilience and can be used by the physician to optimize treatment choicesAssay readout will include biomarkers of mitochondrial healthreactive oxygen specieslysosomal activityas well as cell survivalproliferationand polarityUPCs are the cell source of choice for building a renal resilience in vitro model because these cells reflect the degree of kidney resilience dysfunction of the donor even when cultured in vitroThe aging signature of UPCs in cell cultureas in vivocorrelates with a loss of stem cell specific markers and reduced proliferation potentialUPCs from older individuals have been shown to proliferate less than those from younger individualsAimof the project is to establish that in vitro kidney tubules generated from UPCs replicate kidney proximal tubule biomarkers both in young and aged individualsMilestoneand to measure and compare biomarkers for mitochondrial healthreactive oxygen specieslysosomal activitycell survivalcell proliferationand cell polarity in chips derived from young and aged individualsMilestoneAimis to then use these biomarkers for establishing the range of cellular resiliency in kidney chips from young and aged individuals in response to stress conditionssuch as transient hypoxiaMilestoneand exposure to nephrotoxic compound cisplatinMilestoneThe purpose of Aimis to demonstrate significant difference in stress response between kidney chips from healthy young individuals in comparison to aged individuals for at least one of the two tested stressorshypoxia or cisplatinMilestoneThis Phase I project will focus on establishing feasibility for future product development and subsequent clinical studies for regulatory approval Project Narrative The project aims to develop a novel urine test for assessing the health status of a patient s kidneysThe test involves collecting living kidney cells from the patient s urinegrowing them into functional kidney tubulesand subjecting the tubules to conditions that challenge kidney resilienceThe response of the tubules grown from the patient s cells provide information about the patient s kidney health and resilience and can be used by the physician to optimize treatment choices