PROJECT SUMMARY / ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD)., the most common genetic kidney disease in the world, is characterized by progressive kidney tubule cyst growth, and after decades of tubule damage, it leads to declining glomerular filtration rate (GFR) and kidney failure. By the time this GFR decline is detected, nearly half the original functional glomeruli and tubules are irreversibly lost. Currently, there is no cure for ADPKD and the vasopressin receptor antagonist tolvaptan is the only drug approved by the FDA to slow progression Tolvaptan slows GFR decline, but is expensive, difficult to take, and has considerable side effects. There is an unmet need to study novel tubular biomarkers in persons with ADPKD with the goal of improving early identification and quantification of risk for progression, targeted treatment for the highest risk individuals, and enrichment methods for future clinical trials. We have worked extensively to expand the paradigm of tubular function in kidney disease. We have demonstrated the utility of a focused kidney tubule health panel (KTHP) consisting of proximal tubule injury, tubulo-interstitial inflammation, repair and fibrosis, and secretion in the general population, and among those with CKD, HIV, and heart failure. However, persons with ADPKD were not included in these studies, and our preliminary data demonstrate that several of these tubule markers are particularly perturbed in APDKD. Our goal is to develop an ADPKD-specific KTHP which will incorporate different dimensions of tubular health and injury, improve kidney failure risk prognostication of persons, and evaluate the potential salient effects of tolvaptan on tubular health. We propose to use a unique repository of biospecimens at multiple timepoints from over 2,700 persons with ADPKD who were enrolled in the Phase 3 TEMPO 3:4 and REPRISE trials – both are placebo-controlled trials of tolvaptan in ADPKD. In Aim 1 we will develop and compare KTHP dimensions and correlate them with ADPKD severity, with the hypothesis that these markers will identifying ADPKD patients at highest risk for rapid kidney disease progression, above and beyond currently available clinical and imaging measures. Leveraging the design of the clinical trials, we will compare the effect of tolvaptan versus placebo on tubule health markers (Aim 2). Finally, we will determine whether short-term changes in kidney tubule health biomarkers can predict long-term progression of ADPKD (Aim 3). This comprehensive approach to phenotypying tubular health will advance the role of tubular biomarkers in risk stratification, patient identification, and monitoring response to treatment in ADPKD.