Project Summary/Abstract Chronic kidney disease (CKD) is highly prevalent (≈15% of the population), costly (≈ $ 64 billion yearly) and associated with a high mortality rate (109.7 per 1,000 patient-years). Known risk factors, such as diabetes, explain only part of the variance in risk for CKD. To help prevent CKD, research is urgently needed to identify novel risk factors associated with early decline in glomerular filtration rate (GFR) and incident CKD. A promising area is mental health disorders. Depression has been reported to be associated with GFR decline and CKD. In contrast, no research has investigated whether post-traumatic stress disorder (PTSD), a common psychiatric diagnosis in WTC responders (≈10- 20%), is associated with kidney disease. Preliminary studies of WTC in 2,266 subjects revealed that PTSD had a 1.74 fold higher association with GFR decline (compared to stable GFR, after adjustment of all major CKD risk factors) providing novel evidence for the PTSD/CKD association. Additional studies revealed that severe PTSD and PTSD with co-morbid depression that a stronger association with GFR decline suggesting a dose-response relationship. The objectives of this research proposal are to test the hypotheses that severity/course of PTSD can predict the risk of CKD. This study will also test the hypothesis that kidney disease and PTSD share genetic/protein biomarkers. Using all available WTC Responder data from > 10,000 patients over a longer follow-up period and studying the association of longitudinal changes in PTSD, medications and co-morbid conditions with changes in GFR, this study will establish the association between PTSD and incident CKD. This data will be used to develop risk prediction models. Using polygenic risk scores for PTSD and CKD and stored proteomic data, this study will identify gene/protein variants related to common pathways between PTSD and CKD/GFR decline. This research proposal will address a current gap in the field by contributing to the understanding of how chronic mental stress contributes to kidney disease in the WTC responders and will lead to further studies on the effects of mental trauma on the kidneys. Using the significant clinical, laboratory and genetic/protein risk factors identified, this R21 project will lead to the development of sophisticated CKD risk prediction models for testing in prospective studies in a future R01/UO1. Results could lead to clinicians risk stratifying patients through genomics/proteomics and PTSD severity and inform future clinical trials of patients with chronic mental stress. The candidate is firmly committed to a career in translational nephrology research, has a solid personal background of training in both basic (PhD from Yale) and clinical science and is very strongly supported by his institutional leadership and by the Director and Principal Investigator of the Stony Brook WTC Wellness Program. The candidate has assembled a diverse team of co-investigators and ...