PROJECT SUMMARY There are over 400,000 patients in the United States that are dependent on the life-preserving benefits of maintenance hemodialysis (HD). However, debilitating physical symptoms are estimated to affect over 50% of patients during the HD procedure, often resulting in reduced quality of life. Despite decades of experience, the exact timing, session-to-session variability, and potential etiologies of such symptoms remain unclear. Our prior work has suggested that rapid rates of decline in plasma osmolality may play an important role in both blood pressure decline and symptoms (such as chest pain and headache) early in the course of HD sessions; while others suggest that inaccurate volume assessment and higher rates of ultrafiltration may play a role later in the HD session. To address these gaps in knowledge, in Aim 1, we propose a detailed analysis of the timing, frequency and variability of patient symptoms in a prospective cohort of contemporary HD patients. In Aim 2, we will leverage innovative point-of-care methods to aid in the assessment of volume status, and determine the association of osmolality decline, ultrafiltration rate and objective volume metrics (lung ultrasound and inferior vena cava diameter) with patient symptoms during HD. In summary, our proposals are clinically relevant, feasible and innovative. Moreover, they will provide important preliminary data that is highly relevant to future interventional studies and R01 applications. Building on the underlying pathophysiology and our experience in performance of clinical trials, our proposals have the potential to improve care for patients undergoing maintenance HD for kidney failure.