PROJECT SUMMARY Elevated blood pressure (BP) is one of the most important, potentially modifiable risk factors for cardiovascular disease (CVD) events and death. Hemodialysis (HD) patients are at particularly high risk for these adverse outcomes. Yet the management of BP in this population remains uncertain due to conflicting associations depending on setting of BP measurement. We and others have reported a paradoxical, U-shaped association of pre-dialysis systolic BP (SBP) with CVD events and death, where the nadir of the U-shape is 140-160 mmHg. However, in these same patients, the association between out-of-dialysis unit SBP and risk of mortality and CVD is linear. We hypothesize that targeting out-of-dialysis unit (e.g. home) SBP rather than pre-dialysis SBP (the current practice) will lead to different treatment actions and better outcomes. This would be a paradigm shift since targeting home BP is not recommended by guidelines nor is practiced by most clinicians. To test feasibility of home BP measurement and treatment in HD patients, we completed a 4-month pilot clinical trial (NCT03459807) of 50 HD patients at 2 centers randomized to treatment of home SBP vs. pre- dialysis SBP target of <140 mmHg. This pilot trial confirmed that our strategy to measure and treat home SBP in HD patients was feasible (with excellent recruitment/retention and adherence to home BP measurement; and successful adoption of a standardized treatment algorithm). We also identified several patient-level facilitators of adherence to home BP measurement including: weekly home BP measurement schedule; text message reminders; and use of technology for automated BP transmission. From these data, we hypothesize that ongoing barriers to adoption of home BP into practice include: (1) lack of data on the effect of treatment of home BP on important intermediate outcomes; (2) lack of data from other centers in the U.S. to show generalizability (as most of the U.S. literature is from a single center); (3) lack of longitudinal data on the effect of targeting pre-dialysis BP on home BP (and vice versa, in part to show that home BP cannot be predicted from dialysis unit BP); (4) lack of knowledge of physician-level barriers to adopt treatment of home BP in HD patients; and (5) lack of long-term adherence data using modern technology to support clinical adoption. To address these gaps, we now propose a larger (N=200) two-center cross-over randomized clinical trial with longer follow-up (12 month) targeting a home SBP goal vs. a pre-dialysis SBP goal of <140 mmHg in HD patients. The data generated from this study will lay the foundation for several next steps, including a larger, multi-center trial to test treatment using different home BP targets to reduce rates of CVD and mortality in HD patients as well as an implementation science trial to integrate home BP measurement into clinical care.