United States Veterans have disproportionately higher risk for end stage renal disease (ESRD) compared to the general population. Veterans with ESRD on maintenance hemodialysis (HD) suffer from alarmingly high mortality rates and hospitalizations mainly related to cardiovascular disease. Extracellular volume (ECV) excess is a primary contributing factor to cardiovascular disease and the heightened mortality rate in HD patients. Extracellular volume excess remains difficult to identify in clinical practice, and the standard approach to fluid management in the clinical setting involves arbitrary trial and error attempts to remove fluid without invoking hemodynamic instability such as intradialytic hypotension. Bioimpedance spectroscopy (BIS) is a useful research tool for assessing ECV; however, it is not feasible in routine practice, and there is little data on how its use affects intermediate and hard clinical outcomes. There is an unmet need for an approach to guide ultrafiltration in clinical practice that addresses both reduction of ECV and other mortality outcomes as well as minimization of intradialytic hypotension. The long-term goal of this study is to develop a more precise, patient-specific fluid management approach to be tested in a large clinical trial aimed at reducing mortality in Veterans on HD. The overall objective of this project is to utilize our novel, patient-specific ultrafiltration algorithm as an intervention in a clinical trial using mortality risk factors as the primary outcomes. The central hypothesis is that prescribing ultrafiltration prospectively based on an individual patient’s intradialytic blood pressure slopes (IBPS) from recent treatments is superior to standard care at reducing ambulatory blood pressure and ECV without increasing risk for intradialytic hypotension. Aim 1 will use an un-blinded, controlled randomized clinical trial to demonstrate the effects of an IBPS-based ultrafiltration prescription compared to standard clinical practice. Each month, updated ultrafiltration prescriptions for the IBPS group will be determined based on the most recent treatment data. The primary outcome will be change in mean systolic 44-hour ambulatory blood pressure after 4 months. Other outcomes will include 1) change in post-HD ECV/body weight using multifrequency bioimpedance spectroscopy, 2) change in post-HD total peripheral resistance index using a non-invasive cardiac output monitor, and 3) between-group comparison of the frequency of intradialytic hypotension and intradialytic symptoms. Aim 2 will involve a cross sectional analysis of baseline data of subjects from Aim 1 in addition to consecutive enrollment of additional hypertensive HD patients. In addition to Aim 1 measurements, subjects will undergo transthoracic echocardiograms on a non- HD day to obtain measurements of left ventricular ejection fraction as a metric of systolic function, mitral inflow and mitral annulus velocities as a metric of diastolic functio...