PROJECT SUMMARY Chronic kidney disease (CKD) is a major public health concern that has reached epidemic proportions. Hypertension is a leading modifiable risk factor for cardiovascular disease (CVD) and end-stage kidney disease, yet 50-70% of adults with CKD fail to achieve blood pressure (BP) control to <130/80 mmHg. A key process linking high systolic BP (SBP) to CVD is vascular endothelial dysfunction, mediated by excessive reactive oxygen species (ROS)-induced oxidative stress and reductions in nitric oxide (NO) bioavailability. NO is also critical in the regulation of renal blood flow (RBF), which is intimately related to BP and vascular function. Guidelines recommend a stepwise combination of lifestyle modifications and drug therapy to lower BP, yet adherence to lifestyle modifications such as aerobic exercise is poor in patients with CKD. Drug regimens often involve multiple medications, as hypertension is challenging to control in CKD. High-resistance inspiratory muscle strength training (IMST) is a novel lifestyle intervention involving repeated inhalations against a resistive load using a hand-held device. In a randomized, double-blind, sham controlled, parallel group design, R21-funded pilot study in 36 midlife/older men and women with baseline SBP ≥120 mmHg, we showed that IMST (30 breaths [5 minutes]/day at 75% of maximal inspiratory pressure, 6 days [30 minutes]/week for 6 weeks) had excellent adherence (95% of prescribed sessions completed) and lowered casual (resting) SBP by 9±2 mmHg. IMST improved endothelial function (brachial artery flow-mediated dilation, FMDBA) by 40%, linked to increased endothelial NO synthase (eNOS) activation and NO bioavailability, reduced ROS production and oxidative stress, and changes in circulating factors. Importantly, the effects of IMST on SBP and FMDBA were even greater in individuals with an estimated glomerular filtration rate (eGFR) <75 mL/min/1.73m2. To establish the efficacy of high-resistance IMST in midlife/older adults (≥50 years) with moderate-to-severe CKD (eGFR 20-59 mL/min/1.73m2) and inadequately controlled hypertension (SBP 130-159 mm Hg), we propose a randomized, parallel group, sham-controlled, double-blind, clinical trial to evaluate the effects of a clinically relevant treatment duration of IMST (3 months) on SBP, FMDBA, NO bioavailability, eNOS activation, ROS/oxidative stress, circulating factors, and RBF. Aim 1: To measure casual SBP (primary outcome) and 24-hour (ambulatory) SBP (secondary outcome) before (baseline) and after 3 months of IMST or Sham training. Aim 2: To measure FMDBA (secondary outcome) before and after IMST or Sham training. Aim 3: To determine: a) endothelial cell culture eNOS, NO and ROS production pre-post IMST or Sham serum exposure; b) markers of oxidative stress and antioxidant status in biopsied endothelial cells; c) the identity of the plasma metabolites involved; d) RBF by functional magnetic resonance imaging. Aim 4: To assess adherence (completed:prescribed sessions), safety, and tolerability of IMST vs. Sham.

PROJECT NARRATIVE More than 80% of individuals with chronic kidney disease have concomitant hypertension and the majority fail to achieve blood pressure control <130/80 mmHg, leading to high risk of cardiovascular diseases and end- stage kidney disease. A stepwise combination of lifestyle modifications and drug therapy is recommended to lower blood pressure; however, adherence to time-intensive lifestyle interventions such as aerobic exercise in patients with chronic kidney disease is poor. This clinical trial seeks to establish the efficacy of high-resistance inspiratory muscle strength training, a novel time-efficient lifestyle intervention, for lowering systolic blood pressure and improving endothelial function in midlife and older adults with moderate-to-severe chronic kidney disease and inadequately controlled hypertension, and to use innovate translational assessments to understand the mechanisms involved.