Inspiratory muscle strength training for lowering systolic blood pressure in midlife and older adults with chronic kidney disease
Project Number5R01DK130266-04
Contact PI/Project LeaderCHONCHOL, MICHEL BENJAMIN Other PIs
Awardee OrganizationUNIVERSITY OF COLORADO DENVER
Description
Abstract Text
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.
Public Health Relevance Statement
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.
National Institute of Diabetes and Digestive and Kidney Diseases
CFDA Code
847
DUNS Number
041096314
UEI
MW8JHK6ZYEX8
Project Start Date
01-September-2021
Project End Date
30-June-2026
Budget Start Date
01-July-2024
Budget End Date
30-June-2025
Project Funding Information for 2024
Total Funding
$535,533
Direct Costs
$379,146
Indirect Costs
$156,387
Year
Funding IC
FY Total Cost by IC
2024
National Institute of Diabetes and Digestive and Kidney Diseases
$535,533
Year
Funding IC
FY Total Cost by IC
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