Inspiratory Muscle Strength Training in Chronic Kidney Disease

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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, which is due in part to increased reactive oxygen species and decreased nitric oxide. Nitric oxide is also critical in the regulation of renal blood flow, which is intimately related to blood pressure and vascular function. High-resistance inspiratory muscle strength training (IMST) is a novel lifestyle intervention involving repeated inhalations against a resistive load using a hand-held device. This study will test whether high-resistance IMST (75% of maximal inspiratory pressure [75% PImax]; 30 breaths [5 min]/day, 6 days [30 min]/week) vs. Sham training (15% PImax) reduces resting systolic blood pressure in midlife and older adults (>50 years) with moderate-to-severe CKD and inadequately controlled hypertension. Changes in 24-hr systolic blood pressure and endothelial function (brachial artery flow-mediated dilation) are secondary outcomes. Innovative translational techniques will be used to provide mechanistic insight, including serum incubation in endothelial cell culture, metabolomics analysis, endothelial cell collections, and assessment of renal blood flow by magnetic resonance imaging.

Official Title
-----------------
Inspiratory Muscle Strength Training for Lowering Systolic Blood Pressure in Midlife and Older Adults With Chronic Kidney Disease

Conditions
-----------------
Chronic Kidney Diseases, Hypertension, Aging, Blood Pressure

Intervention / Treatment
-----------------
* Device: IMST
* Device: Sham Training


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 50 years or older; women must be post-menopausal Chronic kidney disease stage 3 or 4 (estimated glomerular filtration rate with the 4 CKD-EPI 2021 race-free equation: 20-59 mL/min/1.73m^2; stable renal function in the past 3 months) History of inadequately controlled hypertension (systolic blood pressure 120-159 mmHg on two separate days) and on a stable antihypertensive regimen for the past 6 weeks Weight stable in the prior 3 months (<5% weight change) and willing to remain weight stable throughout the study Ability to provide informed consent Exclusion Criteria: Patients with advanced chronic kidney disease requiring chronic dialysis Significant pulmonary disorders including: chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, or uncontrolled asthma History of spontaneous pneumothorax, collapsed lung due to traumatic injury that has not fully healed, burst eardrum that has not fully healed, or other conditions of the eardrum Significant co-morbid conditions with a life expectancy of < 1 year History of severe congestive heart failure (i.e., ejection fraction <35%) History of hospitalization within the last month Albuminuria (albumin to creatinine ratio > 2200 mg/g Current smoker Immunosuppressant agents taken in the past 12 months. Steroids used for the treatment of gout are acceptable; however, patients should not be using steroids within 2 weeks (or 14 days) prior to the vascular testing (rationale: may confound vascular testing) Known malignancy Inability to cooperate with or clinical contraindication for magnetic resonance imaging including: severe claustrophobia, implants, devices, or non-removable body piercings (these individuals can participate in the study but are excluded from the MRI procedure) Illicit drug use or alcohol dependence/abuse, which in the opinion of the investigators, would prohibit compliance with the study intervention

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMST<br>This group will perform high-resistance (75% of maximal inspiratory pressure) inspiratory muscle strength training (IMST), 30 inhalations/session, 6 days/week. | Device: IMST<br>* Inspiratory muscle strength training (IMST) is a form of physical training that utilizes the diaphragm and accessory respiratory muscles to repeatedly inhale against resistance using a handheld device.<br>|
| Sham Comparator: Control<br>This group will perform low-resistance (15% of maximal inspiratory pressure) inspiratory muscle strength training, 30 inhalations/session, 6 days/week. | Device: Sham Training<br>* Repeated inhalations against a low resistance will be performed using a handheld device.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Casual Systolic Blood Pressure | Casual (resting) measures of systolic blood pressure (mmHg) will be measured in triplicate over the brachial artery of the non-dominant arm after 5 minutes of quiet rest, with 1 minute of recovery between each measure, using an automated oscillometric sphygmomanometer. | Baseline, 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 24-Hour Ambulatory Systolic Blood Pressure | Brachial artery systolic blood pressure (mmHg) will be measured automatically every 20 minutes for a 24-hour period by an ambulatory blood pressure monitor and will be averaged over the entire 24-hour period. | Baseline, 3 months | 
| Change in Brachial Artery Flow-Mediated Dilation | Flow-mediated dilation of the brachial artery will be performed using ultrasonography and analyzed with a commercially available software package as percent change in diameter from baseline following reactive hyperemia. | Baseline, 3 months |