Clinical trial NCT04911491: Inspiratory Muscle Strength Training in Chronic Kidney Disease
Official title: Inspiratory Muscle Strength Training for Lowering Systolic Blood Pressure in Midlife and Older Adults With Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Chronic Kidney Diseases
Hypertension
Aging
Blood Pressure
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: University of Colorado, Boulder
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-06-03
Enrollment: 108
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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. Changes and cerebrovascular and cognitive function will be assessed as part of a sub-study.

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 (\<2 kg weight change) and willing to remain weight stable throughout the study. Participants using glucagon-like peptide-1 receptor agonists or planning to start them during the study are excluded unless they have achieved weight stability for at least 3 months prior to enrollment.
* 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

Primary outcomes:
measure: Change in Casual Systolic Blood Pressure
timeFrame: Baseline, 3 months
Secondary outcomes:
measure: Change in 24-Hour Ambulatory Systolic Blood Pressure
timeFrame: Baseline, 3 months
measure: Change in Brachial Artery Flow-Mediated Dilation
timeFrame: Baseline, 3 months
Other outcomes:
measure: Change in Ex Vivo Nitric Oxide Production
timeFrame: Baseline, 3 months
measure: Change in Ex Vivo HUVEC eNOS Activation
timeFrame: Baseline, 3 months
measure: Change in Ex Vivo Reactive Oxygen Species Production
timeFrame: Baseline, 3 months
measure: Change in Endothelial Cell Protein Expression of MnSOD
timeFrame: Baseline, 3 months
measure: Change in Endothelial Cell Protein Expression of NADPH oxidase
timeFrame: Baseline, 3 months
measure: Change in Endothelial Cell Abundance of Nitrotyrosine
timeFrame: Baseline, 3 months
measure: Change in Renal Blood Flow
timeFrame: Baseline, 3 months
measure: Adherence
timeFrame: 3 months
measure: Safety (adverse events)
timeFrame: 3 months
measure: Tolerability (drop-out due to adverse events)
timeFrame: 3 months
measure: Change in Casual Diastolic Blood Pressure
timeFrame: Baseline, 3 months
measure: Change in 24-Hour Ambulatory Diastolic Blood Pressure
timeFrame: Baseline, 3 months
measure: Change in Endothelium-Independent Dilation
timeFrame: Baseline, 3 months
measure: Change in middle cerebral artery cerebrovascular reactivity
timeFrame: Baseline, 3 months
measure: Change in internal carotid artery cerebrovascular reactivity
timeFrame: Baseline, 3 months
measure: Change in middle cerebral artery pulsatility index
timeFrame: Baseline, 3 months
measure: Change in brain blood flow
timeFrame: Baseline, 3 months
measure: Change in NIH toolbox cognitive function
timeFrame: Baseline, 3 months
measure: Change in executive function
timeFrame: Baseline, 3 months
Locations:
city: Aurora
country: United States
facility: University of Colorado - Anschutz Medical Campus
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Kristen Nowak, PhD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Colorado, Denver
name: Michel Chonchol, MD
role: PRINCIPAL_INVESTIGATOR
References: