Inspiratory Muscle Strength Training in Chronic Kidney Disease
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: IMST This group will perform high-resistance (75% of maximal inspiratory pressure) inspiratory muscle strength training (IMST), 30 inhalations/session, 6 days/week. |
Device: IMST
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.
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| Sham Comparator: Control This group will perform low-resistance (15% of maximal inspiratory pressure) inspiratory muscle strength training, 30 inhalations/session, 6 days/week. |
Device: Sham Training
Repeated inhalations against a low resistance will be performed using a handheld device.
|
Outcome Measures
Primary Outcome Measures
- Change in Casual Systolic Blood Pressure [Baseline, 3 months]
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.
Secondary Outcome Measures
- Change in 24-Hour Ambulatory Systolic Blood Pressure [Baseline, 3 months]
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.
- Change in Brachial Artery Flow-Mediated Dilation [Baseline, 3 months]
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.
Other Outcome Measures
- Change in Ex Vivo Nitric Oxide Production [Baseline, 3 months]
Human umbilical vein endothelial cells will be incubated with basal media supplemented with 10% human serum collected from participants and stained with the fluorescent probe DAF-FM diacetate to detect nitric oxide production production in response to acetylcholine.
- Change in Ex Vivo HUVEC eNOS Activation [Baseline, 3 months]
Human umbilical vein endothelial cells will be treated with 10% human serum and protein expression of cell lysates will be determined by capillary electrophoresis immunoassay.
- Change in Ex Vivo Reactive Oxygen Species Production [Baseline, 3 months]
Human umbilical vein endothelial cells will be incubated with basal media supplemented with 10% human serum collected from participants and stained with the fluorescent probe CellROX Deep Red to detect reactive oxygen species production.
- Change in Endothelial Cell Protein Expression of MnSOD [Baseline, 3 months]
In a sub-group of participants, endothelial will be obtained from peripheral veins via endovascular biopsy, recovered by centrifugation, fixed, and analyzed for protein expression of MnSOD in collected endothelial cells relative to human umbilical vein endothelial cells using immunofluorescence.
- Change in Endothelial Cell Protein Expression of NADPH oxidase [Baseline, 3 months]
In a sub-group of participants, endothelial will be obtained from peripheral veins via endovascular biopsy, recovered by centrifugation, fixed, and analyzed for protein expression of NADPH oxidase in collected endothelial cells relative to human umbilical vein endothelial cells using immunofluorescence.
- Change in Endothelial Cell Abundance of Nitrotyrosine [Baseline, 3 months]
In a sub-group of participants, endothelial will be obtained from peripheral veins via endovascular biopsy, recovered by centrifugation, fixed, and analyzed for abundance of nitrotyrosine in collected endothelial cells relative to human umbilical vein endothelial cells using immunofluorescence.
- Change in Renal Blood Flow [Baseline, 3 months]
Magnetic resonance imaging will be used to determine flow of the renal arteries.
- Adherence [3 months]
Adherence will be evaluated as percent of completed training sessions at the required workload using data stored on the training device.
- Safety (adverse events) [3 months]
Safety will be evaluated as the number of participants with treatment-related adverse events in each group.
- Tolerability (drop-out due to adverse events) [3 months]
Tolerability will assessed as the rate at which enrolled subjects drop out due to adverse events.
- Change in Casual Diastolic Blood Pressure [Baseline, 3 months]
Casual (resting) measures of diastolic 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.
- Change in 24-Hour Ambulatory Diastolic Blood Pressure [Baseline, 3 months]
Brachial artery diastolic 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.
- Change in Endothelium-Independent Dilation [Baseline, 3 months]
Endothelium-independent dilation will be determined using ultrasonography and analyzed with a commercially available software package as percent chance in brachial artery diameter following 0.4 mg of sublingual nitroglycerin.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Aged 50 years or older; women must be post-menopausal
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Chronic kidney disease stage 3 or 4 (estimated glomerular filtration rate with the 4-variable MDRD prediction equation: 20-59 mL/min/1.73m^2; stable renal function in the past 3 months)
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History of inadequately controlled hypertension (systolic blood pressure 130-159 mmHg on two separate days) and on a stable antihypertensive regimen for the past 3 months
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Weight stable in the prior 3 months (<2 kg weight change) and willing to remain weight stable throughout the study
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Ability to provide informed consent
Exclusion Criteria:
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Patients with advanced chronic kidney disease requiring chronic dialysis
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Significant pulmonary disorders including: chronic obstructive pulmonary disease, interstitial lung disease, cystic fibrosis, or uncontrolled asthma
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Significant co-morbid conditions with a life expectancy of < 1 year
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History of severe congestive heart failure (i.e., ejection fraction <35%)
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History of hospitalization within the last month
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Proteinuria > 5 g/day
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Current smoker
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Immunosuppressant agents taken in the past 12 months
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Known malignancy
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Inability to cooperate with or clinical contraindication for magnetic resonance imaging including: severe claustrophobia, implants, devices, or non-removable body piercings
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Colorado - Anschutz Medical Campus | Aurora | Colorado | United States | 80045 |
Sponsors and Collaborators
- University of Colorado, Denver
- University of Colorado, Boulder
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
- Principal Investigator: Kristen Nowak, PhD, MPH, University of Colorado - Anschutz Medical Campus
- Principal Investigator: Kristen Nowak, MD, University of Colorado - Anschutz Medical Campus
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 21-3000
- R01DK130255