Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney|
- Change from baseline in Flow mediated dilation at 6 months. [ Time Frame: Baseline and 6 months. ] [ Designated as safety issue: No ]FMD will be determined using high-resolution ultrasonography. ECG-gated end-diastolic ultrasound images and Doppler flow of the brachial artery will be acquired during baseline and FMD conditions. For FMD, reactive hyperemia will be produced by inflating a blood pressure cuff around the forearm to 250 mmHg for 5 minutes followed by rapid deflation. Brachial artery endothelial independent dilation will be determined by measuring brachial artery dilation for 10 minutes after administration of sublingual nitroglycerin (0.4 mg). A available software package (Vascular Analysis Tools 5.8.1, Medical Imaging Applications, LLC, Iowa City, IA) will be used to concurrently acquire ECG-gated brachial artery diameters. Brachial artery dilation will be determined as the mm and % change from baseline diameter. Doppler blood flow velocity will be obtained at baseline and for 2 minutes after cuff release.
- Change from baseline in vascular stiffness at 6 months. [ Time Frame: Baseline and 6 months ] [ Designated as safety issue: No ]Aortic pulse wave velocity, a measure of large elastic arterial stiffness, and carotid compliance, a measure of large artery distensibility, will be determined. A transcutaneous custom tonometers (Noninvasive Hemodynamics Workstation, Cardiovascular Engineering Inc., Norwood, MA) will be positioned at the aorta and femoral artery to measure pulse wave velocity, and carotid artery compliance (and the β-stiffness index, a more blood pressure independent measure of local arterial stiffness) will be measured non-invasively using simultaneous high-resolution ultrasonography and applanation tonometry).
- Change in circulating markers of oxidative stress at 6 months. [ Time Frame: Baseline and 6 months. ] [ Designated as safety issue: No ]All markers of oxidative stress will be assayed by multiplexed validated liquid chromatography (LC)/ LC-mass spectrometry (MS)/ MS.
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||December 2016|
|Estimated Primary Completion Date:||December 2016 (Final data collection date for primary outcome measure)|
Placebo Comparator: Sugar Pill
|Drug: Sugar pill|
Background: Cardiovascular complications are currently the major causes of mortality among patients with autosomal dominant polycystic kidney disease (ADPKD). Therefore, testing valid interventions to reduce morbidity and mortality within this population is of high priority. It is well documented that endothelial dysfunction coupled with abnormalities in markers of oxidative stress and inflammation develops early in ADPKD even before there is a significant decline in kidney function. Aldosterone levels are increased in patients with ADPKD and may contribute to cardiovascular disease by impairing endothelial function, and reducing vascular compliance. Of note, aldosterone antagonists have been shown to improve endothelial dysfunction in a number of studies in other patient populations. However, there has been no clinical interventional studies specifically targeting endothelial dysfunction in ADPKD. Our main goal is to establish the efficacy of an aldosterone antagonist (spironolactone) for treating vascular endothelial dysfunction and large elastic artery stiffness in ADPKD patients with preserve kidney function. A key secondary goal is to determine the integrative physiological (i.e., whole limb/artery to molecular) mechanisms underlying the beneficial effects of spironolactone.
- Six months of an aldosterone antagonist will increase endothelium-dependent dilation (EDD) and reduce large elastic artery stiffness in ADPKD patients with preserve kidney function.
- The improvements in EDD after aldosterone antagonist will be associated with reduced circulating and endothelial cell markers of oxidative stress and inflammation.
- The improvements in large elastic artery stiffness after aldosterone antagonist will be associated with reduced circulating and endothelial cell markers of oxidative stress and inflammation, and changes in markers of structural protein turnover.
Impact on the Field: The expected results will provide the first insight into the:
- Efficacy of an aldosterone antagonist for the primary treatment of vascular dysfunction in ADPKD patients with preserve kidney function.
- Cellular and molecular physiological mechanisms by which these treatment benefits are conferred.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01853553
|United States, Colorado|
|Aurora, Colorado, United States, 80045|
|Principal Investigator:||Michel B Chonchol, MD||University of Colorado, Denver|