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Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

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ClinicalTrials.gov Identifier: NCT01853553
Recruitment Status : Completed
First Posted : May 15, 2013
Last Update Posted : March 27, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
The proposed research will determine the effectiveness of blocking aldosterone for improving the health and function of arteries in patients with autosomal dominant polycystic kidney disease (ADPKD). The study also will provide insight into how blocking aldosterone improves artery health by determining the physiological mechanisms (biological reasons) involved. Overall, the proposed research will provide important new scientific evidence upon which physicians can base recommendations to patients with ADPKD to decrease risk of developing cardiovascular diseases.

Condition or disease Intervention/treatment
ADPKD Drug: Spironolactone Drug: Sugar pill

Detailed Description:

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.

Working Hypotheses:

  1. 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.
  2. The improvements in EDD after aldosterone antagonist will be associated with reduced circulating and endothelial cell markers of oxidative stress and inflammation.
  3. 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.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney
Study Start Date : July 2013
Primary Completion Date : January 2017
Study Completion Date : January 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Spironolactone
Active arm
Drug: Spironolactone
Placebo Comparator: Sugar Pill
Drug: Sugar pill

Outcome Measures

Primary Outcome Measures :
  1. Change from baseline in Flow mediated dilation at 6 months. [ Time Frame: Baseline and 6 months. ]
    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.

Secondary Outcome Measures :
  1. Change from baseline in vascular stiffness at 6 months. [ Time Frame: Baseline and 6 months ]
    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).

Other Outcome Measures:
  1. Change in circulating markers of oxidative stress at 6 months. [ Time Frame: Baseline and 6 months. ]
    All markers of oxidative stress will be assayed by multiplexed validated liquid chromatography (LC)/ LC-mass spectrometry (MS)/ MS.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 79 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Aged 30-79 years;
  • Adults with ADPKD diagnosis based on Ravine criteria aged ≥ 30 years
  • Estimated glomerular filtration rate ≥ 60 ml/min/1.73m2
  • Hypertension defined as a systolic BP > 130 mm Hg and/or diastolic BP > 80 mmHg based on 3 separate measurements within the past year and currently on a minimum dose of an angiotensin converting enzyme inhibitor (minimum dose 10 mg P.O qd) or angiotensin receptor blocker (i.e., Losartan 25 mg P.O qd)
  • If using antioxidants and/or omega-3 fatty acids, must discontinue 4 weeks prior to participation
  • Free from alcohol dependence or abuse
  • Mini-mental state examination score ≥ 24; ability to provide informed consent
  • BMI < 40 kg/m2 (FMD measurements can be inaccurate in severely obese patients)
  • Not taking medications that interact with agents administered during experimental sessions (e.g., sildenafil interacts with nitroglycerin)
  • Use of birth control in women of childbearing potential

Exclusion Criteria:

  • • Average serum potassium >5.5 millequivalents or any single serum potassium > 6.0 millequivalents within the previous 6 months

    • Receiving an aldosterone antagonist within the previous 6 months
    • Use of a potassium sparing diuretic
    • Uncontrolled hypertension
    • History of liver disease
    • History of heart failure (EF < 35%)
    • History of hospitalizations within the last 3 months
    • Active infection or antibiotic therapy
    • Warfarin use
    • Immunosuppressive therapy within the last year
    • Pregnancy
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01853553

United States, Colorado
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado, Denver
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Michel B Chonchol, MD University of Colorado, Denver
More Information

Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01853553     History of Changes
Other Study ID Numbers: 13-1440
First Posted: May 15, 2013    Key Record Dates
Last Update Posted: March 27, 2017
Last Verified: March 2017

Additional relevant MeSH terms:
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Kidney Diseases, Cystic
Kidney Diseases
Urologic Diseases
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Natriuretic Agents