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. !!

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097081-01A1
Application #
8575255
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Flessner, Michael Francis
Project Start
2013-06-07
Project End
2016-03-31
Budget Start
2013-06-07
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$335,947
Indirect Cost
$118,447
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Nowak, Kristen L; Wang, Wei; Farmer-Bailey, Heather et al. (2018) Vascular Dysfunction, Oxidative Stress, and Inflammation in Autosomal Dominant Polycystic Kidney Disease. Clin J Am Soc Nephrol 13:1493-1501
Nowak, Kristen L; Farmer, Heather; Cadnapaphornchai, Melissa A et al. (2017) Vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 32:342-347
Nowak, Kristen L; Cadnapaphornchai, Melissa A; Chonchol, Michel B et al. (2016) Long-Term Outcomes in Patients with Very-Early Onset Autosomal Dominant Polycystic Kidney Disease. Am J Nephrol 44:171-8
Nowak, Kristen L; Farmer, Heather; Cadnapaphornchai, Melissa A et al. (2016) Vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant :