ADPKD Clinical Trial
Official title:
Mineralocorticoid Antagonism and Endothelial Dysfunction in Autosomal Dominant Polycystic Kidney
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.
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.
;
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