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

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

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: 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.

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). Higher values correspond to greater stiffness.

All markers of oxidative stress will be assayed by multiplexed validated liquid chromatography (LC)/ LC-mass spectrometry (MS)/ MS.

Inclusion Criteria: Aged 20-55 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) 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 or any other drug that could contribute to hyperkalemia Uncontrolled hypertension Current smokers or history of smoking in the past 12 months 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

Nowak KL, Gitomer B, Farmer-Bailey H, Wang W, Malaczewski M, Klawitter J, You Z, George D, Patel N, Jovanovich A, Chonchol M. Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Trial. Am J Kidney Dis. 2019 Aug;74(2):213-223. doi: 10.1053/j.ajkd.2018.12.037. Epub 2019 Feb 23.