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Assessment of Vascular Function in Patients With Chronic Kidney Disease
Published on: June 16, 2014
Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A
Kristen L Nowak1, Berenice Gitomer1, Heather Farmer-Bailey1
1Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
Insights
Aldosterone antagonism with spironolactone reduced systolic blood pressure in early-stage autosomal dominant polycystic kidney disease (ADPKD) patients. However, it did not improve vascular dysfunction, such as arterial stiffness or endothelial function.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Pharmacology
Background:
- Vascular dysfunction, including endothelial dysfunction and arterial stiffness, is an early characteristic of autosomal dominant polycystic kidney disease (ADPKD).
- Aldosterone excess is implicated in promoting endothelial dysfunction and arterial stiffness through oxidative stress and inflammation.
- Aldosterone antagonism is hypothesized to mitigate vascular dysfunction in early-stage ADPKD.
Purpose of the Study:
- To investigate the effect of aldosterone antagonism on vascular dysfunction in patients with early-stage ADPKD.
- To assess whether spironolactone improves endothelial function and reduces arterial stiffness in this patient population.
Main Methods:
- A prospective, randomized, double-blind, placebo-controlled trial was conducted.
- 61 adults with early-stage ADPKD received either spironolactone (50mg/d) or a placebo for 24 weeks.
- Primary endpoint was change in brachial artery flow-mediated dilation (FMDBA); secondary endpoint was change in carotid-femoral pulse-wave velocity (CFPWV).
Main Results:
- Spironolactone did not significantly alter FMDBA or CFPWV compared to placebo.
- Systolic blood pressure was reduced in the spironolactone group (P=0.04).
- No significant changes were observed in markers of oxidative stress or inflammation.
Conclusions:
- Twenty-four weeks of aldosterone antagonism with spironolactone effectively lowered systolic blood pressure in early-stage ADPKD patients.
- Spironolactone did not demonstrate a significant benefit in improving vascular function (endothelial function or arterial stiffness) in this cohort.
- Limitations include a low level of baseline vascular dysfunction and the absence of aldosterone measurements.
Rationale & Objective:
Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD.
Study Design:
Prospective, randomized, controlled, double-blind, clinical trial.
Setting & Participants:
61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor.
Intervention:
Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks.
Outcomes:
Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point.
Results:
60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress.
Limitations:
Low level of baseline vascular dysfunction; lack of aldosterone measurements.
Conclusions:
24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD.
Funding:
NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation.
Trial Registration:
Registered at ClinicalTrials.gov with study number NCT01853553.
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