Kidney Week

Abstract: FR-PO200

Mineralocorticoid Antagonism and Vascular Oxidative Stress and Inflammation in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized-Controlled Trial

Session Information

• Vascular Biology and Dysfunction
  November 03, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Hypertension

• 1103 Vascular Biology and Dysfunction

Authors

• Nowak, Kristen L., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Kristen L. Nowak,

• Wang, Wei, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Wei Wang,

• Gitomer, Berenice Y., University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Berenice Y. Gitomer,

• Jovanovich, Anna Jeanette, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Anna Jeanette Jovanovich,

• Farmer-Bailey, Heather, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Heather Farmer-Bailey,

• Chonchol, Michel, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States

Michel Chonchol,

Background

Oxidative stress and inflammation are present in early autosomal dominant polycystic kidney disease (ADPKD) and contribute to reduced nitric oxide bioavailability and arterial dysfunction. Aldosterone may further exacerbate oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular oxidative stress and inflammation in patients with early-stage ADPKD.

Methods

In a randomized, controlled, double-blind trial, n=60 adults 30-55 years of age with ADPKD, normal kidney function (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m²), and receiving the maximum tolerable dose of an angiotensin converting enzyme inhibitor were randomized to receive either spironolactone (titrated to maximum dose of 50 mg/day) or placebo for 6 months. As secondary endpoints in this trial, we measured protein expression of NADPH oxidase, interleukin-6 (IL-6), nuclear factor k B (NFκB), and phosphorylated endothelial nitric oxide synthase (PeNOS) in vascular endothelial cells (ECs) collected from a peripheral vein of study participants, and change in brachial artery flow-mediated dilation (FMD_BA) in response to an acute infusion of ascorbic acid as an index of vascular endothelial oxidative stress.

Results

Participants were 34±10 (mean±s.d.) years of age, 53% female and 80% White, with an eGFR of 94+21ml/min/1.73m². Acute infusion of ascorbic acid improved FMD_BA at baseline (8.4±5.9 vs. 9.5±5.7%, p<0.05). After 6 months, ascorbic acid continued to improve FMD_BA in both the spironolactone and placebo group, indicating no reduction in vascular endothelial oxidative stress. Similarly, there was no change in EC protein expression of the oxidant enzyme NADPH oxidase. IL-6 and PeNOS EC expression were also unchanged. However, EC expression of the pro-inflammatory transcription factor NFκB was reduced in the spironolactone group (0.51±0.13 vs. 0.43±0.08 [immunofluorescence intensity relative to HUVEC control]; p<0.05) with no change in the placebo group (0.48±0.10 vs. 0.48±0.09).

Conclusion

Six months of aldosterone antagonism with spironolactone does not reduce ADPKD-associated vascular oxidative stress, but may attenuate vascular inflammation.

Funding

• NIDDK Support