Kidney Week

Abstract: FR-PO1154

Inorganic Nitrate for Improving Vascular Endothelial Function in CKD: A Randomized, Placebo-Controlled Clinical Trial

Session Information

• CKD: Kidney Function and Extrarenal Complications
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2302 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Authors

• Rossman, Matthew J., University of Colorado Boulder, Boulder, Colorado, United States

Matthew J. Rossman, PhD

• Darvish, Sanna, University of Colorado Boulder, Boulder, Colorado, United States

Sanna Darvish, MS

• Ludwig, Katelyn, University of Colorado Boulder, Boulder, Colorado, United States

Katelyn Ludwig, PhD

• Ikoba, Akpevweoghene P., University of Colorado Boulder, Boulder, Colorado, United States

Akpevweoghene P. Ikoba, MS

• Coppock, Mckinley, University of Colorado Boulder, Boulder, Colorado, United States

Mckinley Coppock

• Berryman-Maciel, Morgan, University of Colorado Boulder, Boulder, Colorado, United States

Morgan Berryman-Maciel, MS

• Murray, Kevin O., University of Colorado Boulder, Boulder, Colorado, United States

Kevin O. Murray, MSc, PhD

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

Michel Chonchol, MD, FASN

• Seals, Douglas R., University of Colorado Boulder, Boulder, Colorado, United States

Douglas R. Seals, PhD

Background

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). A key antecedent to CVD in CKD is vascular endothelial dysfunction mediated by declines in nitric oxide (NO) bioavailability due to excess reactive oxygen species (ROS)-related oxidative stress. Here, we tested the safety and efficacy of targeting the nitrate-nitrite-NO pathway with inorganic nitrate for improving endothelial function in indviduals with mild renal dysfunction through moderate CKD.

Methods

Twenty-six older men and women with mild renal dysfunction to stage III CKD (estimated glomerular filtration rate [eGFR; CKD-EPI]: 40-89 mL/min/1.73m²) underwent 3 months of supplementation with nitrate-rich beetroot juice (BRJ: 70 mL, 6.45 mmol nitrate/day) (n=13, 7 women; age: 65±2 yrs; eGFR: 68±2 mL/min/1.73m²) or nitrate-depleted BRJ (placebo) (n=15, 8 women; age: 67±2 yrs; eGFR: 78±3 mL/min/1.73m²) in a randomized, placebo-controlled, parallel-group design clinical trial. Endothelial function assessed by brachial artery flow-mediated dilation (FMD_BA) was the primary outcome. To determine mechanisms of action, acetylcholine-stimulated NO production (DAR-4M-AM) and ROS bioactivity (CellROX) were assessed in human aortic endothelial cells (HAECs) exposed to 10% subject serum collected before/after nitrate-rich BRJ or placebo supplementation.

Results

Nitrate-rich BRJ supplementation was safe, well-tolerated and increased FMD_BA by 26% (pre: 4.7±0.7%, post: 5.9±0.8%; p=0.03). FMD_BA did not change with placebo (pre: 4.6±0.9%, post: 4.5±0.8%; p>0.05). The improvement in FMD_BA with nitrate-rich BRJ was negatively associated with baseline eGFR (r=0.41, p=0.02). Diastolic blood pressure was reduced by ~2 mmHg with nitrate-rich BRJ (P<0.05), but other traditional CVD risk factors were unchanged (p>0.05). NO production was 7% higher (p=0.05) and ROS bioactivity was 25% lower (p=0.02) in HAECs exposed to serum collected after vs. before nitrate-rich BRJ; there were no changes with serum obtained pre-post placebo (P>0.05).

Conclusion

Nitrate-rich BRJ holds promise for improving endothelial function in CKD, in part by inducing changes to the circulating milieu that increase NO production and lower oxidative stress in endothelial cells.

Funding

• NIDDK Support