Albuminuria Is Associated with Endothelial Dysfunction and Elevated Plasma Endothelin-1 in Sickle Cell Anemia

• Type of Material: Article
• Authors: Kenneth I. Ataga, University of North Carolina; Vimal K. Derebail, University of North Carolina; Melissa Caughey, University of North Carolina; Laila Elsherif, University of North Carolina; Jessica H. Shen, University of North Carolina; Susan K. Jones, University of North Carolina; Poulami Maitra, University of North Carolina; David M. Pollock, University of Alabama at Birmingham; Jianwen Cai, University of North Carolina; David Archer, Emory University; Alan L. Hinderliter, University of North Carolina
• Language: English
• Date: 2016-09-26
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Ataga et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0162652
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 11
• Issue: 9
• Start Page: e0162652
• End Page: e0162652
• Grant/Funding Information: This work was supported by National Heart, Lung and Blood Institute grants R01HL111659 (KIA, JC, DRA, ALH), U01HL117659 (KIA, JC) and U01HL117684 (DMP), and by an award from the North Carolina State Sickle Cell Program.
• Keywords: NITRIC-OXIDE BIOAVAILABILITY; GROWTH-FACTOR; Pathogenesis; MEDIATED VASODILATION; Nephrology; Tyrosine kinases; Urine; PULMONARY-HYPERTENSION; Growth factors; VASCULOPATHY; VEGF-A; KIDNEY-DISEASE; DIABETIC-NEPHROPATHY; Blood plasma; EXPRESSION; Arteries; HYDROXYUREA; Bilirubin; Science & Technology; Hemoglobin; Multidisciplinary Sciences
• Research Categories: Health Sciences, Pathology; Health Sciences, General

Abstract

Background: The pathogenesis of albuminuria in SCD remains incompletely understood. We evaluated the association of albuminuria with measures of endothelial function, and explored associations of both albuminuria and measures of endothelial function with selected biological variables (vascular endothelial growth factor [VEGF], endothelin-1 [ET-1], soluble fms-like tyrosine kinase-1 [sFLT-1], soluble vascular cell adhesion molecule-1 [soluble VCAM-1] and plasma hemoglobin). Methods: Spot urine measurements for albumin-creatinine ratio (UACR) and 24-hour urine protein were obtained. Endothelial function was assessed using brachial artery ultrasound with measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NTMD) and hyperemic velocity. Results: Twenty three subjects with varying degrees of albuminuria were evaluated. UACR was significantly correlated with FMD (ρ = -0.45, p = 0.031). In univariate analysis, UACR was correlated with VEGF (ρ = -0.49; 95% CI: -0.75 –-0.1, p = 0.015), plasma hemoglobin (ρ = 0.50; 95% CI: 0.11–0.75, p = 0.013) and ET-1 (ρ = 0.40; 95% CI: -0.03–0.69, p = 0.06). Multivariable analysis showed significant associations of ET-1 (estimate: 455.1 [SE: 198.3], p = 0.02), VEGF (estimate: -1.1 [SE: 0.53], p = 0.04) and sFLT-1 (estimate: -1.14 [SE: 0.49], p = 0.02) with UACR. Only ET-1 (estimate: -8.03 [SE: 3.87], p = 0.04) was significantly associated with FMD in multivariable analyses. Finally, UACR was correlated with both 24-hour urine protein (ρ = 0.90, p < 0.0001) and urine aliquots for albumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001). Conclusion: This study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD. Elevated circulating levels of ET-1 may contribute to SCD-related glomerulopathy by mediating endothelial dysfunction.