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


CONCLUSIONS
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.
Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, United States of America.
Kenneth I
http://orcid.org/0000-0002-4501-9982
KI
Ataga
Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, United States of America.
Vimal K
VK
Derebail
Division of Cardiology, University of North Carolina, Chapel Hill, NC, United States of America.
Melissa
M
Caughey
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, United States of America.
Laila
L
Elsherif
Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, United States of America.
Jessica H
JH
Shen
Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, United States of America.
Susan K
SK
Jones
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States of America.
Poulami
P
Maitra
Division of Nephrology, The University of Alabama at Birmingham, Birmingham, AL, United States of America.
David M
DM
Pollock
Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States of America.
Jianwen
J
Cai
Department of Pediatrics, Emory University, Atlanta, GA, United States of America.
David R
DR
Archer
Division of Cardiology, University of North Carolina, Chapel Hill, NC, United States of America.
Alan L
AL
Hinderliter
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