Abstract
BackgroundThe 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).MethodsSpot 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.ResultsTwenty 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).ConclusionThis 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.
Highlights
The survival of patients with sickle cell disease (SCD) into adulthood is associated with an increased incidence of organ dysfunction
urine measurements for albumin-creatinine ratio (UACR) was correlated with vascular endothelial growth factor (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)
This study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD
Summary
The survival of patients with sickle cell disease (SCD) into adulthood is associated with an increased incidence of organ dysfunction. Similar to patients with coronary artery disease, atherosclerosis and its risk factors, patients with SCD exhibit impaired endothelium-dependent vascular reactivity, measured as flow-mediated dilation (FMD) of the brachial artery [3,4,5] or as the increase in flow induced by infusion of acetylcholine [6]. Multiple studies show associations of both albuminuria and elevated serum creatinine levels with echocardiography-derived tricuspid regurgitant jet velocity (TRV) and other vasculopathic complications in SCD [7,8,9,10] suggesting a shared pathophysiology. Despite the compelling evidence of endothelial dysfunction in SCD, its role in the pathophysiology of SCD-related complications remains poorly defined. 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)
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