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

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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.

No MeSH data available.


Related in: MedlinePlus

Scatter Plot and Regression Line Between Flow-Mediated Dilation and Albuminuria in Sickle Cell Anemia: Urine albumin-creatinine ratio is significantly correlated with FMD (ρ = -0.45; 95% CI: -0.72 –-0.04, p = 0.031).
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pone.0162652.g001: Scatter Plot and Regression Line Between Flow-Mediated Dilation and Albuminuria in Sickle Cell Anemia: Urine albumin-creatinine ratio is significantly correlated with FMD (ρ = -0.45; 95% CI: -0.72 –-0.04, p = 0.031).

Mentions: UACR was negatively correlated with FMD (ρ = -0.45; 95% confidence interval [CI]: -0.72 –-0.04, p = 0.031) (Fig 1). In addition, a linear regression model showed that for every 1% increase in FMD, UACR decreased by 28.7 mcg/mg (p = 0.0076). Although FMD appeared to be lowest in patients with severely increased albuminuria, no significant difference was observed when FMD was evaluated in the 3 albuminuria categories (p = 0.16) (Fig 2). In a multinomial logistic regression model, the odds of severely increased albuminuria appeared to be reduced by 24% (odds ratio [OR]: 0.76; 95% CI: 0.57–1.01) for every 1% increase in FMD, while the odds of moderate albuminuria appeared to be reduced by 9% (OR: 0.91; 95% CI: 0.72–1.45). There was a trend towards an association between FMD and UACR after controlling for the baseline arterial diameter, although this was not statistically significant (p = 0.1). No significant correlations were observed between UACR and NTMD (ρ = -0.32 95% CI: -0.67–0.14, p = 0.15) or between UACR and hyperemic velocity (ρ = 0.08; 95% CI: -0.37–0.51, p = 0.73). In addition, neither NTMD nor hyperemic velocity was significantly associated with albuminuria when it was assessed as a categorical variable. The values of the measures of endothelial function based on albuminuria categories are shown in Table 2.


Albuminuria Is Associated with Endothelial Dysfunction and Elevated Plasma Endothelin-1 in Sickle Cell Anemia
Scatter Plot and Regression Line Between Flow-Mediated Dilation and Albuminuria in Sickle Cell Anemia: Urine albumin-creatinine ratio is significantly correlated with FMD (ρ = -0.45; 95% CI: -0.72 –-0.04, p = 0.031).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036885&req=5

pone.0162652.g001: Scatter Plot and Regression Line Between Flow-Mediated Dilation and Albuminuria in Sickle Cell Anemia: Urine albumin-creatinine ratio is significantly correlated with FMD (ρ = -0.45; 95% CI: -0.72 –-0.04, p = 0.031).
Mentions: UACR was negatively correlated with FMD (ρ = -0.45; 95% confidence interval [CI]: -0.72 –-0.04, p = 0.031) (Fig 1). In addition, a linear regression model showed that for every 1% increase in FMD, UACR decreased by 28.7 mcg/mg (p = 0.0076). Although FMD appeared to be lowest in patients with severely increased albuminuria, no significant difference was observed when FMD was evaluated in the 3 albuminuria categories (p = 0.16) (Fig 2). In a multinomial logistic regression model, the odds of severely increased albuminuria appeared to be reduced by 24% (odds ratio [OR]: 0.76; 95% CI: 0.57–1.01) for every 1% increase in FMD, while the odds of moderate albuminuria appeared to be reduced by 9% (OR: 0.91; 95% CI: 0.72–1.45). There was a trend towards an association between FMD and UACR after controlling for the baseline arterial diameter, although this was not statistically significant (p = 0.1). No significant correlations were observed between UACR and NTMD (ρ = -0.32 95% CI: -0.67–0.14, p = 0.15) or between UACR and hyperemic velocity (ρ = 0.08; 95% CI: -0.37–0.51, p = 0.73). In addition, neither NTMD nor hyperemic velocity was significantly associated with albuminuria when it was assessed as a categorical variable. The values of the measures of endothelial function based on albuminuria categories are shown in Table 2.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus