Inviting an author to review:
Find an author and click ‘Invite to review selected article’ near their name.
Search for authorsSearch for similar articles
82
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references37

          • Record: found
          • Abstract: found
          • Article: not found

          Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.

          Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

            The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The importance of endothelin-1 for vascular dysfunction in cardiovascular disease.

              Endothelin (ET)-1 is a potent vasoconstrictor peptide originally isolated from endothelial cells. Its production is stimulated in a variety of different cell types under the influence of risk factors for cardiovascular disease and during the development of cardiovascular disease. Based on these observations and the biological effects induced by ET-1, including profound vasoconstriction, pro-inflammatory actions, mitogenic and proliferative effects, stimulation of free radical formation and platelet activation, ET-1 has been implicated as an important factor in the development of vascular dysfunction and cardiovascular disease. In the following the pathogenic role of ET-1, the mechanisms underlying the involvement of ET-1 for the development of vascular dysfunction and the potentially beneficial therapeutic effects of selective ET(A) and dual ET(A)/ET(B) receptor antagonists will be discussed. In particular the changes of pathophysiological importance mediated by ET-1 in clinical studies are reviewed. These changes may be of significance for the development of various cardiovascular diseases beyond pulmonary arterial hypertension which is the currently approved indication for ET receptor antagonists.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 September 2016
                2016
                : 11
                : 9
                : e0162652
                Affiliations
                [1 ]Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC, United States of America
                [2 ]Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, United States of America
                [3 ]Division of Cardiology, University of North Carolina, Chapel Hill, NC, United States of America
                [4 ]Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, United States of America
                [5 ]Department of Biostatistics, University of North Carolina, Chapel Hill, NC, United States of America
                [6 ]Division of Nephrology, The University of Alabama at Birmingham, Birmingham, AL, United States of America
                [7 ]Department of Pediatrics, Emory University, Atlanta, GA, United States of America
                Université Claude Bernard Lyon 1, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: KIA.

                • Formal analysis: PM JC.

                • Funding acquisition: KIA DRA DMP.

                • Investigation: KIA MC LE JS SKJ DMP ALH.

                • Methodology: KIA VKD JC ALH.

                • Resources: KIA DMP.

                • Supervision: KIA.

                • Writing – original draft: KIA.

                • Writing – review & editing: VKD MC LE JS SKJ PM DMP JC ALH DRA.

                Author information
                http://orcid.org/0000-0002-4501-9982
                Article
                PONE-D-16-20154
                10.1371/journal.pone.0162652
                5036885
                27669006
                f2476763-f6c6-4af8-9b49-268f780322fd
                © 2016 Ataga et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 May 2016
                : 28 August 2016
                Page count
                Figures: 4, Tables: 5, Pages: 15
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: R01HL111659
                Award Recipient :
                Funded by: National Heart, Lung, and Blood Institute (US)
                Award ID: R01HL111659
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;
                Award ID: U01HL117659
                Award Recipient :
                Funded by: National Heart, Lung, and Blood Institute (US)
                Award ID: U01HL117684
                Award Recipient :
                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. We acknowledge the Clinical and Translational Research Center at the University of North Carolina at Chapel Hill, which is funded by National Center for Advancing Translational Sciences grant UL1RR025747.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Urine
                Biology and Life Sciences
                Biochemistry
                Proteins
                Hemoglobin
                Biology and Life Sciences
                Biochemistry
                Enzymology
                Enzymes
                Protein Kinases
                Tyrosine Kinases
                Biology and Life Sciences
                Biochemistry
                Proteins
                Enzymes
                Protein Kinases
                Tyrosine Kinases
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Bile
                Bilirubin
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Bile
                Bilirubin
                Biology and Life Sciences
                Physiology
                Body Fluids
                Bile
                Bilirubin
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Bile
                Bilirubin
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Growth Factors
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Growth Factors
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Hematology
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogenesis
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Medicine and Health Sciences
                Anatomy
                Cardiovascular Anatomy
                Blood Vessels
                Arteries
                Custom metadata
                All relevant data are within the paper and its Supporting information files.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article