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

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Sep 27

PMID 27669006

Citations 19

Authors

Kenneth I Ataga

Vimal K Derebail

Melissa Caughey

Laila Elsherif

Jessica H Shen

Susan K Jones

Poulami Maitra

David M Pollock

Jianwen Cai

David R Archer

Alan L Hinderliter

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Rybicki A, Benjamin L . Increased levels of endothelin-1 in plasma of sickle cell anemia patients. Blood. 1998; 92(7):2594-6. View

Tharaux P, Hagege I, Placier S, Vayssairat M, Kanfer A, Girot R . Urinary endothelin-1 as a marker of renal damage in sickle cell disease. Nephrol Dial Transplant. 2005; 20(11):2408-13. DOI: 10.1093/ndt/gfi111. View

Gladwin M, Schechter A, Ognibene F, Coles W, Reiter C, Schenke W . Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation. 2003; 107(2):271-8. DOI: 10.1161/01.cir.0000044943.12533.a8. View

Hohenstein B, Hausknecht B, Boehmer K, Riess R, Brekken R, Hugo C . Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int. 2006; 69(9):1654-61. DOI: 10.1038/sj.ki.5000294. View

Detterich J, Kato R, Rabai M, Meiselman H, Coates T, Wood J . Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood. 2015; 126(6):703-10. PMC: 4528063. DOI: 10.1182/blood-2014-12-614370. View

Foster R, Hole R, Anderson K, Satchell S, Coward R, Mathieson P . Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes. Am J Physiol Renal Physiol. 2003; 284(6):F1263-73. DOI: 10.1152/ajprenal.00276.2002. View

Ramzy D, Rao V, Tumiati L, Xu N, Sheshgiri R, Miriuka S . Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway. Circulation. 2006; 114(1 Suppl):I319-26. DOI: 10.1161/CIRCULATIONAHA.105.001503. View

Hebbel R, Vercellotti G, Nath K . A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis. Cardiovasc Hematol Disord Drug Targets. 2009; 9(4):271-92. PMC: 2914570. DOI: 10.2174/1871529x10909040271. View

Reiter C, Wang X, Tanus-Santos J, Hogg N, Cannon 3rd R, Schechter A . Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002; 8(12):1383-9. DOI: 10.1038/nm1202-799. View

10.

Noubouossie D, Key N, Ataga K . Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev. 2016; 30(4):245-56. PMC: 4919240. DOI: 10.1016/j.blre.2015.12.003. View

11.

Laurin L, Nachman P, Desai P, Ataga K, Derebail V . Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease. Nephrol Dial Transplant. 2013; 29(6):1211-8. PMC: 4038249. DOI: 10.1093/ndt/gft295. View

12.

Saraf S, Zhang X, Kanias T, Lash J, Molokie R, Oza B . Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia. Br J Haematol. 2013; 164(5):729-39. PMC: 3945021. DOI: 10.1111/bjh.12690. View

13.

Ergul A, Johansen J, Stromhaug C, Harris A, Hutchinson J, Tawfik A . Vascular dysfunction of venous bypass conduits is mediated by reactive oxygen species in diabetes: role of endothelin-1. J Pharmacol Exp Ther. 2004; 313(1):70-7. DOI: 10.1124/jpet.104.078105. View

14.

Sivaskandarajah G, Jeansson M, Maezawa Y, Eremina V, Baelde H, Quaggin S . Vegfa protects the glomerular microvasculature in diabetes. Diabetes. 2012; 61(11):2958-66. PMC: 3478549. DOI: 10.2337/db11-1655. View

15.

De Castro L, Jonassaint J, Graham F, Ashley-Koch A, Telen M . Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol. 2007; 83(1):19-25. DOI: 10.1002/ajh.21058. View

16.

Saleh A, Hillen H, Duits A . Levels of endothelial, neutrophil and platelet-specific factors in sickle cell anemia patients during hydroxyurea therapy. Acta Haematol. 1999; 102(1):31-7. DOI: 10.1159/000040964. View

17.

Bartolucci P, Habibi A, Stehle T, Di Liberto G, Rakotoson M, Gellen-Dautremer J . Six Months of Hydroxyurea Reduces Albuminuria in Patients with Sickle Cell Disease. J Am Soc Nephrol. 2015; 27(6):1847-53. PMC: 4884099. DOI: 10.1681/ASN.2014111126. View

18.

Baelde H, Eikmans M, Lappin D, Doran P, Hohenadel D, Brinkkoetter P . Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int. 2007; 71(7):637-45. DOI: 10.1038/sj.ki.5002101. View

19.

Levey A, Stevens L, Schmid C, Zhang Y, Castro 3rd A, Feldman H . A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009; 150(9):604-12. PMC: 2763564. DOI: 10.7326/0003-4819-150-9-200905050-00006. View

20.

Ataga K, Moore C, Jones S, Olajide O, Strayhorn D, Hinderliter A . Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006; 134(1):109-15. DOI: 10.1111/j.1365-2141.2006.06110.x. View