Raised Plasma Robo4 and Cardiac Surgery-Associated Acute Kidney Injury
File(s)
Author(s)
Burke-Gaffney, A
Svermova, T
Mumby, S
Finney, SJ
Evans, TW
Type
Journal Article
Abstract
Objective: Endothelial dysfunction associated with systemic inflammation can contribute to organ injury/failure following
cardiac surgery requiring cardiopulmonary bypass (CPB). Roundabout protein 4 (Robo4), an endothelial-expressed
transmembrane receptor and regulator of cell activation, is an important inhibitor of endothelial hyper-permeability. We
investigated the hypothesis that plasma levels of Robo4 are indicative of organ injury, in particular acute kidney injury (AKI),
after cardiac surgery.
Methods: Patients (n = 32) undergoing elective cardiac surgery with CPB were enrolled, prospectively. Plasma Robo4
concentrations were measured pre-, 2 and 24 h post-operatively, using a commercially available ELISA. Plasma and
endothelial markers of inflammation [interleukin (IL) -6, -8, -10: von Willibrand factor (vWF) and angiopoeitin-2 (Ang-2)] and
the AKI marker, neutrophil gelatinase-associated lipocalin (NGAL), were also measured by ELISA.
Results: Plasma Robo4 increased significantly (p,0.001) from pre-operative levels of 25156904 pg/ml to 447361915 pg/
ml, 2 h after surgery; and returned to basal levels (26826979 pg/ml) by 24 h. Plasma cytokines, vWF and NGAL also
increased 2 h post-operatively and remained elevated at 24 h. Ang-2 increased 24 h post-operatively, only. There was a
positive, significant correlation (r = 0.385, p = 0.0298) between Robo-4 and IL-10, but not other cytokines, 2 h postoperatively.
Whilst raised Robo4 did not correlate with indices of lung dysfunction or other biomarkers of endothelial
activation; there was a positive, significant correlation between raised (2 h) plasma NGAL and Robo4 (r = 0.4322, p = 0.0135).
When patients were classed as AKI or non-AKI either using NGAL cut-off of 150 ng/ml, or the AKI Network (AKIN) clinical
classification; plasma Robo4 was significantly higher (p = 0.0073 and 0.003, respectively) in AKI vs. non-AKI patients (NGAL
cut-off: 535062191 ng/ml, n = 16 vs. 359561068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025–8079, n = 6; vs. 3727 pg/ml, IQR
1962–3727, n = 26) subjects.
Conclusion: Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB; and higher levels in
patients with AKI suggest a link between endothelial dysregulation and onset of AKI.
cardiac surgery requiring cardiopulmonary bypass (CPB). Roundabout protein 4 (Robo4), an endothelial-expressed
transmembrane receptor and regulator of cell activation, is an important inhibitor of endothelial hyper-permeability. We
investigated the hypothesis that plasma levels of Robo4 are indicative of organ injury, in particular acute kidney injury (AKI),
after cardiac surgery.
Methods: Patients (n = 32) undergoing elective cardiac surgery with CPB were enrolled, prospectively. Plasma Robo4
concentrations were measured pre-, 2 and 24 h post-operatively, using a commercially available ELISA. Plasma and
endothelial markers of inflammation [interleukin (IL) -6, -8, -10: von Willibrand factor (vWF) and angiopoeitin-2 (Ang-2)] and
the AKI marker, neutrophil gelatinase-associated lipocalin (NGAL), were also measured by ELISA.
Results: Plasma Robo4 increased significantly (p,0.001) from pre-operative levels of 25156904 pg/ml to 447361915 pg/
ml, 2 h after surgery; and returned to basal levels (26826979 pg/ml) by 24 h. Plasma cytokines, vWF and NGAL also
increased 2 h post-operatively and remained elevated at 24 h. Ang-2 increased 24 h post-operatively, only. There was a
positive, significant correlation (r = 0.385, p = 0.0298) between Robo-4 and IL-10, but not other cytokines, 2 h postoperatively.
Whilst raised Robo4 did not correlate with indices of lung dysfunction or other biomarkers of endothelial
activation; there was a positive, significant correlation between raised (2 h) plasma NGAL and Robo4 (r = 0.4322, p = 0.0135).
When patients were classed as AKI or non-AKI either using NGAL cut-off of 150 ng/ml, or the AKI Network (AKIN) clinical
classification; plasma Robo4 was significantly higher (p = 0.0073 and 0.003, respectively) in AKI vs. non-AKI patients (NGAL
cut-off: 535062191 ng/ml, n = 16 vs. 359561068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025–8079, n = 6; vs. 3727 pg/ml, IQR
1962–3727, n = 26) subjects.
Conclusion: Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB; and higher levels in
patients with AKI suggest a link between endothelial dysregulation and onset of AKI.
Date Issued
2014-10-31
Date Acceptance
2014-09-30
Citation
PLOS One, 2014, 9 (10)
ISSN
1932-6203
Publisher
Public Library of Science
Journal / Book Title
PLOS One
Volume
9
Issue
10
Copyright Statement
© 2014 Burke-Gaffney 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.
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
MICROVASCULAR ENDOTHELIAL-CELLS
ACUTE LUNG INJURY
CARDIOPULMONARY BYPASS
ROUNDABOUT RECEPTOR
INFLAMMATORY RESPONSE
BARRIER DYSFUNCTION
MAGIC ROUNDABOUT
BIOMARKERS
SEPSIS
PERMEABILITY
Publication Status
Published
Article Number
e111459