title: Raised plasma Robo4 and cardiac surgery-associated acute kidney injury.
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 2515 ± 904 pg/ml to 4473 ± 1915 pg/ml, 2 h after surgery; and returned to basal levels (2682 ± 979 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 post-operatively. 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: 5350 ± 2191 ng/ml, n = 16 vs. 3595 ± 1068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025-8079, n = 6; vs. 3727 pg/ml, IQR 1962-3727, n = 26) subjects.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Vascular Biology, Cardiovascular Sciences, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Burke-Gaffney
authors.affiliation: Vascular Biology, Cardiovascular Sciences, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Svermova
authors.affiliation: Vascular Biology, Cardiovascular Sciences, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sharon
authors.initials: S
authors.lastname: Mumby
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Finney
authors.affiliation: National Institute for Health Research Respiratory Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Evans
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood* / Q000209:etiology*; D000368:Aged; D006348:Cardiac Surgical Procedures / Q000009:adverse effects*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D011183:Postoperative Complications / Q000097:blood*; D011956:Receptors, Cell Surface / Q000097:blood*; D012306:Risk; D000097905:Roundabout Proteins
chemical_list: D011956:Receptors, Cell Surface; C462951:ROBO4 protein, human; D000097905:Roundabout Proteins