title: The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients: Results from a Prospective Pilot Study.
abstract: BACKGROUND
  Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with severe sepsis.
  
  
  OBJECTIVE
  1) To explore the reliability of Skin Autofluorescence (AF) as an index of tissue AGEs in ICU patients, 2) to compare its levels to healthy controls, 3) to describe the time course of AGEs and influencing factors during ICU admission, and 4) to explore their association with disease severity, outcome, and markers of oxidative stress and inflammation.
  
  
  METHODS
  Skin AF, serum N"-(carboxyethyl)lysine (CEL), N"-(carboxymethyl)lysine (CML), and soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU patients with multiple organ failure and compared to age-matched healthy controls. Correlations with (changes in) clinical parameters of disease severity, LDL dienes, and CRP were studied and survival analysis for in-hospital mortality was performed.
  
  
  RESULTS
  Forty-five ICU patients (age: 59±15 years; 60% male), and 37 healthy controls (59±14; 68%) were included. Skin AF measurements in ICU patients were reproducible (CV right-left arm: 13%, day-to-day: 10%), with confounding effects of skin reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients vs healthy controls (2.7±0.7 vs 1.8±0.3 au; p<0.001). Serum CEL (23±10 vs, 16±3 nmol/gr protein; p<0.001), LDL dienes (19 (15-23) vs. 9 (8-11) μmol/mmol cholesterol; <0.001), and sRAGE (1547 (998-2496) vs. 1042 (824-1388) pg/ml; p = 0.003) were significantly higher in ICU patients compared to healthy controls, while CML was not different (27 (20-39) vs 29 (25-33) nmol/gr protein). While CRP and LDL dienes decreased significantly, Skin AF and serum AGEs and sRAGE did not change significantly during the first 7 days of ICU admission. CML and CEL were strongly correlated with SOFA scores and CML above the median at baseline was associated with increased risk for mortality (Hazard ratio 3.3 (1.3-8.3); p = 0.01). All other markers did not correlate with disease severity and did not predict mortality.
  
  
  CONCLUSIONS
  This study demonstrates that markers for the AGE-RAGE axis are elevated in critically ill patients compared to healthy controls but remain stable for at least 7 days despite clearly fading inflammation and oxidative stress. Circulating AGEs may be associated with disease severity and outcome. Further research should be conducted to elucidate the role of the AGE-RAGE axis in the exaggerated inflammatory response leading to multiple organ failure and death, and whether or not this may be a target for treatment.
authors.affiliation: Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: John H
authors.initials: JH
authors.lastname: Meertens
authors.affiliation: Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Nienhuis
authors.affiliation: Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Joop D
authors.initials: JD
authors.lastname: Lefrandt
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Institute of Public Health and Clinical Nutrition, Department of Clinical Chemistry, University of Eastern Finland, Kuopio, Finland.|Eastern Finland Laboratory Center, Kuopio, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Nyyssönen
authors.affiliation: Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jack J M
authors.initials: JJ
authors.lastname: Ligtenberg
authors.affiliation: Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Andries J
authors.initials: AJ
authors.lastname: Smit
authors.affiliation: Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Zijlstra
authors.affiliation: Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Mulder
mesh_terms: D001663:Bilirubin / Q000097:blood; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016638:Critical Illness / Q000401:mortality*; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism*; D017052:Hospital Mortality; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism; D007362:Intensive Care Units; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010343:Patient Admission; D010865:Pilot Projects; D011379:Prognosis; D011446:Prospective Studies; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D012867:Skin / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D002097:C-Reactive Protein; D001663:Bilirubin