Soluble RAGE and the RAGE ligands HMGB1 and S100A12 in critical illness: impact of glycemic control with insulin and relation with clinical outcome.
Systemic inflammation often leads to complications in critically ill patients. Activation of the receptor for advanced glycation end-products (RAGE) generates inflammatory cytokines, proteases, and oxidative stress and may link inflammation to subsequent organ damage. Furthermore, hyperglycemia-induced oxidative stress increases RAGE ligands and RAGE expression. We hypothesized that preventing hyperglycemia during critical illness reduces the risk of excessively enhanced RAGE signaling, which could relate to clinical outcomes and risk of death. In 405 long-stay surgical intensive care unit patients randomized to intensive or conventional insulin treatment, serum concentrations of soluble RAGE (decoy receptor) and the RAGE ligands high-mobility group box 1 (HMGB1) and S100A12 were measured on admission, day 7, and last day. These were compared with levels in 71 matched control subjects and with C-reactive protein (CRP) as a routinely monitored inflammation marker. On admission, soluble RAGE, HMGB1, S100A12, and CRP were higher in patients than in controls. The HMGB1, S100A12, and CRP remained elevated throughout intensive care unit stay, whereas soluble RAGE decreased to levels lower than in controls by day 7. Unexpectedly, insulin treatment did not affect the circulating levels of these markers. In univariable analysis, elevated levels of soluble RAGE on admission were associated with adverse outcome, including circulatory failure, kidney failure, liver dysfunction, and mortality. The associations with circulatory and kidney failure remained significant in multivariable logistic regression analysis corrected for baseline risk factors. Critical illness affects components of RAGE signaling, unaffected by insulin treatment. Elevated on-admission soluble RAGE was associated with adverse outcomes.
Clinical Department and Laboratory of Intensive Care Medicine, Division Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
Catherine
C
Ingels
Inge
I
Derese
Pieter J
PJ
Wouters
Greet
G
Van den Berghe
Ilse
I
Vanhorebeek
D018806:APACHE; D000368:Aged; D016470:Bacteremia / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016638:Critical Illness / Q000628:therapy*; D005260:Female; D024243:HMGB1 Protein / Q000097:blood*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000097:blood; D007328:Insulin / Q000627:therapeutic use*; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood; D011379:Prognosis; D011446:Prospective Studies; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood*; D009418:S100 Proteins / Q000097:blood*; D000067616:S100A12 Protein
C000593871:AGER protein, human; D015415:Biomarkers; D001786:Blood Glucose; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D000067759:Receptor for Advanced Glycation End Products; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D002097:C-Reactive Protein