The clinical significance of circulating soluble RAGE in patients with severe sepsis.

Abstract

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in the pathogenesis of inflammatory diseases. However, the significance of the soluble isoform of RAGE (sRAGE) has not been clarified in critical illness. We investigated circulating sRAGE in blood samples from septic patients. In this cross-sectional study, criteria for inclusion were patients with severe sepsis and age older than 18 years. Samples were collected within 24 hours after the diagnosis of sepsis and also from healthy volunteers. The levels of sRAGE and RAGE signaling pathway-associated biologic parameters were measured with an enzyme-linked immunosorbent assay kit. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were calculated at the time of patient enrollment. We used the International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm to assess coagulopathy. Included were 24 septic patients and 12 healthy volunteers. Serum sRAGE level was significantly increased in the patients compared with healthy controls. Significant correlations were found between sRAGE levels and APACHE II, SOFA, and ISTH DIC scores. The increase in sRAGE levels also correlated with the upregulation of interleukin-6, soluble vascular adhesion molecule 1, and plasminogen activator inhibitor 1 levels and a reduction in platelet count. The fraction of sRAGE other than the endogenous secreted form of RAGE (esRAGE) was augmented in the patients. We demonstrated for the first time that the serum level of sRAGE increased with the progression of DIC and the severity of sepsis, suggesting that circulating sRAGE reflects RAGE signaling pathway activity, which induces the excessive inflammatory response involved in endothelial injury and coagulopathy and that its measurement may be useful as a biomarker for sepis. Prognostic study, level IV.