sRAGE is Elevated in Septic Patients and Associated With Patients Outcome

Background

(1) To evaluate in septic patients the plasma levels of soluble receptor for advanced glycation end products (sRAGE), a soluble splice variant of the full length receptor RAGE, which is involved in acute inflammation (2) to determine whether sRAGE could be used as a potential diagnostic and prognostic marker in sepsis in the surgical intensive care unit.

Materials and methods

An observational clinical noninterventional pilot study in a surgical intensive care unit with patients admitted to the intensive care unit over a 6-mo period with clinical evidence of severe sepsis or septic shock.

Results

Twenty-nine intensive care patients were enrolled in the study within the first 24 h after onset of severe sepsis or septic shock. Eight healthy volunteers served as controls. Plasma sRAGE concentrations were elevated in septic patients compared with healthy volunteers (1764 ± 138 versus 1026 ± 177 pg/mL, P < 0.05). Additionally, nonsurvivors after 28 days have had higher plasma sRAGE concentrations than survivors (2302 ± 189 versus 1326 ± 112 pg/mL, P < 0.001). Receiver operating characteristic curve analysis of plasma sRAGE concentrations of septic patients showed a specificity of 75% and a sensitivity of 84.6% with 1596 pg/mL as cutoff.

Conclusions

This is the first study showing elevated plasma sRAGE concentrations in septic patients. It is noteworthy that nonsurvivors had higher plasma sRAGE concentrations than survivors, suggesting that sRAGE is related to severity and outcome of septic patients. Further clinical studies are required to investigate the usefulness of sRAGE as a new sepsis marker.

Introduction

Sepsis remains an important clinical and economic challenge for intensive care units throughout the world. Severe complications such as multi-organ failure with high mortality and the lack of specific diagnostic tools characterize the clinical situation in sepsis [1].

The receptor for advanced glycation end products (RAGE) is a member of the Ig superfamily and a multi-ligand receptor interacting with a diverse class of ligands [2]. RAGE has been shown to be involved in the pathogenesis of several chronic diseases [2].

Recently, we clarified the role of RAGE in experimental sepsis, showing that RAGE-dependent activation of nuclear factor-kappa B (NF-κB) plays a central role in modulating mortality after cecal ligation and puncture (CLP) [3].

RAGE has secretory isoforms referred to as soluble RAGE (sRAGE), which comprise the extracellular ligand-binding domain but are lacking the cytosolic and transmembrane domains. It is noteworthy that sRAGE has the same ligand binding specificity and therefore competes with cell-bound RAGE and serves as a decoy abrogating cellular activation. In a sepsis model of CLP-induced sepsis the administration of exogenous sRAGE did slightly improve survival [3].

In humans, endogenous sRAGE (esRAGE) is produced by alternative splicing of RAGE mRNA. esRAGE, however, does not represent the entire pool of sRAGE present in the bloodstream and it is speculated that sRAGE can also be cleaved proteolytically from the membranous RAGE. However, little is known about the functional role of endogenous levels of sRAGE/esRAGE in healthy patients. In nondiabetic patients sRAGE was elevated in parallel with serum advanced glycation endproduct (AGE) levels [4]. In contrast, Koyama et al. found that esRAGE was inversely associated with carotid or femoral atherosclerosis and seems to be a protective factor for the metabolic syndrome and atherosclerosis [5].

Indeed, there is a lack of knowledge regarding the role of sRAGE/esRAGE in sepsis. In view of these data, the aim of this work was to set up a pilot study to investigate whether total pool of sRAGE is increased in plasma of septic patients. Furthermore, we assessed the ability of sRAGE to predict mortality in patients with severe sepsis or septic shock.