Shock/sepsis/trauma/critical caresRAGE is Elevated in Septic Patients and Associated With Patients Outcome1
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.
Section snippets
Materials and Methods
This observational clinical study was conducted in the surgical intensive care unit of the University Hospital of Heidelberg, Germany, after the study protocol was approved by the local ethical committee in accordance with the Helsinki Declaration of 1975.
Eight healthy volunteers served as controls. Twenty-nine consecutive patients of the surgical intensive care unit were enrolled in the study within the first 24 h after onset of severe sepsis or septic shock. Patients were classified according
sRAGE Measurement in Plasma of Healthy Volunteers and Patients
To test if sRAGE concentrations of septic patients differ from healthy controls, blood samples of eight controls and 29 septic patients were performed. Plasma sRAGE concentrations were higher in septic patients than in healthy volunteers (1764 ± 138 versus 1026 ± 177 pg/mL, P < 0.05) (Fig. 1).
sRAGE Measurement in Plasma of Survivors and Nonsurvivors
To determine whether sRAGE may serve as an early marker of septic patients outcome, we divided the septic patients according to 28 d mortality in survivors (n = 16) and nonsurvivors (n = 13) and compared
Discussion
To the best of our knowledge, this is the first manuscript reporting elevated plasma sRAGE levels in septic patients. We demonstrate elevated sRAGE levels in sepsis. Furthermore, we found an increased sRAGE concentration in plasma of nonsurvivors compared with survivors of sepsis. After all, larger clinical studies are indicated to review the potential role of sRAGE as a potential new sepsis marker.
In the United States, sepsis is the main cause of death in non-cardiologic intensive care units
Acknowledgments
The authors thank C. Rosenhagen for excellent practical help.
References (19)
- et al.
Epidemiology of severe sepsis around the world
Endocr Metab Immune Dis Drug Targets
(2006) - et al.
RAGE in inflammation: A new therapeutic target?
Curr Opin Invest Drugs
(2006) - et al.
Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response
J Clin Invest
(2004) - et al.
Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects
Metabolism
(2006) - et al.
Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis
Arterioscler Thromb Vasc Biol
(2005) - et al.
ACCP/SCCM consensus conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis
Chest
(1992) - et al.
Measures, markers, and mediators: Toward a staging system for clinical sepsisA report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25 and 26, 2000
Crit Care Med
(2003) - et al.
NH2 terminal pro-brain natriuretic peptide plasma level as an early marker of prognosis and cardiac dysfunction in septic shock patients
Crit Care Med
(2005) - et al.
Time-course of sTREM (soluble triggering receptor expressed on myeloid cells)-1, procalcitonin, and C-reactive protein plasma concentrations during sepsis
Crit Care Med
(2005)
Cited by (111)
Biomarkers of sepsis
2023, Molecular Medical Microbiology, Third EditionEffect of the consumption of yacon flour and energy-restricted diet on glycation markers, and association between these markers and factors linked to obesity in adults with excess body weight: A randomized, double-blind, placebo-controlled clinical trial
2021, NutritionCitation Excerpt :This indicates that sRAGE does not always have a protective role, since in these studies there was an association between sRAGE and AGEs, which are known to exacerbate inflammation and oxidative stress [51], as well as an association between sRAGE and diabetes complications [46]. Some authors state that sRAGE is associated with inflammation [52–54]. The results of in vitro studies suggest a new role for sRAGE in inflammation mediated by monocytes and in neutrophil survival and differentiation [55].
Pathophysiology of the Acute Respiratory Distress Syndrome: Insights from Clinical Studies
2021, Critical Care ClinicsCitation Excerpt :sRAGE levels in the plasma have been studied extensively in ARDS, and elevated levels are associated with disease severity, adverse clinical outcomes, and diffuse changes on CT scans of the lungs.46–49 Although sRAGE is promising, its specificity to ARDS remains uncertain and has been implicated as a marker of severity in community-acquired pneumonia50 and in sepsis.51,52 Markers of endothelial injury are also elevated in ARDS and specifically sepsis-associated ARDS.53
Pathophysiology of Neonatal Sepsis
2017, Fetal and Neonatal Physiology, 2-Volume Set
- 1
Christian Bopp and Stefan Hofer contributed equally to this work.