Associations between Soluble Receptor for Advanced Glycation End Products (sRAGE) and S100A12 (EN-RAGE) with Mortality in Long-term Hemodialysis Patients

Abstract

Hemodialysis (HD) patients experience vascular calcification, ultimately leading to high mortality rates. Previously, we reported associations between soluble receptor for advanced glycation end products (sRAGEs) and extracellular newly identified RAGE-binding protein S100A12 (EN-RAGE) and vascular calcification. Here, we extended our observations, investigating whether these biomarkers may be useful for predicting cardiovascular morbidity and mortality in these subjects. Thus, we evaluated the relationship between sRAGE and S100A12 and mortality in long-term HD patients. This was a prospective observational cohort study in 199 HD patients from an extended analysis of our previous study. Plasma sRAGE, S100A12, comorbidities, and other traditional risk factors were investigated. The cumulative incidences for death using Cox proportional hazards regression were evaluated in multivariable analyses. The observation period was 44 months. During the observation period, 27 (13.6%) patients died. Univariate analysis demonstrated that S100A12 was correlated with diabetes (P = 0.040) and high-sensitivity C-reactive protein (hsCRP) (P = 0.006). In multivariable analyses, plasma sRAGE (hazard ratio [HR] = 1.155; 95% confidence interval [CI] = 0.612–2.183; P = 0.656) and S100A12 (HR = 0.960; 95% CI = 0.566–1.630; P = 0.881) were not associated with mortality in HD patients, although traditional predictors of mortality, including age, history of cardiovascular diseases (CVDs), and serum levels of albumin and hsCRP were related to mortality. Powerful predictors of mortality were age, CVD, and albumin levels. Plasma sRAGE and S100A12 may be weak surrogate markers for predicting all-cause mortality in patients undergoing HD, although S100A12 was partly related to diabetes and inflammation.

Role of the Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Prognostic Factor for Mortality in Hemodialysis and Peritoneal Dialysis Patients

“…The role of sRAGE as a predictor of mortality in patients on dialysis is still under debate. The few studies that have been performed in this field up until now failed to observe any association [ 22 , 24 – 26 ]. Only a single study observed a trend, although not statistically significant, towards increased mortality with higher rather than lower sRAGE levels [ 25 ].…”

“…Despite a link between levels of sRAGE with parameters of inflammation, oxidative stress, atherosclerosis, and heart failure (HF) in CKD-G5D [ 16 – 20 ], prior studies failed to observe a strong association with patient outcomes [ 21 – 24 ]. However, there are a limited number of studies in this field, and they are difficult to compare due to differences in study design and patient features.…”

“…However, there are a limited number of studies in this field, and they are difficult to compare due to differences in study design and patient features. In particular, most studies have been focused on accompanying atherosclerosis and vascular calcification as a part of ESRD [ 21 – 24 ].…”

Relation of postoperative serum S100A12 levels to delirium and cognitive dysfunction occurring after hip fracture surgery in elderly patients

“…However, some mechanisms have been proposed, among which inflammation and its related brain injury play the key roles (Cerejeira, Nogueira, Luís, Vaz-Serra, & Mukaetova-Ladinska, 2012;Neerland et al, 2016;Vasunilashorn et al, 2017). It plays a crucial role in immune response and acts as a damage-associated molecular pattern protein, signaling through the receptor for advanced glycation end products (RAGE) (Jung et al, 2017;Khorramdelazad et al, 2015;Zhao et al, 2016). Treatment comprises both nonpharmacologic and pharmacologic interventions.…”

“…S100A12 is a member of the S100 gene family of calcium-binding proteins. It plays a crucial role in immune response and acts as a damage-associated molecular pattern protein, signaling through the receptor for advanced glycation end products (RAGE) (Jung et al, 2017;Khorramdelazad et al, 2015;Zhao et al, 2016). Clearly, RAGE has been found in the central nervous system and emerges as a central regulator of brain inflammatory processes (Hu et al, 2018;Li et al, 2017;Villarreal et al, 2014).…”