Critical Appraisal of Advanced Glycation End Products (AGEs) and Circulating Soluble Receptors for Advanced Glycation End Products (sRAGE) as a Predictive Biomarkers for Cardiovascular Disease in Hemodialysis Patients

Abstract

The interaction of advanced glycation end products (AGE) and their receptors promote vascular complications of diabetes in hemodialysis (HD) patients. The soluble form of the receptor for the advanced glycation end-products (sRAGE) has been studied as a vascular biomarker in various diseases with controversial results. Our aim was to evaluate the association of the serum levels of the AGEs and their receptor sRAGE with cardiovascular disease (CVD) and the cardiovascular risk factors among HD patients. There were 130 HD patients and 80 age and gender matched control subjects were involved; 31.5% of the HD group were diabetic, which was an underlying cause of renal impairment; 36.1% had CVD, which was comprising 44.7% of diabetics and 55.3% of non-diabetic patients. The AGEs and sRAGE were assessed by enzyme linked immunosorbent assay (ELISA). In addition, the lipid profile, glycemic indices, pre-dialysis renal function tests, and hemoglobin % (Hb) were evaluated. The results show that the circulating AGEs and sRAGE levels were significantly higher in the HD patients. Those with underlying diabetes displayed higher sRAGE levels, which were positively correlated with hyperglycemia, HbA1C, and total cholesterol (TC). The HD patients with an increased serum sRAGE exhibited more cardiovascular risk factors (hypercholesterolemia and anemia) with a high prevalence of CVD. Using a linear regression analysis, we found a significant association of sRAGE with CVD and TC among HD patients, regardless of whether associating diabetes was an underlying cause of renal impairment. Overall, the HD patients displayed significantly higher serum AGEs with a concomitant increase in the circulating sRAGE levels, mainly in the diabetic HD, which were significantly associated with the CVD (independent predictors) and CV risk factors (hypercholesterolemia), mainly sRAGEs, regardless of the underlying diabetes mellitus. This highlights the prognostic role of AGEs and sRAGE in HD patients regardless of underlying cause in order to predict the risk for CVD.

Role of Advanced Glycation End Products on Aortic Calcification in Patients with Type 2 Diabetes Mellitus

“…On the other hand, we find an association between circulating AGEs and HbA1c. Similar results have been found in other studies [35] where AGEs levels were higher in patients with poor glycemic control measured by HbA1c [54,[57][58][59]. It is important to consider that the extent and duration of hyperglycemia are predicted by increased levels of HbA1c, which is considered an acceptable marker.…”

The Role of Advanced Glycation End Products and Its Soluble Receptor in Kidney Diseases

“…sRAGE was not only connected with DM and renal disorders, but was also associated with CVD (independent predictors) and their risk factors (hypercholesterolemia), regardless of DM. This underscores the prognostic relevance of AGEs and sRAGE in HD patients, independent of the underlying etiology, in predicting CVD risk [ 68 ]. sRAGE influences the vascular calcification process, even after controlling for established CV risk variables [ 61 , 73 ], and has anti-inflammatory properties by inhibiting the interactions of AGEs with cell surfaces [ 61 ].…”

“…Exposure to high-glucose PD fluids may exacerbate such alterations [ 67 ]. The amount of AGEs was non-significantly different in uremic patients with and without DM [ 68 ]. Baseline SAF, but not serum CML, was substantially linked with the risk of all-cause and cardiovascular disease (CVD) mortality in the China Cooperative Study on Dialysis (CCSD), a multicenter prospective cohort study of 1634 HD patients.…”

“…In HD patients, sRAGE is increased due to decreased kidney function, which is a strong determinant of sRAGE levels, and is not significantly modified by dialysis therapy [ 60 , 61 , 62 , 63 , 64 , 69 , 70 ]. Besides the rise in circulating AGEs and sRAGE due to impaired kidney function, the sRAGE concentration might also be elevated in uremia to defend against the harmful effects of AGEs, within a counter-regulatory mechanism against vascular endothelial injury [ 10 , 56 , 63 , 64 , 68 ]. sRAGE showed a negative relationship between residual diuresis and acute-phase reactants (fibrinogen and orosomucoid) [ 60 ].…”

Hemodialysis Patients with Higher Serum Levels of Soluble Receptor for Advanced Glycation End Products Have an Increased Risk for Arteriovenous Fistula Failure

“…Based on the available experimental data, one would expect sRAGE to be a protective factor for a cardiovascular event. However, in a clinical setting, many reports associated increased sRAGE to atherosclerosis, coronary artery disease, chronic kidney disease, enhanced inflammation, and oxidative stress [6, 10, 11, 21]; sRAGE is also a link to worse cardiovascular and overall prognosis: it predicts cardiovascular events and cardiovascular mortality in HD patients [22, 23].…”