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A receptor-based bioadsorbent to target advanced glycation end products in chronic kidney disease.

ABSTRACT: The accumulation of advanced glycation end products (AGEs) has been reported to be a major contributor to chronic systemic inflammation. AGEs are not efficiently removed by hemodialysis or the kidney of a chronic kidney disease (CKD) patient. The goal of this study was to develop a receptor for AGEs (RAGE)-based bioadsorbent device that was capable of removing endogenous AGEs from human blood. The extracellular domain of RAGE was immobilized onto agarose beads to generate the bioadsorbent. The efficacy of AGE removal from saline, serum, and whole blood; biological effects of AGE reduction; and hemocompatibility and stability of the bioadsorbent were investigated. The bioadsorbent bound AGE-modified bovine serum albumin (AGE-BSA) with a binding capacity of 0.73?±?0.07?mg AGE-BSA/mL bioadsorbent. The bioadsorbent significantly reduced the concentration of total AGEs in serum isolated from end-stage kidney disease patients by 57%. AGE removal resulted in a significant reduction of vascular cell adhesion molecule-1 expression in human endothelial cells and abolishment of osteoclast formation in osteoclast progenitor cells. A hollow fiber device loaded with bioadsorbent-reduced endogenous AGEs from recirculated blood to 36% of baseline levels with no significant changes in total protein or albumin concentration. The bioadsorbent maintained AGE-specific binding capacity after freeze-drying and storage for 1 year. This approach provides the foundation for further development of soluble RAGE-based extracorporeal therapies to selectively deplete serum AGEs from human blood and decrease inflammation in patients with diabetes and/or CKD.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4016998 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A receptor-based bioadsorbent to target advanced glycation end products in chronic kidney disease.

Zhang Yangrong Y Lapidos Karen A KA Gal-Moscovici Anca A Sprague Stuart M SM Ameer Guillermo A GA

Artificial organs 20131111 6

The accumulation of advanced glycation end products (AGEs) has been reported to be a major contributor to chronic systemic inflammation. AGEs are not efficiently removed by hemodialysis or the kidney of a chronic kidney disease (CKD) patient. The goal of this study was to develop a receptor for AGEs (RAGE)-based bioadsorbent device that was capable of removing endogenous AGEs from human blood. The extracellular domain of RAGE was immobilized onto agarose beads to generate the bioadsorbent. The e ...[more]

PMID: 24206165

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Project description:Advanced glycation end products (AGEs) accumulation may be involved in the progression of CKD-bone disorders. We sought to determine the relationship between AGEs measured in the blood, skin, and bone with histomorphometry parameters, bone protein, gene expression, and serum biomarkers of bone metabolism in patients with CKD stages 3 to 5D patients. Serum levels of AGEs were estimated by pentosidine, glycated hemoglobin (A1c), and N-carboxymethyl lysine (CML). The accumulation of AGEs in the skin was estimated from skin autofluorescence (SAF). Bone AGEs accumulation and multiligand receptor for AGEs (RAGEs) expression were evaluated by immunohistochemistry; bone samples were used to evaluate protein and gene expression and histomorphometric analysis. Data are from 86 patients (age: 51 ± 13 years; 60 [70%] on dialysis). Median serum levels of pentosidine, CML, A1c, and SAF were 71.6 pmol/mL, 15.2 ng/mL, 5.4%, and 3.05 arbitrary units, respectively. AGEs covered 3.92% of trabecular bone and 5.42% of the cortical bone surface, whereas RAGEs were expressed in 0.7% and 0.83% of trabecular and cortical bone surfaces, respectively. AGEs accumulation in bone was inversely related to serum receptor activator of NF-κB ligand/parathyroid hormone (PTH) ratio (R = -0.25; p = 0.03), and RAGE expression was negatively related to serum tartrate-resistant acid phosphatase-5b/PTH (R = -0.31; p = 0.01). Patients with higher AGEs accumulation presented decreased bone protein expression (sclerostin [1.96 (0.11-40.3) vs. 89.3 (2.88-401) ng/mg; p = 0.004]; Dickkopf-related protein 1 [0.064 (0.03-0.46) vs. 1.36 (0.39-5.87) ng/mg; p = 0.0001]; FGF-23 [1.07 (0.4-32.6) vs. 44.1 (6-162) ng/mg; p = 0.01]; and osteoprotegerin [0.16 (0.08-2.4) vs. 6.5 (1.1-23.7) ng/mg; p = 0.001]), upregulation of the p53 gene, and downregulation of Dickkopf-1 gene expression. Patients with high serum A1c levels presented greater cortical porosity and Mlt and reduced osteoblast surface/bone surface, eroded surface/bone surface, osteoclast surface/bone surface, mineral apposition rate, and adjusted area. Cortical thickness was negatively correlated with serum A1c (R = -0.28; p = 0.02) and pentosidine levels (R = -0.27; p = 0.02). AGEs accumulation in the bone of CKD patients was related to decreased bone protein expression, gene expression changes, and increased skeletal resistance to PTH; A1c and pentosidine levels were related to decreased cortical thickness; and A1c levels were related to increased cortical porosity and Mlt. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Project description:BackgroundChronic kidney disease (CKD) is a condition associated with progressive loss of kidney function and kidney damage. The two common causes of CKD are diabetes mellitus and hypertension. Other causes of CKD also include polycystic kidney disease, obstructive uropathy and primary glomerulonephritis. The receptor for advanced glycation end-products (RAGE) is a multi-ligand cell surface receptor of the immunoglobulin superfamily and it has been associated with kidney disease in both non-diabetic and diabetic patients. Presently, data on the association between RAGE polymorphisms and CKD in the Malaysian population is limited, while numerous studies have reported associations of RAGE polymorphisms with diabetic complications in other populations. The present study aims to explore the possibility of using RAGE polymorphisms as candidate markers of CKD in Malaysian population by using association analysis.MethodsA total of 102 non-diabetic CKD patients, 204 diabetic CKD patients and 345 healthy controls were enrolled in the study. DNA isolated from blood samples were subjected to genotyping of RAGE G82S, -374T/A, -429T/C, 1704G/T and 2184A/G polymorphisms using real-time polymerase chain reaction (PCR). The 63-bp deletion, a polymorphism in the RAGE gene promoter, was genotyped using conventional PCR method and visualized using agarose gel electrophoresis. The collective frequencies of genotypes with at least one copy of the minor alleles of the four polymorphisms were compared between the non-diabetic CKD patients, diabetic CKD patients and healthy controls.ResultsAfter adjustment of age, gender and ethnic groups in binary logistic regression analysis, the G82S CT + TT genotypes were associated with non-diabetic CKD patients when compared with diabetic CKD patients (p = 0.015, OR = 1.896, 95% CI = 1.132-3.176). After further adjustment of CKD comorbidities, the G82S CT + TT genotypes were still associated with non-diabetic CKD patients when compared with diabetic CKD patients (p = 0.011, OR = 2.024, 95% CI = 1.178-3.476). However, it cannot be suggested that G82S polymorphism was associated with CKD in non-diabetic patients in this study. This is because there were no significant differences in the frequencies of G82S CT + TT genotypes between non-diabetic CKD patients and healthy controls. In addition, the RAGE -374T/A, -429T/C, 1704G/T, 2184A/G and 63-bp deletion polymorphisms were also not associated with non-diabetic CKD patients and diabetic CKD patients in this study.ConclusionThe G82S, -374T/A, -429T/C, 1704G/T, 2184A/G and 63-bp deletion polymorphisms examined in this study were not associated with chronic kidney disease in the Malaysian patients.

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A receptor-based bioadsorbent to target advanced glycation end products in chronic kidney disease.

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A receptor-based bioadsorbent to target advanced glycation end products in chronic kidney disease.

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