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      Association of Advanced Glycoxidation End Products and Inflammation Markers with Thrombosis of Arteriovenous Grafts in Hemodialysis Patients

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          Background/Aims: Intimal hyperplasia at the venous anastomosis of arteriovenous dialysis grafts (AVGs) is a common and costly complication in hemodialysis (HD) patients. Previous studies have shown significant accumulation of advanced glycation end products (AGEs) within the lesions, suggesting a pathogenic role for these compounds in this condition. Methods: We retrospectively analyzed data from 139 HD patients, including 58 subjects with AVGs, to determine any relationship between serum AGEs and other circulating markers, e.g. C-reactive protein (CRP), tumor necrosis factor (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), plasminogen activator inhibitor type 1 and vascular endothelial growth factor, with the presence of graft thrombosis, an index of venous intimal hyperplasia. Results: Patients with previously thrombosed AVGs exhibited significantly higher levels of serum AGEs (42 ± 18 vs. 28± 8 U/ml), CRP (1.4 ± 1.1 vs. 0.6 ± 0.4 mg/dl) and VCAM-1 (3,172 ± 696 vs. 2,447 ± 1,101 ng/ml) than those with uncomplicated AVGs, variances that were mostly attributed to diabetes difference. There was no difference regarding the levels of the parameters studied between patients with AVGs and other forms of vascular access. Conclusions: These results support an association between circulating AGEs, markers of inflammation and endothelial function and intimal hyperplasia at the venous anastomosis of AVGs in HD patients. The implication is that there may be a therapeutic role for anti-AGE interventions in the management of this common clinical condition.

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          Most cited references 14

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          Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor.

          Proliferation of smooth muscle cells (SMCs) represents an important event in vascular lesion formation. Despite the common belief that growth factors contribute to the development of the atherosclerotic plaque, until now there has been no direct evidence for a role of mitogens in the development of arterial lesions. Balloon catheter injury of the rat carotid artery is accompanied by death of medial SMCs and is typically followed by proliferation of SMCs with subsequent formation of an intimal lesion. Our hypothesis is that injury causes mitogens to be released from dead cells, which then stimulate cell proliferation. One such mitogen that may be important in this process is basic fibroblast growth factor (bFGF), which can be detected immunocytochemically in SMCs and endothelial cells of adult rat carotid arteries. Systemic injection of a neutralizing antibody against bFGF prior to balloon catheterization significantly decreased the induced SMC proliferation by approximately 80%. The intimal lesion that developed within 8 days after injury, however, was not significantly reduced. The results of this study support the concept that endogenous bFGF is the major mitogen controlling the growth of vascular smooth muscle cells following injury. These data may have implications for the observed failure of endarterectomy and angioplasty procedures.
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            Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access.

            The pathological role of oxidative stress in patients treated by hemodialysis has gained increasing recognition in recent years. Because complications related to vascular access are a major source of morbidity, immunohistochemical evidence of oxidative stress and activation of growth factors were examined in native arteriovenous (AV) fistulae (n = 11) and expanded polytetrafluoroethylene (ePTFE) grafts (n = 15) recovered from hemodialysis patients at the time of surgical revision or resection. To show the presence of oxidative stress in tissues, three markers were chosen: N(epsilon)(carboxymethyl)lysine, a structurally identified advanced glycation end product; 4-hydroxy-2,3-nonenol, a lipid peroxidation product; and redox-active transition metals bound to proteins, a source of Fenton chemistry-generated free radicals. Markers of cell growth and proliferation were endothelin-1 (ET-1), a potent mitogenic peptide implicated in the formation of intimal hyperplasia; transforming growth factor-beta (TGF-beta), a stimulus to vascular cell growth and matrix production; and platelet-derived growth factor (PDGF), a mediator of intimal hyperplasia. All specimens studied showed significant intimal hyperplasia. In general, the neointima close to the vascular lumen of the AV fistula and the pseudointima close to the lumen of the ePTFE graft were positive for oxidative stress markers. At sites of injury, especially in the presence of histological evidence of inflammation and healing, expression of oxidative markers was particularly intense. Prominent staining of PDGF was shown at sites of anastomotic hyperplasia and in neovasculature. TGF-beta was associated with proliferation or repair in both AV fistulae and ePTFE grafts. ET-1 staining was most intense in the neointima and pseudointima. This study showed histochemical colocalization of markers of oxidative stress with growth factors known to contribute to intimal hyperplasia.
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              Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients.

              Levels of advanced glycation end products (AGEs), well-known proinflammatory compounds, are markedly elevated in patients with renal failure, raising the speculation that they have a role as cardiovascular risk factors in this population. Although elevated AGE levels in patients with renal failure have been attributed to impaired renal clearance and increased endogenous AGE formation, recent data suggest an important role for diet as a source of AGEs. To determine the relationship between dietary AGE content and serum AGE levels, a cross-sectional study was performed in our long-term dialysis patients. Dietary AGE intake was estimated by means of dietary records and questionnaires, and sera were obtained for measurement of 2 well-characterized AGEs, carboxymethyl-lysine (CML) and methylglyoxal (MG) derivatives. The study population included 189 patients; 139 hemodialysis and 50 peritoneal dialysis patients. Serum CML level correlated significantly with dietary AGE intake, based on either 3-day food records (r = 0.5; P = 0.003) or dietary questionnaires (r = 0.22; P = 0.03). Although no correlation was observed with nutrient intake (protein, fat, saturated fat, or carbohydrate), both serum CML and MG levels correlated with blood urea nitrogen (r = 0.2; P = 0.03 and r = 0.2; P = 0.02, respectively) and serum albumin levels (r = 0.16; P = 0.04 and r = 0.18; P = 0.02, respectively). Data indicate that dietary AGE content, independently of other diet constituents, is an important contributor to excess serum AGE levels in patients with renal failure. Moreover, the lack of correlation between serum AGE levels and dietary protein, fat, and carbohydrate intake indicates that a reduction in dietary AGE content can be obtained safely without compromising the content of obligatory nutrients.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                May 2006
                02 June 2006
                : 26
                : 2
                : 181-185
                aDivision of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, N.Y., USA, and bEndocrine Unit, Second Department of Internal Medicine, Research Institute, ‘Attikon’ University Hospital, Athens, Greece
                93122 Am J Nephrol 2006;26:181–185
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 3, References: 23, Pages: 5
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                Original Report: Patient-Oriented, Translational Research


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