**3.2.2 Inflammation**

ESRD is associated with a chronic inflammatory state, characterized by the elevation of circulating cytokines and chemokines 91. This inflammation has been proposed to play an important role in the initiation and progression of atherosclerosis in ESRD, but may also play a significant role in vascular access stenosis. Support for this paradigm comes from

(upstream events) which may contribute to early AVF failure, include 4,72-81: (1) small diameter sizes in the vein and artery, (2) surgical injury at the time AV fistula placement, (3) previous venipunctures, (4) development of accessory veins after surgery, (5) hemodynamic shear stress at the AV anastomosis, (6) a genetic predisposition to vascular constriction and

The subsequent sections will focus on the downstream events and three main mechanisms responsible for neointimal hyperplasia such as oxidative stress, inflammation, endothelial

Many of the upstream mechanisms above (particularly hemodynamic shear stress and angioplasty injury) have been documented to result in an increase in the production of free radicals and its downstream products nitrotyrosine and latter (peroxynitrate). The latter is a potent upregulator of the matrix metalloproteinases (MMPs) 82,83. MMPs are key enzymes that cause breakdown of extracellular matrix proteins such as collagen and elastin which facilitate the migration of vascular smooth muscle cells (VSMCs) in neointimal hyperplasia formation 84. MMPs, paradoxically, have also been shown to facilitate a beneficial dilatation of the feeding artery (through degradation of the internal elastic laminae) in both rabbit and mouse AVF models 82,85. Experimental studies of AVGs have demonstrated a differential upregulation of MMP-2 at the graft-vein anastomosis, with early expression (9 days) in the adventitia and a later expression (19 days) within the intima, supporting the concept of cellular migration from the adventitia to the intima 86. Furthermore, linkages between hemodynamic shear stress and the expression of oxidative stress markers and cytokines have also been described in a porcine model of AVG stenosis 87. Clinical studies of stenotic and thrombotic AVGs and AVFs have also demonstrated an upregulation of MMPs 88, and have documented the co-localization of oxidative stress markers with inflammatory cytokines such as transforming growth factor-beta (TGF-), and platelet-derived growth

Heme-oxygenase-1 (HO-1) is an important enzyme pathway which has been shown to confer protective effects in the vascular endothelium and other organ systems through its anti-inflammatory, antioxidant, or antiproliferative actions and properties 89. Experimental studies in AVFs have described an increase in both the magnitude of arteriovenous stenosis and the frequency of thrombosis following the creation of AVFs in HO-1 knock out mice (increased baseline oxidative stress) as compared to wild type animals 90. Furthermore, in the HO-1 knockout mice, there was significant induction of MMP-9 expression in the vein at 1 week compared to wild type mice, suggesting that MMP expression in vascular tissue and its deleterious effects with regard to promoting cellular migration may in part be inhibited by HO-1. Clinical studies have demonstrated a higher frequency of AVF failure in patients with heme-oxygenase-1 (HO-1) gene polymorphisms with long GT repeats (resulting in

ESRD is associated with a chronic inflammatory state, characterized by the elevation of circulating cytokines and chemokines 91. This inflammation has been proposed to play an important role in the initiation and progression of atherosclerosis in ESRD, but may also play a significant role in vascular access stenosis. Support for this paradigm comes from

neointimal hyperplasia, and (7) pre-existing venous neointimal hyperplasia.

factor (PDGF), within the neointima of both stenotic AVGs and AVFs 60.

dysfunction, and alternative origins of neointimal-derived cells.

**3.2.1 Oxidative stress** 

increased oxidative stress) 73.

**3.2.2 Inflammation** 

recent work in which uremic mice developed a 2-3 fold greater magnitude of neointimal hyperplasia at the arteriovenous anastomosis as compared to non-uremic animals in a mouse model of AVF stenosis 92, and a recent study which showed marked upregulation of monocyte chemoattractant protein-1 (MCP-1) in the venous segment of AVF compared to rats deficient in the MCP-1 gene 93.

In clinical studies, possible linkages have described the presence of inflammatory cells (macrophages and lymphocytes), cytokines such as TGF-ß and insulin-like growth factor-1 (IGF-1) and the magnitude of neointimal hyperplasia and venous stenosis within stenotic AVFs 94.

Local bioincompatability to synthetic polytetrafluoroethylene (PTFE) material in AVGs could also result in local inflammation 95. In vitro studies have demonstrated that conditioned media obtained after the interaction of peripheral blood mononuclear cells (PBMCs) with PTFE graft material resulted in a significant upregulation of smooth muscle cell proliferation as compared to control media 96. This proliferative response has been shown to be attenuated by tumor necrosis-alpha (TNF-) inhibitors 96. Furthermore, the presence of macrophages that line PTFE graft material has been described in both experimental and clinical AVG stenosis with co-expression of inflammatory cytokines such as basic fibroblast growth factor (bFGF) 61,97.
