**1.1.1 Arteriovenous fistula**

AVFs are the preferred vascular access for hemodialysis patients, because once mature and functional, they require fewer interventions to maintain patency and develop fewer infections compared to AVGs 9-13. However, AVFs have higher rates of nonmaturation and longer maturation times compared to AVGs, which may lead to prolonged periods of CVC dialysis 9,14,15. Recent reports from the United States have shown that up to 60% of AVFs never mature adequately to be successfully cannulated for dialysis 16 compared to 20-25 years ago where the nonmaturation rates in AVFs was approximately 10% 12.

days 6,56, increased risk of 1-year mortality 49, and 60-70% higher risk of subsequent AVF failure 32,57. The cost of treating one CVC-related bacteremia in the United States has been estimated to be as high as \$45,000 per episode with an average of \$22,000 per bacteremic

**3. Pathology and pathophysiologic mechanisms of hemodialysis vascular** 

Venous stenosis that occurs in both AVFs and AVGs is primarily due to neointimal hyperplasia. Venous stenosis in AVGs most frequently arises from the development of aggressive neointimal hyperplasia, characterized by (a) the presence of alpha smooth muscle actin positive cells myofibroblasts, and microvessels within the neointima, (b) an abundance of extracellular matrix components, (c) angiogenesis (neovascularization) within the neointima and adventitia, (d) a macrophage layer lining the perigraft region, and (e) an increased expression of mediators and inflammatory cytokines such as TGF-β, PDGF, and

While the neointimal hyperplasia in AVFs is similar to AVGs in regards to pathogenesis, the venous stenosis that develops in AVFs is highly influenced by the capacity of the vein to vasodilitate and vascular injury from surgical technique 65. In AVFs the two main etiologies of failure are an initial failure to mature (nonmaturation) and a subsequent (late) venous stenosis 4. Similar to AVGs, venous neointimal hyperplasia in late AVF stenosis has been shown to be composed primarily of alpha smooth muscle actin positive cells, together with expression of mediators and cytokines such as TGF-β, PDGF, and endothelin within the media and intima of the vein 60,65. However, recently, the lesion of AVF nonmaturation at 6 weeks after AVF creation has also been described to have significant neointimal hyperplasia 66.

The pathogenesis of venous neointimal hyperplasia in AVG stenosis and late AVF stenosis has been well described and is commonly divided into upstream and downstream events4. Upstream events are characterized as the initial events and insults that are responsible for endothelial and smooth muscle cell injury, which leads to a cascade of mediators (downstream events) that regulate oxidative stress, endothelial dysfunction, and inflammation (eventually resulting in venous neointimal hyperplasia). Upstream events that are believed to contribute to the pathogenesis of neointimal hyperplasia include 4,62,67-70: (1) surgical trauma at the time of AV surgery, (2) hemodynamic shear stress at the veinartery or vein-graft anastomosis, (3) bioincompatability of the AVG, (4) vessel injury due to dialysis needle punctures, (5) uremia resulting in endothelial dysfunction, and (6) repeated angioplasties causing further endothelial injury. Downstream events represent the response to endothelial (vascular) injury from the upstream events, resulting in the migration of smooth muscle cells from the media to the intima and eventually the development of

The pathogenesis in AVFs that fail to mature (early failure) for dialysis, in contrast to AVG and late AVF failure, remains poorly understood. At a histological level early AVF failure is also characterized by aggressive neointimal hyperplasia in both animal and human models, seen as early as 1 month in animals 63,71 and 3 months in humans 64,66. The underlying factors

**3.1 Pathology of Hemodialysis Vascular Access Stenosis in AVF and AVG** 

**3.2 Pathophysiologic mechanisms of neointimal hyperplasia formation in** 

endothelin within the media, neointima and adventitia 59-64.

episode 58.

**access dysfunction** 

**hemodialysis access dysfunction** 

neointimal hyperplasia 65.
