**5. Mechanism of stenosis and thrombosis**

The mechanism responsible for the development of intimal hyperplasia and resultant venous stenosis is poorly understood. Stenosis, leading to thrombosis may require repeated procedures to maintain access patency and is the number one contributor to access failure. Several factors contributing to the development of intimal hyperplasia include: endothelial cell (EC) dysfunction from high blood flow and resultant shear stress; underlying histology of the vein; geometry of the anastomosis and angles of bends in vein; vascular remodeling; oxidative stress and inflammatory mediators that result from the hemodialysis procedure itself, and rheological factors such as viscosity (Table 1). Future studies that look at these factors will guide treatment trials to improve outcomes.


Table 1. Factors influencing Intimal Hyperplasia

#### **5.1 Shear stress**

When a fistula is created a vein is subjected to intense arterial pressure and flow. A vein is asked to behave as an artery perhaps without the anatomic make-up to undergo remodeling. The anatomy and physiology in a native artery is a constructive model to understand the mechanism of stenosis as it applies to venous stenosis in an AVF. A blood vessel is made of endothelial cells (EC) which form the lining of the vessel. These cells are normally aligned longitudinally. Vascular smooth muscle (VSM) cells align around the EC circumferentially. An arteriole has a thicken VSM layer when compared to a vein. Blood flow exerts pressure on the EC in a perpendicular direction. Shear stress is the frictional force per unit area from flowing blood which acts parallel to the EC that line the vessel. In

The creation of a fistula results in blood flow from an artery to a vein that is inherently nonphysiologic in many ways. The initial flow rate in the radial artery of 20-30 mL/min increases to 200-300 mL/min immediately after creation of an AV fistula, reaching flow rates of 600-1200 mL/min after maturation (Wedgewood, 1984). In addition, the blood flow in the vein is not pulsatile prior to fistula insertion, whereas it is after the fistula is created. High fistula blood flow, a prerequisite for venous dilation and a requirement for easy cannulation and adequate dialysis, is accompanied by high arterial pressure being transmitted to the vein. This intense increase in flow rate and pressure has a profound effect on the hemodynamics in the downstream vein (Albayrak, 2006). The dramatically increased arterial blood flow at the time of fistula creation ultimately leads to an overall increase in shear stress, early on an observed low shear stress is evident which is thought to contribute

The mechanism responsible for the development of intimal hyperplasia and resultant venous stenosis is poorly understood. Stenosis, leading to thrombosis may require repeated procedures to maintain access patency and is the number one contributor to access failure. Several factors contributing to the development of intimal hyperplasia include: endothelial cell (EC) dysfunction from high blood flow and resultant shear stress; underlying histology of the vein; geometry of the anastomosis and angles of bends in vein; vascular remodeling; oxidative stress and inflammatory mediators that result from the hemodialysis procedure itself, and rheological factors such as viscosity (Table 1). Future studies that look at these

> **Shear Stress Histology Geometry Vascular Remodeling Oxidative Stress Rheology**

When a fistula is created a vein is subjected to intense arterial pressure and flow. A vein is asked to behave as an artery perhaps without the anatomic make-up to undergo remodeling. The anatomy and physiology in a native artery is a constructive model to understand the mechanism of stenosis as it applies to venous stenosis in an AVF. A blood vessel is made of endothelial cells (EC) which form the lining of the vessel. These cells are normally aligned longitudinally. Vascular smooth muscle (VSM) cells align around the EC circumferentially. An arteriole has a thicken VSM layer when compared to a vein. Blood flow exerts pressure on the EC in a perpendicular direction. Shear stress is the frictional force per unit area from flowing blood which acts parallel to the EC that line the vessel. In

to intimal hyperplasia and resultant venous stenosis and ultimate thrombosis.

**4. Physiology of a fistula access** 

**5. Mechanism of stenosis and thrombosis** 

factors will guide treatment trials to improve outcomes.

Table 1. Factors influencing Intimal Hyperplasia

**5.1 Shear stress** 

straight regions of vessels, blood flow is in the same direction (laminar) and EC are quiescent with high laminar shear stress and resultant low oxidative stress, cell turnover and permeability. When a fistula is created blood vessels divide or curve and complex flow patterns may develop. When this happens EC are subjected to disturbed shear stress with higher levels of oxidative stress and inflammation which may result in vascular remodeling (Hahn, 2009).

The anastomosis of the fistula is also important to the development of intimal hyperplasia. The primary mode of failure of a fistula access relates to outflow stenosis caused by anastomotic intimal hyperplasia. When an anastomosis is created, the trauma causes activation of chemotactic factors which result in smooth muscle migration from the media to the intima. The resultant EC dysfunction with abnormal NO production may cause dysregulation of vascular tone. Smooth muscle cells continue to migrate and proliferate with resultant intimal hyperplasia. The end result may be decreased anastomotic compliance (Lin 2005).

This schematic of this process eventually leading to fistula failure is depicted in Figure 5. When a fistula is placed there is a bend or curve created at the anastomosis. This causes a turbulent blood flow, injury to EC, decreased WSS and resultant intimal hyperplasia. There is flow restriction that results and eventual worsened intimal hyperplasia that leads to further flow restriction with the end result of stenosis. The stenotic surface leads to heamostasis and further thrombus formation. Ultimately the fistula fails as a consequence of the stenosis.

Fig. 5. Proposed cycle of fistula creation which eventually leads to intimal hyperplasia and fistula failure

Hemodialysis Access: The Fistula 27

and resultant inflammation may develop with repeated interventional angiography

When a fistula is placed, matures and is cannulated for hemodialysis an inflammatory environment is created which leads to changes in vascular biology that may contribute to the development of intimal hyperplasia. EC dysfunction from altered shear stress as described above leads to release of nitric oxide and arterial dialation in response to increase flow rates (Dixon, 2009). It has been observed that when arterial dialation occurs, there is continued increase in shear stress that does not always normalize, suggesting that arterial

With evidence of histologic inflammation, there is upregulation of numerous cytokine and genes the cause smooth muscle proliferation and collagen deposition. Histologic injury to the vein is mediated by easly upregulation of mRNA for MCP-1, PAI-1, and endothelin -1 and later upregulation of mRNA for fibrogenic cytokine, transforming growth factor–B. (Dixon 2009). These studies demonstrate that the vein responds to pressure and shear stress by upregulating genes that lead to NIH. Future attempts to decrease these inflammatory mediators with pharmacologic therapy may prove effective to avert the inevitable intimal

Another significant factor which affects blood flow through a fistula is rheology, the characteristics of blood cells. The size, shape, deformeability, aggregation and whole blood viscosity (WBV) of blood have been shown to affect circulatory hemodynamics (Cho, 2008). Increased WBV may be detrimental causing increased peripheral resistance and sludging in post capillary venules (Pop, 2002). Patients with a history of peripheral vascular disease and diabetes, which are common in patients with ESRD, are associated with increased WBV. Over half of patients with ESRD have underlying diabetes and hypertension and it is

 Given that elevated WBV causes impaired circulation, it is likely that rheology, specifically WBV, contributes to the development of fistula stenosis and thrombosis. This area is the

When a patient begins hemodialysis the start of hemodialysis is accompanied with anxiety regarding the surgical placement of the access along with needle cannulation. Excessive dilation of the fistula may be of major concern for patients. These issues should be addressed through education and not prevent patients from receiving the benefits of a well functioning access. The education and timing of the access placement to coincide with the initiation of hemodialysis is of paramount importance. It is imperative that attention to the placement of dialysis access is discussed when it is determined that a patient will need

Once an AVF is surgically placed, it usually takes two months for the vein to mature to allow for cannulation. Although some fistulas mature within weeks, others may require up

ultimately leading to fibrosis of the vein and eventual access failure.

adaptation to fistula creation may be incomplete. (Damers, 2005)

**5.5 Oxidative stress and inflammation** 

hyperplasia and fibrosis that may develop.

predicted that these patients have elevated WBV.

subject of future investigation.

chronic hemodialysis.

**6. Cannulation techniques for AVF** 

**5.6 Rheology** 

#### **5.2 Histology of the vein**

Arterial and venous dialation is critical for fistula maturation. There is no exact definition of fistula maturation, but it is considered mature when it can routinely be cannulated with 2 needles and deliver a minimum blood flow (typically 350 to 450 mL/min) for a total duration of dialysis ( usually 3-5 hours). Impaired dialation may be due to both structural and or functional factors. Pathologic analysis of the muscular artery and cephalic vein from patients with ESRD have demonstrated neo-intimal thickening (Wall, 2006). Other findings include increase radial artery intimal-media thickness which is correlated with decreased fistula maturation (Dixon, 2009). Many of these pathologic findings are present in the vein at the time of fistula placement and influence the outcome of the fistula.

## **5.3 Geometry**

A fistula is created by an anastomosis creating a curve or bend to the vessel. The anastomosis is usually by and end-to-side design but occasionally by a side-to-side design. This creates a change from laminar flow to turbulent flow and as described above, the result is increased shear stress on EC with resultant intimal hyperplasia. This process may also be occurring in native conditions such as occurs in the cephalic arch. Hammes reviewed 45 venograms from BCF access and made measurements of the cephalic arch angle (global) and minimum radius of curvature and cephalic vein diameter (local measurements). Both global and local measurements showed evidence of having two distinct arch angles. Diabetics more commonly had a wider angle and less evidence of cephalic arch stenosis whereas non-diabetics had a wider angle and increased incidence of stenosis. (Hammes, 2009). These findings suggest that geometry influences hemodynamics and resultant stenosis.
