**5.4 Vascular remodeling**

Vascular remodeling, first described by Glagov in 1987, refers to the ability of a vessel to change dimensions by vasoconstriction or vasodilatation, adjusting to flow changes to prevent stenosis. He reported that atherosclerotic arterial lumen narrowing was not simply the result of enlargement of the plaque lesion, but rather the vascular failure of the vessel to remodel to maintain a diameter so as not to inhibit blood flow (Korshunov, 2007). In a fistula, the vein and artery must remodel to a certain degree so as not to develop intimal hyperplasia or fibrosis.

In experimental models, when a fistula is first created, the cross-sectional area of the arterial wall increases with increased elastin, collagen and possibly smooth muscle cells( Driss, 1997). In human studies, this does not occur, but after a year, the artery appears to thicken circumferentially which may lead to defective remodeling (Dammers, 2005). Venous dialation occurs rapidly after the anastomosis due to increased areterial pressure and continues to dilate over several weeks attaining blood flow by 4-6 weeks (Dixon, 2006). Over time, venous thickening occurs and is characterized by intimal hyperplasia, smooth muscle cell proliferation and increased extracellular matrix production (Nath, 2003). If intimal hyperplasia develops and leads to clinically significant stenosis a venogram with angioplasty is usually preformed to dialate the venous stenosis. Early on the lesion may be responsive to angioplasty. At this point, there is no doubt remodeling taking place that is maintaining the diameter of the lumen. Over time with repeated use of the fistula, trauma

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

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

Vascular remodeling, first described by Glagov in 1987, refers to the ability of a vessel to change dimensions by vasoconstriction or vasodilatation, adjusting to flow changes to prevent stenosis. He reported that atherosclerotic arterial lumen narrowing was not simply the result of enlargement of the plaque lesion, but rather the vascular failure of the vessel to remodel to maintain a diameter so as not to inhibit blood flow (Korshunov, 2007). In a fistula, the vein and artery must remodel to a certain degree so as not to develop intimal

In experimental models, when a fistula is first created, the cross-sectional area of the arterial wall increases with increased elastin, collagen and possibly smooth muscle cells( Driss, 1997). In human studies, this does not occur, but after a year, the artery appears to thicken circumferentially which may lead to defective remodeling (Dammers, 2005). Venous dialation occurs rapidly after the anastomosis due to increased areterial pressure and continues to dilate over several weeks attaining blood flow by 4-6 weeks (Dixon, 2006). Over time, venous thickening occurs and is characterized by intimal hyperplasia, smooth muscle cell proliferation and increased extracellular matrix production (Nath, 2003). If intimal hyperplasia develops and leads to clinically significant stenosis a venogram with angioplasty is usually preformed to dialate the venous stenosis. Early on the lesion may be responsive to angioplasty. At this point, there is no doubt remodeling taking place that is maintaining the diameter of the lumen. Over time with repeated use of the fistula, trauma

the time of fistula placement and influence the outcome of the fistula.

**5.2 Histology of the vein** 

**5.3 Geometry** 

stenosis.

**5.4 Vascular remodeling** 

hyperplasia or fibrosis.

and resultant inflammation may develop with repeated interventional angiography ultimately leading to fibrosis of the vein and eventual access failure.

#### **5.5 Oxidative stress and inflammation**

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

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 hyperplasia and fibrosis that may develop.

#### **5.6 Rheology**

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 predicted that these patients have elevated WBV.

 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 subject of future investigation.
