Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis

Abstract

Hemodialysis vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of this vascular access dysfunction is venous stenosis as a result of venous neointimal hyperplasia within the perianastomotic region (arteriovenous fistula) or at the graft-vein anastomosis (polytetrafluoroethylene, or PTFE, grafts). There have been few effective treatments to date for venous neointimal hyperplasia, in part, because of the poor understanding of the pathogenesis of venous neointimal hyperplasia. Therefore, this article will (1) describe the pathology of hemodialysis access stenosis in arteriovenous fistulas and grafts, (2) review and describe both current and novel concepts in the pathogenesis of neointimal hyperplasia formation, (3) discuss current and future novel therapies for treating venous neointimal hyperplasia, and (4) suggest future research areas in the field of hemodialysis vascular access dysfunction.

Figures

Fig 1. Perianastomotic stenosis in an AV Fistula

describes the classic picture of early AV fistula failure with two tight venous stenoses (lower black arrows) in the venous segment of an AV fistula. These lesions are responsible for a very significant morbidity and economic cost. White arrowhead points to the AV anastomosis (courtesy Dr Asif).

Fig 2. Venous neointimal hyperplasia

Figs 2a–d describe H and E (Fig 2a), SMA (Fig 2b), vimentin (Fig 2c) and desmin (Fig 2d) stains on sequential sections of the venous segment of an AV fistula with maturation failure. Note the very significant degree of neointimal hyperplasia (black double headed arrows in Figs 2a and 2b) with relatively less medial hypertrophy (white double headed arrows in Figs 2a and 2b). Note also that while most of the cells within the region of neointimal hyperplasia appear to be SMA +ve, vimentin +ve, desmin −ve myofibroblasts, there are also some SMA +ve, desmin +ve contractile smooth muscle cells present within the neointima (small black arrows in Fig 2d). +ve = positive; −ve = negative (Adapted from Roy-Chaudhury et al. Am J Kidney Dis 2008)

Fig 3. Vascular remodeling versus vessel wall thickening

The top panel in Fig 3 shows a marked increase in lumen size following creation of an AV fistula because of vascular dilatation, despite significant vessel wall thickening/neointimal hyperplasia. In marked contrast the bottom panel documents that even a small amount of vessel wall thickening/neointimal hyperplasia can result in a marked reduction of lumen size if this thickening is accompanied by negative vascular remodeling or vasoconstriction.

Fig 4. Novel local therapies for dialysis access stenosis

Fig 4a shows an endothelial cell loaded gel-foam wrap being placed around the graft-vein anastomosis and proximal venous segment. Fig 4b describes the placement of a paclitaxel eluting wrap around the graft-vein anastomosis. Fig 4c is a diagrammatic representation of the biodegradable reservoir that will be used for VEGF-D gene therapy. Fig 4d is a magnified view of the Adventa® catheter that can deliver therapies to the perivascular region through an endovascular approach.