Novel paradigms for dialysis vascular access: downstream vascular biology--is there a final common pathway?

Abstract

Vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of vascular access dysfunction is venous stenosis from neointimal hyperplasia within the perianastomotic region of an arteriovenous fistula and at the graft-vein anastomosis of an arteriovenous graft. There have been few, if any, effective treatments for vascular access dysfunction because of the limited understanding of the pathophysiology of venous neointimal hyperplasia formation. This review will (1) describe the histopathologic features of hemodialysis access stenosis; (2) discuss novel concepts in the pathogenesis of neointimal hyperplasia development, focusing on downstream vascular biology; (3) highlight future novel therapies for treating downstream biology; and (4) discuss future research areas to improve our understanding of downstream biology and neointimal hyperplasia development.

Figure 1.

Natural history of vascular access dysfunction. Natural history of vascular access dysfunction is defined by a series of progressive vascular injuries. (A) Vein specimen from a patient without CKD. (B) Vein specimen from a patient with stage V CKD receiving new vascular access. (C) Vein specimen from a failed arteriovenous fistula (AVF) at 3 months. (D) Vein specimen from a failed and stenotic AVF after angioplasty procedure. Note progression in venous neointimal hyperplasia development with vascular injury. Part D reproduced from reference 13, with permission. (A) Alpha-smooth muscle cell actin (SMA) x4; (B) SMA x10; (C) SMA x4; (D) SMA x20.

Figure 2.

Histologic and angiographic lesion of venous stenosis in arteriovenous fistula (AVF) and arteriovenous graft (AVG). (A) and (B) represent angiography and histology of AVF nonmaturation. Note aggressive venous neointimal hyperplasia (NH). (C) and (D) represent angiography and histology of AVG stenosis. Note aggressive neointimal hyperplasia at graft-vein anastomosis. Angiographic figures courtesy of Tuschar Vachharajani. Histologic figures courtesy of Prabir Roy-Chaudhury. (A and B) Alpha-smooth muscle cell actin (SMA) x4.

Figure 3.

Upstream and downstream events in hemodialysis vascular access dysfunction. Upstream events result in initial vascular injury. Downstream events are the vascular biologic response to upstream injury. Downstream biology involves mediators of oxidative stress and inflammation that regulate activation, proliferation, and migration of fibroblasts, smooth muscle cells, and myofibroblasts. PTFE, polytetrafluoroethylene.

Figure 4.

Unifying pathway for downstream vascular biology. Heme oxygenase-1 (HO-1) plays a major adaptive and protective role to prevent vascular access dysfunction through its regulation of monocyte chemoattractant protein (MCP-1) and other oxidative stress mediators, such as matrix metalloproteinases (MMP-2 and MMP-9) and peroxynitrite. Increased expression and production of MCP-1 and MMPs and peroxynitrite play an important role in neointimal hyperplasia development. Regulation of MCP-1 expression appears to depend on the level of expression of HO-1 and endothelial nitric oxide synthase. HO-1 may inhibit oxidative stress and inflammation following hemodynamic injury and nitric oxide inhibits endothelial dysfunction that may proceed from oxidative stress and inflammation. Inadequate regulation of these inflammatory and oxidative stress mediators results in a cascade of events leading to activation and proliferation of fibroblasts, myofibroblasts, and smooth muscle cells, and subsequently production of neointimal hyperplasia.