New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

Abstract

Vascular access dysfunction remains a major cause of morbidity and mortality in hemodialysis patients. At present there are few effective therapies for this clinical problem. The poor understanding of the pathobiology that leads to arteriovenous fistula (AVF) and graft (AVG) dysfunction remains a critical barrier to development of novel and effective therapies. However, in recent years we have made substantial progress in our understanding of the mechanisms of vascular access dysfunction. This article presents recent advances and new insights into the pathobiology of AVF and AVG dysfunction and highlights potential therapeutic targets to improve vascular access outcomes.

Keywords: Arteriovenous access; Arteriovenous fistula; Arteriovenous graft.

Figure 1

Pathophysiologic events of successful arteriovenous fistula (AVF) maturation and AVF maturation failure. Left panel describes events of successful AVF maturation and right panel describes events of AVF maturation failure. Successful AVF maturation is dependent on outward vascular remodeling and inhibition of neointimal hyperplasia, regulated through nitric oxide production and appropriate regulation of matrix metalloproteinases. Fibroblast, smooth muscle cell, and myofibroblast activation, migration and proliferation play a key role in neointimal hyperplasia development and AVF maturation failure. Mediators such as heme-oxygenase-1 (HO-1), monocyte chemoattractant protein (MCP-1), kruppel-like factor-2 (KLF-2), transforming growth factor beta (TGF-β1), and high levels of local oxidant stress (e.g., peroxynitrite), play essential roles in regulating cellular proliferation and neointimal hyperplasia development.

Figure 2

Histologic and angiographic lesions of venous stenosis in arteriovenous fistula (AVF) and arteriovenous graft (AVG). (A) Angiographic and (B) histologic features of AVF nonmaturation. Note aggressive venous neointimal hyperplasia (NH) at vein-artery anastomosis. (C) Angiographic and (D) histologic features of AVG stenosis. Note aggressive neointimal hyperplasia at graft–vein anastomosis. Arrows show the histologic features at the site of the angiographic venous stenosis in both AVF and AVG. Images are alpha-smooth muscle actin stain and magnification is 4X. Adapted and reprinted from reference , with permission.

Figure 3

Potential targets and therapies for hemodialysis vascular access dysfunction. This figure summarizes potential molecular targets and cell-based targets for therapies, and ongoing clinical trials evaluating novel therapies in arteriovenous fistula (AVF) and arteriovenous graft (AVG). HO-1, heme oxygenase-1; HO-2, heme-oxygenase-2; IEX-1, immediate early-response gene X-1; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; NO, nitric oxide; NOS, nitric oxide synthase; VEGF-A, vascular endothelial growth factor-A.

Figure 4

Novel adventitial delivery of vascular endothelial growth factor-A (VEGF-A) via lentivirus system. This figure is a representative example of a novel and local adventitial delivery system focused on inhibiting VEGF-A activity. (A) Anti–VEGF-A inhibitor administered at the adventitia of the arteriovenous fistula (AVF) anastomosis via a lentivirus. (B) therapy reduces tissue VEGF-A activity and matrix metalloproteinase (MMP). (C) Therapy inhibits proliferation and migration of fibroblasts and smooth muscle cells within the adventitia to media and intima layers of AVF. (D) neointimal hyperplasia is reduced in the AVF.