Future research directions to improve fistula maturation and reduce access failure

Abstract

With the increasing prevalence of end-stage renal disease, there is a growing need for hemodialysis. Arteriovenous fistulae (AVF) are the preferred type of vascular access for hemodialysis, but maturation and failure continue to present significant barriers to successful fistula use. AVF maturation integrates outward remodeling with vessel wall thickening in response to drastic hemodynamic changes in the setting of uremia, systemic inflammation, oxidative stress, and pre-existent vascular pathology. AVF can fail due to both failure to mature adequately to support hemodialysis and development of neointimal hyperplasia that narrows the AVF lumen, typically near the fistula anastomosis. Failure due to neointimal hyperplasia involves vascular cell activation and migration and extracellular matrix remodeling with complex interactions of growth factors, adhesion molecules, inflammatory mediators, and chemokines, all of which result in maladaptive remodeling. Different strategies have been proposed to prevent and treat AVF failure based on current understanding of the modes and pathology of access failure; these approaches range from appropriate patient selection and use of alternative surgical strategies for fistula creation, to the use of novel interventional techniques or drugs to treat failing fistulae. Effective treatments to prevent or treat AVF failure require a multidisciplinary approach involving nephrologists, vascular surgeons, and interventional radiologists, careful patient selection, and the use of tailored systemic or localized interventions to improve patient-specific outcomes. This review provides contemporary information on the underlying mechanisms of AVF maturation and failure and discusses the broad spectrum of options that can be tailored for specific therapy.

Figure 1

Schematic representation of the venous wall structural changes that occur after AVF creation. AVF successful maturation integrates wall thickening and outward remodeling. A failed AVF can be due to early failure to mature, with failure to develop outward remodeling or wall thickening, or may be due to later development of neointimal hyperplasia and impaired outward remodeling in a previously functional conduit.

Figure 2

Diagram depicting the 3 phases of ECM changes during the adaptive process of AVF maturation. There is an early phase of ECM breakdown from MMP degradation. A transition phase follows with collagen and elastin reorganization of the venous scaffold. A later rebuilding phase strengthens the matrix of the AVF with larger non-collagenous and glycoproteins. TIMP-1, osteopontin and thrombospondin-2 (TSP-2) are highly expressed throughout AVF maturation suggesting regulatory roles for these proteins.