Hemodialysis Vascular Access Dysfunction: A Cellular and Molecular Viewpoint

Abstract

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. The major cause of hemodialysis vascular access dysfunction is venous stenosis as a result of neointimal hyperplasia. Despite the magnitude of the clinical problem, however, there has been a paucity of novel therapeutic interventions in this field. This is in marked contrast to a recent plethora of targeted interventions for the treatment of arterial neointimal hyperplasia after coronary angioplasty. The reasons for this are two-fold. First there has been a relative lack of cellular and molecular research that focuses on venous neointimal hyperplasia in the specific setting of hemodialysis vascular access. Second, there have been inadequate efforts by the nephrology community to translate the recent advances in molecular and interventional cardiology into therapies for hemodialysis vascular access. This review therefore (1) briefly examines the different forms of hemodialysis vascular access that are available, (2) describes the pathology and pathogenesis of hemodialysis vascular access dysfunction in both polytetrafluoroethylene grafts and native arteriovenous fistulae, (3) reviews recent concepts about the pathogenesis of vascular stenosis that could potentially be applied in the setting of hemodialysis vascular access dysfunction, (4) summarizes novel experimental and clinical therapies that could potentially be used in the setting of hemodialysis vascular access dysfunction, and, finally, (5) offers some broad guidelines for future innovative translational and clinical research in this area that hopefully will reduce the huge clinical morbidity and economic costs that are associated with this condition.

Thrombophilia and Arteriovenous Fistula Survival in ESRD

“…In fact, in the United States the annual costs of access failure are approximately $1 billion (1). The main causes of access dysfunction-thrombosis and stenosisare associated with vascular injury and intimal hyperplasia caused by high-shear-rate conditions in the access (2,3).…”

Far-Infrared Therapy

“…An access flow (Qa), Ͻ500 ml/min was associated with an increased risk for access failure and predictive of poorer unassisted patency of native AVF (4). The pathologic features of stenosis of vascular access are composed of intimal hyperplasia, proliferation of smooth muscle cells in the media with subsequent migration to intima, and excessive accumulation of extracellular matrix (5). Despite these findings, little information is available on how to prevent effectively the stenoses of vascular access in HD patients.…”

Novel Paradigms for Dialysis Vascular Access

“…Upstream events are the initial vascular injuries responsible for endothelial and smooth muscle cell injury, which lead to a cascade of mediators (downstream events) that regulate mediators of oxidative stress and inflammation and ultimately result in venous neointimal hyperplasia (8,24) (Figure 3). Common upstream events involved in the pathogenesis of neointimal hyperplasia development include (1) surgical trauma at the time of AV surgery, causing vasospasm and ischemia to the vessel; (2) hemodynamic sheer stress at the vein-artery or vein-graft anastomosis, resulting in low sheer stress and turbulent flow; (3) bioincompatibility in polytetrafluoroethylene grafts; (4) vessel injury from routine needle cannulations; (5) uremia resulting in endothelial dysfunction; and (6) repeated balloon angioplasties to repair venous stenosis causing further endothelial injury, as well as smooth muscle injury within the media.…”

“…The advantages and rationale behind local therapies in dialysis access (8,24), specifically perivascular therapy, are that (1) drug delivery targets the adventitia and may block adventitial activation and fibroblast migration; (2) small amounts of potentially toxic drugs can be delivered to the site of stenosis without concerns of systemic toxicity; and (3) local therapies, tested in dialysis access patients, who are a captive audience, can be an ideal model for testing perivascular therapies in other diseases, such as coronary artery disease and peripheral artery disease because these therapies can be applied at the time of surgery. Two recent examples of perivascular-delivered therapies include (1) endothelial cell-loaded gel foam wraps and (2) recombinant elastase therapy.…”