Burnett S. Kelly

Hemodialysis Vascular Access Dysfunction: From Pathophysiology to Novel Therapies

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of over USD 1 billion per annum. Most hemodialysis grafts fail due to a venous stenosis (venous neointimal hyperplasia) which then results in thrombosis of the graft. Despite the magnitude of the clinical problem there are currently no effective therapies for this condition. The current review (a) describes the pathogenesis and pathology of venous stenosis in dialysis access grafts and (b) discusses the development and application of novel therapeutic interventions for this difficult clinical problem. Special emphasis is laid on the fact that PTFE dialysis access grafts could be the ideal clinical model for testing out novel local therapies to block neointimal hyperplasia.

Novel Therapies for Hemodialysis Vascular Access Dysfunction: Fact or Fiction!

Hemodialysis vascular access dysfunction is a major cause of morbidity in the hemodialysis population and contributes significantly to the overall cost of end-stage renal disease programs. At a histological level, most hemodialysis vascular access dysfunction (in both native arteriovenous fistulae and PTFE dialysis access grafts) is due to venous stenosis and thrombosis, secondary to venous neointimal hyperplasia. However, despite a wealth of experimental and clinical data on the use of novel therapeutic interventions that target neointimal hyperplasia in the setting of coronary artery disease, there are unfortunately no effective therapeutic interventions for hemodialysis vascular access dysfunction at the present time. This is particularly unfortunate, since neointimal hyperplasia in the setting of hemodialysis vascular access fistulae and grafts could be the ideal clinical model to test novel therapeutic interventions for neointimal hyperplasia.

Development of a local perivascular paclitaxel delivery system for hemodialysis vascular access dysfunction: polymer preparation and in vitro activity.

Hemodialysis vascular access dysfunction (HVAD) is currently a huge clinical problem. The major cause of HVAD is venous stenosis (as a result of venous neointimal hyperplasia) which leads to thrombosis in polytetrafluoroethylene dialysis access grafts and fistulae. Despite the magnitude of the clinical problem there are currently no effective therapeutic interventions for this condition. In an attempt to reduce the morbidity associated with HVAD, we have developed and validated a local perivascular paclitaxel release system for use in a pig model of arteriovenous graft stenosis. Ethylene vinyl acetate polymers with 5% paclitaxel were formulated. The release profile of paclitaxel was then manipulated to maximize its biological impact in the in vivo situation. In vitro experiments were performed to confirm that the paclitaxel released from the polymer was biologically active against cell types that were similar to those present in the in vivo lesion of neointimal hyperplasia. Our results demonstrate that the paclitaxel polymer wraps which we have developed are mechanically stable with a burst release phase followed by a slower continuous release phase. The paclitaxel released from these polymeric wraps retains its physicochemical and biological properties and is able to inhibit the proliferation of smooth muscle cells, endothelial cells and fibroblasts in vitro. We believe that these paclitaxel-loaded polymeric wraps could be ideally suited for perivascular drug delivery in the context of dialysis access grafts and fistulae.

In vitro Paclitaxel and Radiation Effects on the Cell Types Responsible for Vascular Stenosis: A Preliminary Analysis

Hemodialysis vascular access dysfunction as a result of venous neointimal hyperplasia in dialysis access grafts and fistulae is currently a huge clinical problem. The aim of this study was to assess the effects of paclitaxel and radiation, both singly and in combination on the proliferation of cell types present within the lesion of venous neointimal hyperplasia (vascular smooth muscle cells, fibroblasts and endothelial cells within the neointimal microvessels). Vascular smooth muscle cells, fibroblasts and endothelial cells were plated onto 96-well plates and exposed to different concentrations and doses of paclitaxel and radiation, respectively (both individually and in combination). Growth inhibition was assessed with an MTT assay. Both paclitaxel and radiation resulted in significant growth inhibition of all three cell types. However, even small doses of paclitaxel appeared to attenuate the antiproliferative effect of radiation on these cell types. Further experiments to elucidate the mechanism behind these findings could result in a better understanding of combination antiproliferative therapies.

External beam radiation therapy for PTFE dialysis grafts: a pilot study

Purpose The aim of this study was to identify the effects of external beam radiation on PTFE dialysis graft dysfunction. Methods Seven patients who underwent PTFE dialysis graft angioplasty were randomized to receive either two 8 Gy doses of external beam radiation or no radiation. The primary endpoint was time to graft thrombosis with a secondary endpoint of time to first intervention. Results There was no statistically significant difference between the two groups in either of the endpoints, although grafts in the radiation group had a shorter time to thrombosis or intervention. Conclusions Our results demonstrate technical feasibility for use of external beam radiation in the setting of dialysis vascular access graft dysfunction. Larger randomized studies are required to identify whether there is a clinical benefit from this intervention.

Abstracts from the Society of Black Academic SurgeonsA pig model of venous neoinitimal hyperplasia in polytetrafluoroethylene dialysis grafts1

Abstract Purpose: Vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. In the United States,

A pig model of venous neoinitimal hyperplasia in polytetrafluoroethylene dialysis grafts 1 1The Society of Black Academic Surgeons expresses its appreciation to Dr. Walter Pories and the editorial staff of Current Surgery for their interest in the Society and the publication of these abstracts.

1 billion per year is spent managing the vascular complications of hemodialysis. Venous neointimal hyperplasia (VNH), with subsequent venous stenosis and thrombosis at the graft-vein anastomosis, constitutes 75% of failed polytetrafluoroethylene vascular grafts. To understand both the pathogenesis and potential therapeutic interventions of VNH, we have validated a model of arteriovenous graft stenosis in pigs. Methods: Goretex loop grafts, 7 cm long × 4 mm ID, were placed bilaterally from the femoral artery to the femoral vein in 12 pigs, using standard operative vascular techniques. Grafts were harvested at 2-, 4-, 7-, 14-, and 28-day time points, and H&E-stained specimens were evaluated for neointimal encroachment into the graft. Immunohistochemistry was performed to demonstrate the expression of factor VIII, smooth muscle α-actin, and Ki67 (a marker of cell proliferation). Results: Venous neointimal hyperplasia was present postoperatively within 14 days at the graft-vein anastomosis and within the proximal vein. It was characterized by prominent angiogenesis within the thickened neointima, a perigraft macrophage layer, extracellular matrix components, and the proliferation of smooth muscle cells and myofibroblasts. Conclusion: The pathognomonic features of VNH visualized in the pig specimens are similar to those identified in human hemodialysis patients, which demonstrates the clinical relevance of this model. Each of these characterized lesions represents a potential site for novel prophylactic and therapeutic interventions, which will diminish the significant human and economic costs associated with dialysis graft dysfunction.

A pig model of venous neoinitimal hyperplasia in polytetrafluoroethylene dialysis grafts1

Abstract Purpose: Vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. In the United States,

Venous neointimal hyperplasia in polytetrafluoroethylene dialysis grafts

1 billion per year is spent managing the vascular complications of hemodialysis. Venous neointimal hyperplasia (VNH), with subsequent venous stenosis and thrombosis at the graft-vein anastomosis, constitutes 75% of failed polytetrafluoroethylene vascular grafts. To understand both the pathogenesis and potential therapeutic interventions of VNH, we have validated a model of arteriovenous graft stenosis in pigs. Methods: Goretex loop grafts, 7 cm long × 4 mm ID, were placed bilaterally from the femoral artery to the femoral vein in 12 pigs, using standard operative vascular techniques. Grafts were harvested at 2-, 4-, 7-, 14-, and 28-day time points, and H&E-stained specimens were evaluated for neointimal encroachment into the graft. Immunohistochemistry was performed to demonstrate the expression of factor VIII, smooth muscle α-actin, and Ki67 (a marker of cell proliferation). Results: Venous neointimal hyperplasia was present postoperatively within 14 days at the graft-vein anastomosis and within the proximal vein. It was characterized by prominent angiogenesis within the thickened neointima, a perigraft macrophage layer, extracellular matrix components, and the proliferation of smooth muscle cells and myofibroblasts. Conclusion: The pathognomonic features of VNH visualized in the pig specimens are similar to those identified in human hemodialysis patients, which demonstrates the clinical relevance of this model. Each of these characterized lesions represents a potential site for novel prophylactic and therapeutic interventions, which will diminish the significant human and economic costs associated with dialysis graft dysfunction.

Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis

Abstract Purpose: Vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population. In the United States,