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Purpose: Hemodialysis vascular access dysfunction is an enormous clinical problem that causes great morbidity and costs well over one billion dollars per annum. The vast majority of hemodialysis vascular access dysfunction occurs as a result of venous stenosis and thrombosis at the graft-vein anastomosis. At a cellular level, this venous stenosis is the result of venous neointimal hyperplasia (VNH). There are, unfortunately, no effective therapies for VNH. The purpose of this study was to assess the role of external radiation therapy in preventing VNH and venous stenosis., Methods and Materials: Seven-centimeter polytetrafluoroethylene loop grafts were placed bilaterally between the femoral artery and vein of 12 Yorkshire Cross pigs. One side was treated with a single 16-Gy dose of external beam radiation with a linear accelerator, while the contralateral side served as an internal control. Swine were killed after 28 days, and the grafts were carefully dissected out and removed. Neointimal hyperplasia and luminal stenosis were then assessed morphometrically at the graft-vessel anastomoses., Results: External beam radiation therapy significantly reduced the amount of luminal stenosis at the graft-vein anastomosis, with minimal local and systemic toxicity., Conclusions: External beam radiation therapy could be a useful and clinically relevant local treatment for venous stenosis in polytetrafluoroethylene dialysis grafts.

Background: In view of the superior T-cell depletion and prolonged half-life of thymoglobulin, we initiated a protocol to administer thymoglobulin intermittently based on peripheral blood CD3+ lymphocyte counts., Methods: In this prospective study, 41 consecutive high-risk cadaver transplant recipients (panel reactive antibody level >30%, repeat transplant recipients, simultaneous pancreas and kidney or pancreas after kidney recipients, prolonged cold-ischemia time, prolonged donor hypotension, non-heart-beating donors) who received thymoglobulin induction therapy were included. The first dose (1.5 mg/kg) of thymoglobulin was administered intraoperatively. CD3+ lymphocyte count in the peripheral blood was determined daily and repeat doses were administered when the CD3+ count was >20 cells/mm3. Calcineurin inhibitors (CI) in low doses were introduced when the allograft function recovered and the serum creatinine level dropped by at least 25% from the pretransplant level. Thymoglobulin treatment was discontinued once therapeutic CI drug levels were achieved. Concomitant immunosuppression consisted of mycophenolate mofetil and prednisone., Results: The mean individual thymoglobulin dose was 104 mg (1.4 mg/kg), and the total cumulative dose per patient was 318 mg (4.2 mg/kg). Patients received an average of three doses and a mean of six CD3 counts were obtained per patient. Introduction of CI was delayed for an average of 6 days posttransplantation. At a mean follow-up of 340 days, two (4.9%) patients died; three (7.3%) renal allografts and two (18.2%) pancreas allografts were lost. Five (12.2%) patients developed a total of six acute rejection episodes. The mean serum creatinine in the 38 patients with a functioning kidney was 1.47 mg/dl, and the mean blood glucose in the 9 pancreas allograft recipients was 89 mg/dl. Cytomegalovirus (CMV) infection occurred in one (2.4%) patient. No posttransplant lymphoproliferative disorders were seen in this patient cohort. The hospital pharmacy charge for a 100-mg dose of thymoglobulin at this center was $2,165, and the laboratory charge for a single CD3 determination was $70. In this study, the average charges per patient for the total dose of thymoglobulin and six CD3 determinations were $7305. In comparison, the charge for daily administration of 104 mg of thymoglobulin (which was the mean dose) for 6 days (mean time to CI therapy initiation) would be $13,510 and for 10 days (mean time to therapeutic CI levels) would be $22,516. This represents a savings of 46% and 68%, respectively., Conclusions: Intermittent thymoglobulin therapy, based on peripheral blood CD3+ lymphocyte counts, is safe and associated with low acute rejection rate in high-risk kidney and kidney-pancreas transplant recipients. A mean of three doses resulted in adequate suppression of CD3+ lymphocytes permitting delayed introduction of CI in low doses until recovery of renal function occurred. When compared to traditional daily administration, intermittent therapy results in significant cost savings and reduces the total cumulative dose of this potent immunosuppressive agent.

Hemodialysis vascular access dysfunction is a major cause of morbidity and hospitalization in the hemodialysis population at a cost of over 1 billion dollars per annum. Venous stenosis and thrombosis as a result of venous neointimal hyperplasia are the major causes of hemodialysis vascular access dysfunction. Despite the magnitude of the clinical problem, there are currently no effective therapies for this condition. We believe that this could be because of an inadequate understanding of the pathogenesis of this condition. At a histological level, venous neointimal hyperplasia (both in human specimens and in a pig model) is characterized by the presence of smooth muscle cells/myofibroblasts, microvessel formation (angiogenesis), and the accumulation of extracellular matrix components, all of which could be potential targets for therapeutic intervention. In particular, polytetrafluoroethylene dialysis access grafts could be the ideal clinical model for testing out novel local therapies to block neointimal hyperplasia. The current review describes the lesion of venous neointimal hyperplasia in human samples and in a pig model and suggests possible future directions for the development of effective local therapies for this condition., (Copyright 2002 by the National Kidney Foundation, Inc.)