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Background: Although tunneled dialysis catheters (TDC) are far from ideal, they still represent the main form of vascular access for most patients beginning dialysis. Catheters are easy to place and allow patients instant access to dialysis, but regardless of these benefits, catheters are associated with a high incidence of significant complications like bloodstream infections, central venous stenosis, thrombosis, and dysfunction. In the present study, we aim to describe and characterize a swine model of catheter dysfunction and bloodstream infection, that recreates the clinical scenario, to help to serve as a platform to develop therapeutic innovations for this important clinical problem. Methods: Six Yorkshire cross pigs were used in this study. Non-coated commercial catheters were implanted in the external jugular recreating the main features of common clinical practice. Catheters were aseptically accessed twice a week for a mock dialysis procedure (flushing in and out) to assess for and identify catheter dysfunction. Animals were monitored daily for infections; once detected, blood samples were collected for bacterial culture and antibiograms. Study animals were euthanized when nonresponsive to treatment. Tissue samples were collected in a standardized fashion for macroscopic inspection and histological analysis. Results: The data analysis revealed an early onset of infection with a median time to infection of 9 days, 40% of the isolates were polymicrobial, and the average time to euthanasia was 20.16 ± 7.3 days. Median time to catheter dysfunction onset was 6 days post-implantation. Postmortem dissection revealed external fibrin sheath and internal thrombosis as the main causes of catheter dysfunction. There was also evidence of central venous stenosis with positive cells for αSMA, CD68, Ki67, Smoothelin, and Vimentin within the venous neointima. Conclusions: The described model represents a reliable and reproducible large animal model of catheter dysfunction and bloodstream infection, which recreates all the main complications of TDC’s and so could be used as a validated large animal model to develop new therapies for TDC related infection, thrombosis/dysfunction and central venous stenosis.

Stents are widely used as scaffolding to open up blood vessel stenosis. A stent can provide early stage scaffolding, increase blood flow, and optimize hemodynamics. Stainless steel is the most popular material for conventional stents, and it has excellent mechanical behavior during deformation. On the downside, stents made of stainless steel remain in the body permanently and may cause complications or lead to occlusion of the vessel. Biodegradable stents that eventually dissolve and disappear in the body are being developed to overcome these shortcomings. However, biodegradable materials such as magnesium alloys are relatively brittle and cannot deform as much as stainless steel. A proper geometry for the stent that allows large displacement and plastic deformation is necessary and required. In this paper, a balloon-expandable design of magnesium AZ31 alloy venous stent is proposed and evaluated. Computational analysis using finite element analysis (FEA) tools simulated the expansion and recoiling process. The stent was expanded from 6.0 mm to 10.0 mm in the radial direction with the expansion ratio of 1.67. Strain and stress distributions, structural stiffness, and radial strength were studied. The maximum stress did not exceed the ultimate tensile strength (in the plastic region) of the stent material, and the maximum strain was 64% of the elongation. The stent design was then fabricated with methods of electro-discharge machining (EDM), laser machining, and electro-polishing. Lastly, these prototyped stents were prepared for future in-vivo experiment in animal models.

Background: Uremic solutes that accumulate in end-stage renal disease (ESRD) contribute to endothelial dysfunction and subsequent cardiovascular disease in ESRD patients. However, the specific mechanisms which mediate uremia-induced endothelial dysfunction in ESRD are not understood. Kruppel-like factors (KLFs) are important regulators of endothelial homeostasis which may be affected by the uremic milieu. In this study, we examined the role and regulation of endothelial KLF2 in mediating endothelial dysfunction in the setting of uremia. Methods and Results: First, we assessed the impact of the uremic milieu on endothelial gene expression utilizing serum from uremic and non-uremic pigs with chronic renal insufficiency. We demonstrate that KLF2 expression was dose-dependently decreased with uremic serum in human umbilical vein endothelial cells (HUVECS) versus normal serum which was reversed by prolonged serum dialysis or the application of laminar shear stress. Carboxymethyl-lysine (CML) modified albumin, a uremic advanced glycation end-product (AGE), also inhibited KLF2 expression. This effect was completely abrogated by receptor for AGE (RAGE) siRNA, as well as by a constitutively active form of IκBα, implicating a role for RAGE activation and the NF-κB signaling pathway. KLF2 suppression also promoted endothelial dysfunction in vitro, as adenoviral overexpression of KLF2 inhibited reactive oxygen species production and leukocyte adhesion in HUVECs treated with uremic serum or CML-AGE. For in vivo translation, we utilized high-frequency ultrasound and quantified flow-mediated dilation of the femoral artery in endothelial-specific KLF2 conditional knockout (cKO) mice after 5 minutes of hindlimb ischemia and demonstrated a 50% reduction in vasodilation in KLF2 cKO mice compared to controls. The lack of femoral artery vasodilation in KLF2 cKO mice was also accompanied by attenuated return of wall shear stress to baseline independent of blood velocity. Conclusions: Collectively, these observations implicate loss of endothelial KLF2 as mediator of endothelial dysfunction in the setting of uremia and suggest that elevating KLF2 expression may be a novel strategy for prevention and treatment of cardiovascular disease in ESRD.

Background Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation. Study Design Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study. Setting & Participants 491 patients with single-stage AVFs who had neither thrombosis nor AVF intervention before a 6-week postoperative ultrasonographic examination and who required maintenance hemodialysis. Predictors Postoperative care processes and complications. Outcomes Attempted cannulation, successful cannulation, and unassisted and overall clinical maturation as defined by the HFM Study criteria. Results AVF cannulation was attempted in 443 of 491 (90.2%) participants and was eventually successful in 430 of these 443 (97.1%) participants. 263 of these 430 (61.2%) reached unassisted and 118 (27.4%) reached assisted AVF maturation (overall maturation, 381/430 [88.6%]). Attempted cannulation was less likely in patients of surgeons with policies for routine 2-week versus later-than-2-week first postoperative visits (OR, 0.21; 95% CI, 0.06-0.70), routine second postoperative follow-up visits (OR, 0.39; 95% CI, 0.15-0.97), and a routine clinical postoperative ultrasound (OR, 0.28; 95% CI, 0.14-0.55). Attempted cannulation was also less likely among patients undergoing procedures to assist maturation (OR, 0.51; 95% CI, 0.27-0.98). Unassisted maturation was more likely for patients treated in facilities with access coordinators (OR, 1.91; 95% CI, 1.17-3.12), but less likely after precannulation nonstudy ultrasounds (OR per ultrasound, 0.42 [95% CI, 0.26-0.68]) and initial unsuccessful cannulation attempts (OR per each additional attempt, 0.90 [95% CI, 0.83-0.98]). Overall maturation was less likely with infiltration before successful cannulation (OR, 0.44; 95% CI, 0.22-0.89). Among participants receiving maintenance hemodialysis before AVF surgery, unassisted and overall maturation were less likely with longer intervals from surgery to initial cannulation (ORs for each additional month of 0.81 [95% CI, 0.76-0.88] and 0.93 [95% CI, 0.89-0.98], respectively) and from initial to successful cannulation (ORs for each additional week of 0.87 [95% CI, 0.81-0.94] and 0.88 [95% CI, 0.83-0.94], respectively). Limitations Surgeons' management policies were assessed only by questionnaire at study onset. Most participants received upper-arm AVFs, planned 2-stage AVFs were excluded, and maturation time windows were imposed. Some care processes may have been missed and the observational design limits causal attribution. Conclusions Multiple processes of care and complications are associated with AVF maturation outcomes.

Remodeling in the arteriovenous fistulas (AVFs) is believed to be a hemodynamic-driven process, which results in extreme changes in the diameter and intima-media thickening (IMT) of vessels over time. This study aims to describe the successful development of techniques that enabled correlation of changes in local and longitudinal wall shear stress (WSS) with the temporal variations of the diameter and IMT in the venous segment of AVFs. An AVF was created between the femoral artery and vein of a 50-kg pig. We have previously shown the successful use of CT-scan and ultrasound techniques for anatomical and flow measurements in AVFs, respectively. In this study, we developed new techniques involving markers (both in vivo and ex vivo), casting (ex vivo), and micro-MRI (ex vivo; 7 Tesla). A radiopaque marker (ROM) was sutured to the AVF at the day of surgery, which was visible in the CT-scan images, micro-MRI, and histology sections. Therefore, ROM served as a fixed local reference for both in vivo and ex vivo states of AVFs. Immediately after sacrificing the pig, a procedure was developed to create a cast from the AVF and thus, maintaining the in vivo state of the AVF during the histology process. Then, micro-MRI and histology techniques were conducted on the AVF to measure IMT in the vein. Along the ROM, the local changes in WSS levels for two cross-sections were tracked at 2D (D: days) and 28D post surgery. WSS levels reduced from 2D to 28D for both cross-sections. Also, the recirculation zones, which formed at 2D for both sections, became smaller in size at 28D. These hemodynamic changes were then mapped onto the corresponding IMT measurements from histology and micro-MRI. It was observed that the recirculation zones at 2D and 28D corresponded to the largest IMT in the two sections. In summary, the new methodologies allowed us to define a fixed local reference at all time points in the AVF, which enabled accurate tracking of local changes in hemodynamics (WSS), configuration (diameter), and structure (IMT) of the venous segment over time. This also empowered study of the interactions between these parameters, which could improve our understanding about the hemodynamic-driven remodeling in AVFs. From a clinical point of view, this information could be translated into local and early therapeutic interventions for dialysis patients.

Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF maturation failure remains a huge clinical problem, often resulting in a prolonged duration of use of tunneled dialysis catheters. In contrast, polytetrafluoroethylene (PTFE) grafts do not suffer from early failure, but have significant problems with later stenosis and thrombosis. This review will initially summarize the pathology and pathogenesis of PTFE graft dysfunction and will then use this as a basis for describing some novel therapies, which may have the potential to reduce PTFE graft dysfunction. Finally, we will emphasize that the introduction of such therapies could be an important first step toward individualizing overall vascular access care.

Arteriovenous fistula (AVF) maturation failure is currently a huge clinical problem. One approach to enhance the AVF maturation rate is an aggressive sequence of balloon angioplasty procedures, often known as balloon-assisted maturation. The goal of the current paper is to explore the pros and cons of this procedure and to try and better identify its impact on AVF maturation.

Although the arteriovenous fistula (AVF) is the preferred mode of dialysis vascular access, AVF maturation failure remains a huge clinical problem, often resulting in a prolonged duration of use of tunneled dialysis catheters. In contrast, polytetrafluoroethylene (PTFE) grafts do not suffer from early failure, but have significant problems with later stenosis and thrombosis. This review will initially summarize the pathology and pathogenesis of PTFE graft dysfunction and will then use this as a basis for describing some novel therapies, which may have the potential to reduce PTFE graft dysfunction. Finally, we will emphasize that the introduction of such therapies could be an important first step toward individualizing overall vascular access care.