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1.  Adventitial Endothelial Implants Reduce Matrix Metalloproteinase-2 Expression and Increase Luminal Diameter in Porcine Arteriovenous Grafts 
Vascular access dysfunction is a major problem in hemodialysis patients, only 50% of arteriovenous grafts (AVG) will remain patent 1 year after surgery. AVG frequently develop stenoses and occlusions at the venous anastomoses, in the venous outflow tract. Lumen diameter is determined not only by intimal thickening but is also influenced by remodeling of the vessel wall. Vascular remodeling requires degradation and reorganization of the extracellular matrix by the degradation enzymes, matrix metalloproteinases (MMPs). In this study, we aimed to provide further insight into the mechanism of endothelial regulation of vascular remodeling and luminal narrowing in AVG.
End-to-side carotid artery-jugular vein polytetrafluoroethylene grafts were created in twenty domestic swine. The anastomoses and outflow vein were treated with Gelfoam® matrices containing allogeneic porcine aortic endothelial cells (PAE, n=10) or control matrices without cells (n=10) and the biological responses to PAE implants investigated 3 and 28-days postoperatively. Pre-sacrifice angiograms were evaluated in comparison to baseline angiograms. Tissue sections were stained with hematoxylin & eosin, Verhoeff’s elastin as well and antibodies specific to MMP-9 and MMP-2 and subjected to histopathological, morphometric and immunohistochemical analysis.
Veins treated with PAE implants had a 2.8-fold increase in venous lumen diameter compared to baseline (P<.05), a 2.3-fold increase in lumen diameter compared to control and an 81% decrease in stenosis (P<.05) compared to control at 28-days. The increase in lumen diameter by angiographic analysis correlated with morphometric analysis of tissue sections. PAE implants increased venous lumen area 2.3 fold (P < .05), decreased venous luminal occlusion 66%, and increased positive venous remodeling 1.9 fold (P< .05) compared to control at 28-days. PAE implants reduced MMP-2 expression at 3 and 28 days, neovascularization at 3 and 28-days and adventitial fibrosis at 28-days, suggesting a role of the implants in controlling the affects of medial and adventitial cells in the response to vascular injury.
These results demonstrate that the adventitial application of endothelial implants significantly reduced MMP-2 expression within the venous wall, increased venous lumen diameter and positive remodeling in a porcine arteriovenous graft model. Adventitial endothelial implants may be useful in decreasing luminal narrowing in a clinical setting.
Clinical Relevance
Vascular access dysfunction is the leading cause of hospitalization and morbidity in patients receiving hemodialysis for end-stage renal disease. Data indicate that the majority of AVG fail due to the formation of stenosis at the vein-graft anastomotic and venous outflow sites. The stenoses result in luminal narrowing and subsequent graft thrombosis and failure. A satisfactory long term pharmacologic means of preventing stenosis due to intimal hyperplasia in hemodialysis grafts has yet to be found. In a large animal model of AVG we show that placement of an adventitial endothelial implant significantly increased venous lumen diameter at 28-days.
PMCID: PMC2702136  PMID: 17826244
2.  Preliminary comparative study of small amplitude helical and conventional ePTFE arteriovenous shunts in pigs 
Intimal hyperplasia (IH), which causes occlusion of arterial bypass grafts and arteriovenous (A-V) shunts, develops preferentially in low wall shear, or stagnation, regions. Arterial geometry is commonly three-dimensional, generating swirling flows, the characteristics of which include in-plane mixing and inhibition of stagnation. Clinical arterial bypass grafts are commonly two-dimensional, favouring extremes of wall shear. We have developed small amplitude helical technology (SwirlGraft) devices and shown them to generate physiological-type swirling flows. Expanded polytetrafluorethylene (ePTFE) grafts, although widely used as A-V shunts for renal dialysis access, are prone to thrombosis and IH. In a small preliminary study in pigs, we have implanted SwirlGraft ePTFE carotid artery-to-jugular vein shunts on one side and conventional ePTFE carotid artery-to-jugular vein shunts contralaterally. There was consistently less thrombosis and IH in the SwirlGraft than conventional shunts. At eight weeks (two animals), the differences were marked, with virtually no disease in the SwirlGraft devices and occlusion of the conventional grafts by thrombosis and IH. The study had limitations, but the lesser pathology in the SwirlGraft devices is likely to have resulted from their geometry and the associated swirling flow. The results could have implications for vascular biology and prolongation of the patency of arterial bypass grafts and A-V shunts.
PMCID: PMC1629072  PMID: 16849184
three-dimensional vascular geometry; swirling flow; physiological-type swirling flow; intimal hyperplasia; stagnation regions; swirl induced mixing
3.  Accumulation of retained nonfunctional arteriovenous grafts correlates with severity of inflammation in asymptomatic ESRD patients 
The contribution of multiple retained nonfunctional arteriovenous grafts (AVGs) to the burden of chronic inflammation in chronic hemodialysis patients has not been well studied. Here, we sought to evaluate the association between plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and albumin and the number of retained nonfunctional AVGs.
This cross-sectional study enrolled 91 prevalent patients undergoing in-center hemodialysis without evidence of infection or inflammation. A baseline blood sample was obtained at study enrollment. A general linear model (GLM) was used to compare levels of biomarkers of systemic inflammation across groups defined by the number of retained, nonfunctional AVGs.
A total of 43 patients had one or more retained thrombosed AVG and had significantly greater plasma log-CRP levels compared with patients without a previous AVG (P= 0.036), regardless of the current AV access type. Using a GLM, we found that for every additional retained thrombosed AVG, plasma log-CRP, log-IL-6 and TNF-alpha concentrations increased significantly by 0.30 mg/L (P= 0.011), 0.18 pg/mL (P= 0.046) and 0.72 pg/mL (P= 0.046), respectively, following adjustment.
Hence, the severity of inflammation increases with the number of retained nonfunctional AVG's, suggesting that AVG accumulation may contribute to the cardiovascular morbidity and mortality associated with chronic inflammation in asymptomatic end-stage renal disease (ESRD) patients. Further study is indicated to determine whether patients with one or more thrombosed, retained AVG may benefit from periodic screening with CRP monitoring to identify those patients who may benefit from AVG resection.
PMCID: PMC3611890  PMID: 23090982
AVG; ESRD; hemodialysis; inflammation
4.  Correlation of Pre-existing Vascular Pathology With Arteriovenous Graft Outcomes in Hemodialysis Patients 
Arteriovenous grafts (AVGs) are prone to neointimal hyperplasia leading to AVG failure. We hypothesized that pre-existing pathologic abnormalities of the vessels used to create AVG (including venous intimal hyperplasia, arterial intimal hyperplasia, arterial medial fibrosis, and arterial calcification) are associated with inferior AVG survival.
Study Design
Prospective observational study.
Setting & Participants
Patients with chronic kidney disease undergoing placement of a new AVG at a large medical center who had vascular specimens obtained at the time of surgery (n=76)
Maximal intimal thickness of the arterial and venous intima, arterial medial fibrosis, and arterial medial calcification.
Outcome & Measurements
Unassisted primary AVG survival (time to first intervention) and frequency of AVG interventions.
55 patients (72%) underwent interventions and 148 graft interventions occurred during 89.9 years of follow-up (1.65 interventions per graft-year). Unassisted primary AVG survival was not significantly associated with arterial intimal thickness (HR, 0.72; 95% CI, 0.40-1.27; p=0.3), venous intimal thickness (HR, 0.64; 95% CI, 0.37-1.10; p=0.1), severe arterial medial fibrosis (HR, 0.58; 95% CI, 0.32-1.06; p=0.6), or severe arterial calcification (HR, 0.68; 95% CI, 0.37-1.31; p=0.3). The frequency of AVG interventions per year was inversely associated with arterial intimal thickness (relative risk [RR], 1.99; 95% CI, 1.16-3.42; p<0.001 for thickness <10 vs >25 μm); venous intimal thickness (RR, 2.11; 95% CI, 1.39-3.20; p<0.001 for thickness <5 vs >10 μm); arterial medial fibrosis (RR, 3.17; 95% CI, 1.96-5.13; p<0.001 for fibrosis <70% vs ≥70%), and arterial calcification (RR, 2.12; 95% CI, 1.31-3.43; p=0.001 for <10% vs ≥10% calcification).
Single center study. Study may be underpowered to demonstrate differences in unassisted primary AVG survival.
Pre-existing vascular pathologic abnormalities in CKD patients may not be significantly associated with unassisted primary AVG survival. However, vascular intimal hyperplasia, arterial medial fibrosis, and arterial calcification may be associated with a decreased frequency of AVG interventions.
PMCID: PMC3778052  PMID: 23746379
5.  Hemodynamic Shear Stress and Endothelial Dysfunction in Hemodialysis Access 
The open urology & nephrology journal  2014;7(Suppl 1 M5):33-44.
Surgically-created blood conduits used for chronic hemodialysis, including native arteriovenous fistulas (AVFs) and synthetic AV grafts (AVGs), are the lifeline for kidney failure patients. Unfortunately, each has its own limitations: AVFs often fail to mature to become useful for dialysis and AVGs often fail due to stenosis as a result of neointimal hyperplasia, which preferentially forms at the graft-venous anastomosis. No clinical therapies are currently available to significantly promote AVF maturation or prevent neointimal hyperplasia in AVGs. Central to devising strategies to solve these problems is a complete mechanistic understanding of the pathophysiological processes. The pathology of arteriovenous access problems is likely multi-factorial. This review focuses on the roles of fluid-wall shear stress (WSS) and endothelial cells (ECs). In arteriovenous access, shunting of arterial blood flow directly into the vein drastically alters the hemodynamics in the vein. These hemodynamic changes are likely major contributors to non-maturation of an AVF vein and/or formation of neointimal hyperplasia at the venous anastomosis of an AVG. ECs separate blood from other vascular wall cells and also influence the phenotype of these other cells. In arteriovenous access, the responses of ECs to aberrant WSS may subsequently lead to AVF non-maturation and/or AVG stenosis. This review provides an overview of the methods for characterizing blood flow and calculating WSS in arteriovenous access and discusses EC responses to arteriovenous hemodynamics. This review also discusses the role of WSS in the pathology of arteriovenous access, as well as confounding factors that modulate the impact of WSS.
PMCID: PMC4189833  PMID: 25309636
Arteriovenous fistula; Arteriovenous grafts; Hemodialysis vascular access; Hemodynamics; Endothelial cells; Shear stress
6.  The Primary Patency of Percutaneous Transluminal Angioplasty in Hemodialysis Patients With Vascular Access Failure 
Korean Circulation Journal  2011;41(9):512-517.
Background and Objectives
Dysfunction of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs) contributes significantly to morbidity and hospitalization in the dialysis population. We evaluated the primary patency of AVFs following percutaneous transluminal angioplasty (PTA) in haemodialysis patients.
Subjects and Methods
We performed 231 interventions in 118 patients with a mean age of 62.1±12.9 years. We performed 122 interventions in 53 AVG patients (44.9%), and 109 interventions in 65 AVF patients (55.1%). If there was thrombosis of the vascular access, urokinase was administered and/or thrombus aspiration was performed. The stent was inserted when balloon dilatation did not expand sufficiently or elastic recoil occurred.
For the 118 patients, the median patency time was 10.45±10.29 months at 92 months of follow-up. The primary patencies for stenotic AVFs at 6, 12, 24, 36, 48, and 60 months were 63.4%, 41.4%, 17.0%, 9.7%, 7.3%, and 2.4%, respectively. The primary patencies for AVGs at 6, 12, 24, and 36 months were 36.9%, 19.5%, 10.8%, 2.1%, respectively, and were obtained by means of the Kaplan-Meier analysis (log rank=6.42, p<0.05). The median patency time was 11.0 months and 4.45 months in the non-thrombus and thrombus groups, respectively. The complication rate was 1.73% (4/231); two cases of pseudoaneurysms and two cases of extravasation were detected. All therapy failures (5/231) occurred in thrombotic lesions of AVGs and were treated surgically.
PTA is an efficacious method for the correction of stenosis of AVFs for hemodialysis, thus prolonging the patency of the fistulas.
PMCID: PMC3193042  PMID: 22022326
Arteriovenous fistulas; Percutaneous transluminal angioplasty; Dialysis
7.  Brachial Artery Ligation with Total Graft Excision is a Safe and Effective Approach to Prosthetic Arteriovenous Graft Infections 
Journal of vascular surgery  2008;48(3):655-658.
While autogenous arteriovenous access is preferred, prosthetic arteriovenous grafts (AVG) are still required in a large number of patients. Infection of AVGs occurs frequently and may cause life-threatening bleeding or sepsis. Multiple treatment strategies have been advocated (ranging from graft preservation to excision with complex concomitant reconstructions), indicating a lack of consensus on appropriate management of infected AVGs. We undertook this study to evaluate if, in the setting of anastomotic involvement, brachial artery ligation distal to the origin of the deep brachial artery accompanied by total graft excision (BAL) is safe and effective.
All prosthetic arteriovenous graft infections managed by a single surgeon between 1995 and 2006 were reviewed retrospectively. Patients were identified from a computerized vascular registry and data were obtained via patient charts and the electronic medical record.
We identified 45 AVG infections in 43 patients. Twenty-one patients (49%) demonstrated arterial anastomotic involvement and were treated with BAL; these form the cohort for this analysis. Mean patient age was 53.2 (SD 9.5) years. The primary etiologies for ESRD were hypertension (29%), HIV (24%), and diabetes (19%). An upper arm AVG was present in 95% of patients; one (5%) had a forearm AVG. The majority of grafts were PTFE (90%). Follow-up was 100% at 1 month, 86% at 3 months, and 67% at 6 months. No ischemic or septic complications occurred in the 21 patients who underwent BAL.
BAL is an effective and expeditious method to deal with an infected arm AVG in frequently critically ill patients with densely scarred wounds. In the short term, BAL appears to be well tolerated without resulting ischemic complications. Further study with longer duration of follow-up is necessary to ascertain whether BAL results in definitive cure, or whether patients may ultimately manifest ischemic changes and require additional intervention.
PMCID: PMC3616396  PMID: 18572370
8.  Outcomes of Endovascular Intervention for Salvage of Failing Hemodialysis Access 
Annals of Vascular Diseases  2011;4(2):87-92.
Objective: To investigate the effectiveness of endovascular balloon angioplasty to preserve the patency of failing hemodialysis arteriovenous fistulas (AVF) and prosthetic arteriovenous grafts (AVG).
Methods: Patients on hemodialysis who received endovascular intervention for access problems were retrospectively analyzed. Fistulography was performed on patients who were suspected to have access stenosis and balloon angioplasty performed in the same setting if a stenosis of ≥50% is detected. Patients were followed up for post-operative complications and access restenosis or failure.
Results: 42 hemodialysis patients with 44 access sites (29 AVFs, 15 AVGs) required endovascular balloon angioplasty. There were no perioperative complications. Technical success rate was 100%. Median time from initial access creation to first balloon angioplasty was 13 months (2–146 months) for AVFs and 8 months (2–71 months) for AVGs. 19 of 44 patients subsequently developed restenosis. Median time for restenosis or access failure was 11 months (1–18 months) for AVFs and 5 months (1–10 months) for AVGs. Kaplan-Meier analysis for access patency after endovascular intervention showed 72% patency at 6 months and 32% at 12 months.
Conclusions: Endovascular balloon angioplasty is effective in restoring patency of failing hemodialysis accesses. Recurrence is common, and repeat interventions are required.
PMCID: PMC3595831  PMID: 23555435
angioplasty; arteriovenous fistula; arteriovenous graft; renal failure; hemodialysis
9.  Variable Lipoprotein Genes of Mycoplasma agalactiae Are Activated In Vivo by Promoter Addition via Site-Specific DNA Inversions  
Infection and Immunity  2003;71(7):3821-3830.
Mycoplasma agalactiae, the etiological agent of contagious agalactia of small ruminants, has a family of related genes (avg genes) which encode surface lipoprotein antigens that undergo phase variation. A series of 13 M. agalactiae clonal isolates, obtained from one chronically infected animal over a period of 7 months, were found to undergo major rearrangement events within the avg genomic locus. We show that these rearrangements regulate the phase-variable expression of individual avg genes. Northern blot analysis and reverse transcription-PCR showed that only one avg gene is transcribed, while the other avg genes are transcriptionally silent. Sequence analysis and primer extension experiments with two M. agalactiae clonal isolates showed that a specific 182-bp avg 5′ upstream region (avg-B2) that is present as a single chromosomal copy serves as an active promoter and exhibits a high level of homology with the vsp promoter of the bovine pathogen Mycoplasma bovis. PCR analysis showed that each avg gene is associated with the avg-B2 promoter in a subpopulation of cells that is present in each subclone. Multiple sequence-specific sites for DNA recombination (vis-like), which are presumably recognized by site-specific recombinase, were identified within the conserved avg 5′ upstream regions of all avg genes and were found to be identical to the recombination sites of the M. bovis vsp locus. In addition, a gene encoding a member of the integrase family of tyrosine site-specific recombinases was identified adjacent to the variable avg locus. The molecular genetic basis for avg phase-variable expression appears to be mediated by site-specific DNA inversions occurring in vivo that allow activation of a silent avg gene by promoter addition. A model for the control of avg genes is proposed.
PMCID: PMC162021  PMID: 12819065
10.  Efficacy of SMART Stent Placement for Salvage Angioplasty in Hemodialysis Patients with Recurrent Vascular Access Stenosis 
Vascular access stenosis is a major complication in hemodialysis patients. We prospectively observed 50 patients in whom 50 nitinol shape-memory alloy-recoverable technology (SMART) stents were used as salvage therapy for recurrent peripheral venous stenosis. Twenty-five stents each were deployed in native arteriovenous fistula (AVF) and synthetic arteriovenous polyurethane graft (AVG) cases. Vascular access patency rates were calculated by Kaplan-Meier analysis. The primary patency rates in AVF versus AVG at 3, 6, and 12 months were 80.3% versus 75.6%, 64.9% versus 28.3%, and 32.3% versus 18.9%, respectively. The secondary patency rates in AVF versus AVG at 3, 6, and 12 months were 88.5% versus 75.5%, 82.6% versus 61.8%, and 74.4% versus 61.8%, respectively. Although there were no statistically significant difference in patency between AVF and AVG, AVG showed poor tendency in primary and secondary patency. The usefulness of SMART stents was limited in a short period of time in hemodialysis patients with recurrent vascular access stenosis.
PMCID: PMC3227441  PMID: 22164331
11.  Prevention of Arteriovenous Shunt Occlusion Using Microbubble and Ultrasound Mediated Thromboprophylaxis 
Palliative shunts in congenital heart disease patients are vulnerable to thrombotic occlusion. High mechanical index (MI) impulses from a modified diagnostic ultrasound (US) transducer during a systemic microbubble (MB) infusion have been used to dissolve intravascular thrombi without anticoagulation, and we sought to determine whether this technique could be used prophylactically to reduce thrombus burden and prevent occlusion of surgically placed extracardiac shunts.
Methods and Results
Heparin‐bonded ePTFE tubular vascular shunts of 4 mm×2.5 cm (Propaten; W.L Gore) were surgically placed in 18 pigs: a right‐sided side‐to‐side arteriovenous (AV, carotid‐jugular) shunt, and a left‐sided arterio‐arterial (AA, carotid‐carotid) interposition shunt in each animal. After shunt implantation, animals were randomly assigned to one of 3 groups. Transcutaneous, weekly 30‐minute treatments (total of 4 treatments) of either guided high MI US+MB (Group 1; n=6) using a 3% MRX‐801 MB infusion, or US alone (Group 2; n=6) were given separately to each shunt. The third group of 6 pigs received no treatments. The shunts were explanted after 4 weeks and analyzed by histopathology to quantify luminal thrombus area (mm2) for the length of each shunt. No pigs received antiplatelet agents or anticoagulants during the treatment period. The median overall thrombus burden in the 3 groups for AV shunts was 5.10 mm2 compared with 4.05 mm2 in AA (P=0.199). Group 1 pigs had significantly less thrombus burden in the AV shunts (median 2.5 mm2) compared with Group 2 (median 5.6 mm2) and Group 3 (median 7.5 mm2) pigs (P=0.006). No difference in thrombus burden was seen between groups for AA shunts.
Transcutaneous US with intravenous MB is capable of preventing thrombus accumulation in arteriovenous shunts without the need for antiplatelet agents, and may be a method of preventing progressive occlusion of palliative shunts.
PMCID: PMC3959668  PMID: 24518555
pediatric; shunt thrombosis; sonothrombolysis; therapeutic ultrasound
12.  Transient Elastic Support for Vein Grafts Using a Constricting Microfibrillar Polymer Wrap 
Biomaterials  2008;29(22):3213-3220.
Arterial vein grafts (AVGs) often fail due to intimal hyperplasia, thrombosis, or accelerated atherosclerosis. Various approaches have been proposed to address AVG failure, including delivery of temporary mechanical support, many of which could be facilitated by peri-vascular placement of a biodegradable polymer wrap. The purpose of this work was to demonstrate that a polymer wrap can be applied to vein segments without compromising viability/function, and to demonstrate one potential application; i.e., gradually imposing the mid-wall circumferential wall stress (CWS) in wrapped veins exposed to arterial levels of pressure.
Poly(ester urethane)urea, collagen, and elastin were combined in solution, and then electrospun onto freshly-excised porcine internal jugular vein segments. Tissue viability was assessed via Live/Dead™ staining for necrosis, and vasomotor-challenge with epinephrine and sodium nitroprusside for functionality. Wrapped vein segments were also perfused for 24-hrs within an ex vivo vascular perfusion system under arterial conditions (pressure=120/80 mmHg; flow=100 mL/min), and CWS was calculated every hour.
Our results showed that the electrospinning process had no deleterious effects on tissue viability, and that the mid-wall CWS vs. time profile could be dictated through the composition and degradation of the electrospun wrap. This may have important clinical applications by enabling the engineering of an improved AVG.
PMCID: PMC2486447  PMID: 18455787
Electrospinning; Vein Graft; Intimal Hyperplasia; Vein Wrap
13.  A Novel Ovine ex vivo Arteriovenous Shunt Model to Test Vascular Implantability 
Cells, Tissues, Organs  2011;195(1-2):108-121.
The major objective of successful development of tissue-engineered vascular grafts is long-term in vivo patency. Optimization of matrix, cell source, surface modifications, and physical preconditioning are all elements of attaining a compatible, durable, and functional vascular construct. In vitro model systems are inadequate to test elements of thrombogenicity and vascular dynamic functional properties while in vivo implantation is complicated, labor-intensive, and cost-ineffective. We proposed an ex vivo ovine arteriovenous shunt model in which we can test the patency and physical properties of vascular grafts under physiologic conditions. The pressure, flow rate, and vascular diameter were monitored in real-time in order to evaluate the pulse wave velocity, augmentation index, and dynamic elastic modulus, all indicators of graft stiffness. Carotid arteries, jugular veins, and small intestinal submucosa-based grafts were tested. SIS grafts demonstrated physical properties between those of carotid arteries and jugular veins. Anticoagulation properties of grafts were assessed via scanning electron microscopy imaging, en face immunostaining, and histology. Luminal seeding with endothelial cells greatly decreased the attachment of thrombotic components. This model is also suture free, allowing for multiple samples to be stably processed within one animal. This tunable (pressure, flow, shear) ex vivo shunt model can be used to optimize the implantability and long-term patency of tissue-engineered vascular constructs.
PMCID: PMC3325602  PMID: 22005667
Animal model; Cardiovascular endothelium; Cardiovascular system; Mechanobiology; Methods of evaluation; Tissue engineering; Vascular biology; Small intestinal submucosa; Thrombogenicity
14.  Patterns of Use of Vascular Catheters for Hemodialysis in Children in the United States 
Arteriovenous fistulas and grafts (AVF/AVG) have been associated with improved clinical outcomes in children and adults with end-stage renal disease (ESRD) on maintenance hemodialysis (HD), but the use of vascular catheters is high. Identifying the reasons for the high prevalence of vascular catheters in children on HD is necessary to assess whether targeted interventions may increase the prevalence of AVF/AVG’s.
Study Design
Retrospective cohort study.
Setting & Participants
Children younger than 18 years on HD in the 2001–2003 ESRD Clinical Performance Measures (CPM) Projects followed in the United States Renal Data System transplant files through December 31, 2004.
Vascular access type and reasons for use of a vascular catheter.
Outcomes & Measurements
Demographic/clinical characteristics, including the reason provided for use of a vascular catheter, and the association of type of vascular access and: {1}patient size, and {2} time to kidney transplantation.
Of 1,284 prevalent pediatric CPM patients examined, 529 (41%) had an AVF/AVG and 755 (59%) had a vascular catheter. Among the 755 children with a catheter, “small body size” was a commonly listed reason (N=142); 49% of these children weighed 20 kilograms or more. Among the 53 patients with catheters described as having an “AVF/AVG maturing” and present in the consecutive ESRD CPM project year, 64% had a functioning AVF/AVG the following year. For those with “transplant scheduled” listed as a reason for a vascular catheter (N=83), 69% were transplanted within 1 year and the median time to transplant was 115 days. Among all children with vascular catheters (N=755), 32.2% were transplanted within 1 year, and the median time to transplant was 264 days, compared to 21.7% and 347 days, respectively, for those with AVF/AVG’s (N=529). Among the 445 incident children in this cohort, 89% had a vascular catheter at dialysis initiation.
Because of study design, only associations can be described.
Vascular catheter use among children on HD is high. This is partially explained by expeditious transplantation and technical barriers to AVF/AVG placement in small children, however only one third of patients with a vascular catheter were transplanted within 1 year. Interventions to decrease vascular catheter use in this population may be necessary.
PMCID: PMC2630524  PMID: 18950912
Pediatric; end-stage renal disease; hemodialysis; vascular access; vascular catheter; transplantation
15.  Early Vascular Access Blood Flow as a Predictor of Long-term Vascular Access Patency in Incident Hemodialysis Patients 
Journal of Korean Medical Science  2010;25(5):728-733.
The long-term clinical benefits of vascular access blood flow (VABF) measurements in hemodialysis (HD) patients have been controversial. We evaluated whether early VABF may predict long-term vascular access (VA) patency in incident HD patients. We enrolled 57 patients, of whom 27 were starting HD with arteriovenous fistulas (AVFs) and 30 with arteriovenous grafts (AVGs). The patients' VABF was measured monthly with the ultrasound dilution technique over the course of the first six months after the VA operation. During the 20.4-month observational period, a total of 40 VA events in 23 patients were documented. The new VA events included 13 cases of stenosis and 10 thrombotic events. The lowest quartile of average early VABF was related to the new VA events. After adjusting for covariates such as gender, age, hypertension, diabetes, VA type, hemoglobin levels, body mass index, parathyroid hormone, and calcium-phosphorus product levels, the hazard ratio of VABF (defined as <853 mL/min in AVF or <830 mL/min in AVG) to incident VA was 3.077 (95% confidence interval, 1.127-8.395; P=0.028). There were no significant relationships between early VABF parameters and VA thrombosis. It is concluded that early VABF may predict long-term VA patency, particularly VA stenosis.
PMCID: PMC2858832  PMID: 20436709
Renal Dialysis; Blood Flow Velocity; Vascular Patency; Indicator Dilution Techniques
16.  Access surgery for hemodialysis in the Cayman Islands: Preliminary results of a vascular access service 
In the Cayman Islands, a vascular access service was created in 2005 to facilitate the creation of vascular access for hemodialysis by local surgeons. The present retrospective audit aims to establish the outcomes of this practice in the Cayman Islands.
Data from the operative log of the Cayman Islands Hospital was collected over a period of 36 months. The data were analyzed using SPSS version 12.0 (SPSS Inc, USA). Statistical analyses were performed using Student’s t tests and Fisher’s exact tests.
A total of 19 operative procedures were performed to create vascular accesses in 12 men and seven women. Thirteen procedures (68%) created autogenous arteriovenous fistulas (AVFs) and six (32%) involved the insertion of a prosthetic arteriovenous graft (AVG). There were six incident dialysis patients, all of whom had an AVF created. The remaining 13 prevalent dialysis patients had new accesses in the form of AVFs (n=7) or AVGs (n=6).
The statistical analyses were limited by sample size, but with AVFs, there were trends toward reduced incidence of secondary failure (four of 13 versus four of six), thrombosis (four of 13 versus two of six), infectious morbidity (zero versus two of six) and less demand for interventions to maintain patency (one of 13 versus two of six) with AVFs. There were also trends toward superior primary (461 days versus 227 days) and secondary (803 days versus 205 days) patency rates for AVFs.
In this setting, the rate of AVF creation exceeds the goals set by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative and the Fistula First Breakthrough Initiative. To ensure continued delivery of modern quality care, further audits of the local practice will be required at regular intervals.
PMCID: PMC2780858  PMID: 22477497
Arteriovenous fistula; Arteriovenous graft; Hemodialysis; Vascular access
17.  Endovascular treatment of stent fracture and pseudoaneurysm formation in arteriovenous fistula dialysis access 
Arteriovenous fistulae (AVF) and grafts (AVG) for hemodialysis access generally provide good long-term solutions for the patient with end-stage renal disease. However, complications of both AVGs and AVFs are common and require a multimodality approach to maintain their patency and continued use. Commonly encountered problems include stenosis, thrombosis, aneurysm or pseudoaneurysm formation, rupture, and infection. Each needs to be addressed on a case-by-case basis. Outflow stenosis, often occurring within the cephalic arch in patients with a brachiocephalic fistula, may occur alone or be discovered in conjunction with other access problems. Pseudoaneurysm of the venous end generally arises from traumatic weakening of the vessel wall, often from repetitive venipuncture. More rare is the fracture of a previously placed stent. We present a case of stent fracture complicated by pseudoaneurysm formation with concomitant stenosis of the cephalic arch treated successfully with single-procedure placement of endovascular stent grafts.
PMCID: PMC3523770  PMID: 23382614
18.  Patient-Derived Endothelial Progenitor Cells Improve Vascular Graft Patency in Rodent Model 
Acta biomaterialia  2011;8(1):201-208.
Late outgrowth endothelial progenitor cells (EPCs) derived from the peripheral blood of patients with significant coronary artery disease were sodded into the lumens of small diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts. Grafts (1 mm inner diameter) were denucleated and sodded either with native EPCs or with EPCs transfected with an adenoviral vector containing the gene for human thrombomodulin (EPC+AdTM). EPC+AdTM was shown to increase the in vitro rate of graft activated protein C (APC) production 4-fold over grafts sodded with untransfected EPCs (p<0.05). Unsodded control and EPC-sodded and EPC+AdTM-sodded grafts were implanted bilaterally into the femoral arteries of athymic rats for 7 or 28 days. Unsodded control grafts, both with and without denucleation treatment, each exhibited 7-day patency rates of 25%. Unsodded grafts showed extensive thrombosis and were not tested for patency over 28 days. In contrast, grafts sodded with untransfected EPCs or EPC+AdTM both had 7-day patency rates of 88-89% and 28-day patency rates of 75-88%. Intimal hyperplasia was observed near both the proximal and distal anastomoses in all sodded graft conditions but did not appear to be the primary occlusive failure event. This in vivo study suggests autologous EPCs derived from the peripheral blood of patients with coronary artery disease may improve the performance of synthetic vascular grafts, although no differences were observed between untransfected EPCs and TM transfected EPCs.
PMCID: PMC3226906  PMID: 21945828
19.  The comparison of the complications of axillobrachial and femorofemoral arteriovenous shunt prostheses in hemodialysis, a 3 year study in Alzahra general hospital 
This study was performed to compare the outcome and complications of axillobrachial and femorofemoral graft as upper and lower limb arteriovenous shunt prostheses.
Materials and Methods:
In a prospective cohort study, we observed and followed-up all cases with a new insertion of ePTFE between February 2006 and February 2009. Assessment of patency and the complication rates of their prostheses were the essential parts of this observation.
In a prospective cohort study, we observed and followed-up all cases with a new insertion of ePTFE between February 2006 and February 2009. Assessment of patency and the complication rates of their prostheses were the essential parts of this observation.
A total of 69 grafts were performed. Forty-nine of them were successfully followed-up (18 femorofemoral and 31 axillobrachial grafts). Immediate primary patency was 100%. For axillobrachial type, primary patency at 1, 3, and 6 months, respectively, was 86%, 60%, and 47%. Secondary patency at 1, 3, and 6 months was 86%, 75%, and 50%, respectively. For femorofemoral type, primary patency at 1, 3, and 6 months, respectively, was 88%, 40%, and 34%. Secondary patency at 1, 3, and 6 months was 94%, 47%, and 41%, respectively. (P > 0.05) Complications included a puncture-site hematoma, thrombosis, infection, venous hypertension, need of an excision and pseudoaneurysm formation. Pseudoaneurysm rate difference between the two groups was interestingly significant, while others were relatively similar; however, the rates were different.
The significant difference of aneurysm rate among our two groups, besides the insignificant difference of other complications and also the similar primary and secondary patency rates, manifest a brilliant guidance chart for the surgeons in order to choose the most compatible site for inserting ePTFE grafts (Gore-tex) as arteriovenous shunt prostheses for HD accessing.
PMCID: PMC3814544  PMID: 24223384
Axillobrachial; end-stage renal disease; femorofemoral; Gore-tex; polytetrafluoroethylene
20.  Infected Prosthetic Dialysis Arteriovenous Grafts: A Single Dialysis Center Study 
Surgical Infections  2012;13(6):366-370.
The prosthetic arteriovenous grafts (AVG) being used increasingly to create hemodialysis access are prone to infections that pose potentially life-threatening infectious and bleeding complications, as well as loss of dialysis access. In this study, we identified the bacteriologic agents of infected AVGs by site swab, blood culture, and prosthesis cultures, and to evaluate the role of microbiological findings in the management of the infection.
We focused on 51 patients with 53 AVGs operated on in our clinic from January 2006 to December 2009. An infected AVG was identified by clinical, ultrasound, and microbiological findings. Sensitivity to antibiotics was determined for all bacterial strains. Isolates were identified by pulsed-field gel electrophoresis (PFGE) of bacterial DNA. In a few cases, positron emission tomography-computed tomography (PET-CT) examination was performed.
Strains of Staphylococcus spp., especially S. aureus, were the most frequent cause of infected AVG. All S. aureus strains were sensitive to methicillin. With the exception of a single case, isolates obtained simultaneously from the skin site and the vascular prosthesis were identical genetically.
Our results suggest that bacterial infectious agents detected in site swab, blood, or graft culture confirm a suspicion of AVG infection. A PET-CT examination can provide confirmation. The combination of microbiologic and radionuclide findings can improve the management of the AVG infection, but surgery remains essential.
PMCID: PMC3532001  PMID: 23216527
21.  Cerebrovascular Accident Secondary to Paradoxical Embolism Following Arteriovenous Graft Thrombectomy 
Case reports in nephrology  2012;2012:183730.
Thrombectomy is a common procedure performed to declot thrombosed dialysis arteriovenous fistula (AVF) or arteriovenous graft (AVG). Complications associated with access thrombectomy like pulmonary embolism have been reported, but paradoxical embolism is extremely rare. We report a case of a 74-year-old black man with past medical history significant for end-stage renal disease (ESRD), atrial fibrillation on anticoagulation with warfarin, who presented to our hospital with lethargy, aphasia, and right-sided hemiparesis following thrombectomy of a clotted AVG. Computed tomography (CT) scan of brain showed a hypodensity within the left posterior parietal lobe. INR was 2.0 on admission. Echocardiogram revealed a normal sized left atrium with no intracardiac thrombus, and bubble study showed the presence of right-to-left shunting. These findings suggest that the stroke occurred as a result of an embolus originating from the AVG. Paradoxical cerebral embolism is uncommon but can occur after thrombectomy of clotted vascular access in ESRD patients. Clinicians and patients should be aware of this serious and potentially fatal complication of vascular access procedure.
PMCID: PMC3914183  PMID: 24533201
22.  Adventitial transplantation of blood outgrowth endothelial cells in porcine haemodialysis grafts alleviates hypoxia and decreases neointimal proliferation through a matrix metalloproteinase-9-mediated pathway—a pilot study 
Purpose. We hypothesized that adventitial transplantation of blood outgrowth endothelial cells (BOEC) to the vein-to-graft anastomosis of polytetrafluoroethylene grafts will reduce neointimal hyperplasia by reducing hypoxia inducible factor-1α (HIF-1α), by increasing angiogenesis in a porcine model of chronic renal insufficiency with haemodialysis polytetrafluoroethylene grafts. Because matrix metalloproteinases (MMPs) have been shown to be involved with angiogenesis, the expression of MMPs and their inhibitors was determined.
Methods. Chronic renal insufficiency was created by subtotal renal infarction and 28 days later, arteriovenous PTFE grafts were placed bilaterally from the carotid artery to the jugular vein. Autologous blood outgrowth endothelial cells labeled with Lac Z were transplanted to the adventitia of the vein-to-graft anastomosis using polyglycolic acid scaffolding and scaffolding only to other side (control). Animals were killed 14 days later and vessels were explanted from the vein-to-graft anastomosis of both sides and underwent immunohistochemical analysis, western blotting and zymography for HIF-1α, MMP-2, MMP-9, TIMP-1 and TIMP-2. BOEC were also made hypoxic and normoxic for 12, 24 and 48 h to determine protein expression for MMPs and TIMPs.
Results. Under hypoxia, BOEC significantly increased the expression of pro MMP-2 by 12 h and TIMP-2 by 24 h when compared to normoxic cells (P < 0.05). Transplantation of BOEC resulted in a significant decrease in both HIF-1α and intima-to-media ratio with a significant increase in both pro and active MMP-9 when compared to control vessels (P < 0.05). MMP-9 activity was localized to the neointima of the transplanted vessels by immunohistochemistry. There was increased CD31 density with engraftment of BOEC cells into the neointima of both the transplanted vessels compared to controls (P = NS).
Conclusion. Transplantation of BOEC resulted in a significant decrease in intimal hyperplasia and HIF-1α with a significant increase in both pro and active MMP-9 that was localized to the neointima of transplanted vessels. The increase in MMP-9 offers a possible mechanism for angiogenesis and the reduced intima-to-media ratio. Furthermore, we observed that BOEC had homed to the neointima of the contralateral vessels that had increased levels of HIF-1α, suggesting that hypoxia may be an important stimulus for BOEC migration.
PMCID: PMC2639314  PMID: 18786975
blood outgrowth endothelial cells; haemodialysis graft failure; hypoxia; restenosis; vascular biology
23.  The Initial Vascular Access Type Contributes to Inflammation in Incident Hemodialysis Patients 
Background. The contribution of the hemodialysis (HD) vascular access type to inflammation is unclear. Methods. We conducted a prospective observational study in an incident HD population. C-reactive protein (CRP), interleukin-6 (IL-6), and interferon-γ-induced protein (IP-10) were measured before and at 6-time points after access placement for 1 year. Results. Sixty-four incident HD patients were included (tunneled catheter (TC), n = 40, arteriovenous fistula (AVF), n = 14, and arteriovenous graft (AVG), n = 10). A mixed effects model was performed to adjust for age, sex, race, coronary artery disease, diabetes mellitus, infections, access thrombosis, initiation of HD, and days after access surgery. In comparison to AVFs, the presence of a TC was associated with significantly higher levels of CRP (P = 0.03), IL-6 (P = 0.07), and IP-10 (P = 0.03). The presence of an AVG was associated with increases in CRP (P = 0.01) and IP-10 (P = 0.07). Conclusions. Patients who initiate HD with a TC or an AVG have a heightened state of inflammation, which may contribute to the excess 90-day mortality after HD initiation.
PMCID: PMC3202132  PMID: 22121485
24.  Computational model of blood flow in the aorto-coronary bypass graft 
Coronary artery bypass grafting surgery is an effective treatment modality for patients with severe coronary artery disease. The conduits used during the surgery include both the arterial and venous conduits. Long- term graft patency rate for the internal mammary arterial graft is superior, but the same is not true for the saphenous vein grafts. At 10 years, more than 50% of the vein grafts would have occluded and many of them are diseased. Why do the saphenous vein grafts fail the test of time? Many causes have been proposed for saphenous graft failure. Some are non-modifiable and the rest are modifiable. Non-modifiable causes include different histological structure of the vein compared to artery, size disparity between coronary artery and saphenous vein. However, researches are more interested in the modifiable causes, such as graft flow dynamics and wall shear stress distribution at the anastomotic sites. Formation of intimal hyperplasia at the anastomotic junction has been implicated as the root cause of long- term graft failure.
Many researchers have analyzed the complex flow patterns in the distal sapheno-coronary anastomotic region, using various simulated model in an attempt to explain the site of preferential intimal hyperplasia based on the flow disturbances and differential wall stress distribution. In this paper, the geometrical bypass models (aorto-left coronary bypass graft model and aorto-right coronary bypass graft model) are based on real-life situations. In our models, the dimensions of the aorta, saphenous vein and the coronary artery simulate the actual dimensions at surgery. Both the proximal and distal anastomoses are considered at the same time, and we also take into the consideration the cross-sectional shape change of the venous conduit from circular to elliptical. Contrary to previous works, we have carried out computational fluid dynamics (CFD) study in the entire aorta-graft-perfused artery domain. The results reported here focus on (i) the complex flow patterns both at the proximal and distal anastomotic sites, and (ii) the wall shear stress distribution, which is an important factor that contributes to graft patency.
The three-dimensional coronary bypass models of the aorto-right coronary bypass and the aorto-left coronary bypass systems are constructed using computational fluid-dynamics software (Fluent 6.0.1). To have a better understanding of the flow dynamics at specific time instants of the cardiac cycle, quasi-steady flow simulations are performed, using a finite-volume approach. The data input to the models are the physiological measurements of flow-rates at (i) the aortic entrance, (ii) the ascending aorta, (iii) the left coronary artery, and (iv) the right coronary artery.
The flow field and the wall shear stress are calculated throughout the cycle, but reported in this paper at two different instants of the cardiac cycle, one at the onset of ejection and the other during mid-diastole for both the right and left aorto-coronary bypass graft models. Plots of velocity-vector and the wall shear stress distributions are displayed in the aorto-graft-coronary arterial flow-field domain. We have shown (i) how the blocked coronary artery is being perfused in systole and diastole, (ii) the flow patterns at the two anastomotic junctions, proximal and distal anastomotic sites, and (iii) the shear stress distributions and their associations with arterial disease.
The computed results have revealed that (i) maximum perfusion of the occluded artery occurs during mid-diastole, and (ii) the maximum wall shear-stress variation is observed around the distal anastomotic region. These results can enable the clinicians to have a better understanding of vein graft disease, and hopefully we can offer a solution to alleviate or delay the occurrence of vein graft disease.
PMCID: PMC555577  PMID: 15745458
25.  Modelling ultrasound-induced mild hyperthermia of hyperplasia in vascular grafts 
Expanded polytetrafluoroethylene (ePTFE) vascular grafts frequently develop occlusive neointimal hyperplasia as a result of myofibroblast over-growth, leading to graft failure. ePTFE exhibits higher ultrasound attenuation than native soft tissues. We modelled the selective absorption of ultrasound by ePTFE, and explored the feasibility of preventing hyperplasia in ePTFE grafts by ultrasound heating. Specifically, we simulated the temperature profiles of implanted grafts and nearby soft tissues and blood under ultrasound exposure. The goal was to determine whether ultrasound exposure of an ePTFE graft can generate temperatures sufficient to prevent cell growth on the graft without damaging nearby soft tissues and blood.
Ultrasound beams from two transducers (1.5 and 3.2 MHz) were simulated in two graft/tissue models, with and without an intra-graft cellular layer mimicking hyperplasia, using the finite-difference time-domain (FDTD) method. The resulting power deposition patterns were used as a heat source for the Pennes bioheat equation in a COMSOL® Multiphysics heat transfer model. 50°C is known to cause cell death and therefore the transducer powers were adjusted to produce a 13°C temperature rise from 37°C in the ePTFE.
Simulations showed that both the frequency of the transducers and the presence of hyperplasia significantly affect the power deposition patterns and subsequent temperature profiles on the grafts and nearby tissues. While neither transducer significantly raised the temperature of the blood, the 1.5-MHz transducer was less focused and heated larger volumes of the graft and nearby soft tissues than the 3.2-MHz transducer. The presence of hyperplasia had little effect on the blood's temperature, but further increased the temperature of the graft and nearby soft tissues in response to either transducer. Skin cooling and blood flow play a significant role in preventing overheating of the native tissues.
Modelling shows that ultrasound can selectively heat ePTFE grafts and produce temperatures that cause cell death on the graft. The temperature increase in blood is negligible and that in the adjacent soft tissues may be minimized by skin cooling and using appropriate transducers. Therefore, ultrasound heating may have the potential to reduce neointimal hyperplasia and failure of ePTFE vascular grafts.
PMCID: PMC3217891  PMID: 22054016

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