Effects of endothelial nitric oxide synthase on mouse arteriovenous fistula hemodynamics.

Newly created arteriovenous fistulas (AVFs) often fail to mature for dialysis use due to disturbed blood flow at and near the AVF anastomosis. The disturbed flow inhibits the endothelial nitric oxide synthase (NOS3) pathway, thus decreasing the production of nitric oxide, a vasodilator. Previously, our group reported that NOS3 expression levels affect AVF lumen size in a mouse model. In this study, we performed MRI-based computational fluid dynamics simulations to investigate the hemodynamical parameters (velocity, wall shear stress (WSS), and vorticity) in a mouse AVF model at day 7 and day 21 post-AVF creation using three NOS3 strains: overexpression (OE), knockout (KO), and wild-type (WT) control. This study is the first to reveal hemodynamics over time in mouse AVFs, consider spatial heterogeneity along the vein, and reveal the effect of NOS3 on the natural history of mouse AVF hemodynamics. From day 7 to day 21, OE has smoother streamlines and had significantly lower vorticity and WSS than WT and KO, suggesting that WSS was attempting to return to pre-surgery baseline, respectively. Our results conclude that the overexpression of NOS3 leads to desired optimal hemodynamics during AVF remodeling. Future studies can investigate enhancing the NOS3 pathway to improve AVF development.

Predialysis Vascular Access Placement and Catheter Use at Hemodialysis Initiation.

BACKGROUND: Current guidelines encourage placement of an arteriovenous (AV) fistula in patients with advanced CKD to avoid initiation of hemodialysis with a central venous catheter. However, the relative merits of predialysis placement of an AV fistula or graft have been poorly studied. METHODS: This study included 380 patients (mean age 59±14 years, 73% Black patients, 51% male) from a large academic medical center who underwent predialysis placement of an AV fistula (286) or AV graft (94). The study quantified three end points: time from access placement to initiation of dialysis, likelihood of starting hemodialysis without a catheter, and number of vascular access procedures before dialysis initiation. RESULTS: The eGFR at access surgery was <10, 10-14, and ≥15 ml/min per 1.73 m 2 in 87 (23%), 179 (47%), and 114 (30%) patients, respectively. The median time from access surgery to hemodialysis initiation was 69, 156, and 429 days in patients with an eGFR of <10, 10-14, and ≥15 ml/min per 1.73 m 2 , respectively ( P < 0.001). Hemodialysis was initiated within 2 years of access surgery in 298 (78%) of the patients. Catheter-free hemodialysis initiation was higher in patients with an AV graft versus an AV fistula when the eGFR was <10 ml/min per 1.73 m 2 (88% versus 43%; odds ratio [OR], 9.10 [95% confidence interval, 2.74 to 26.4]) and when the eGFR was 10-14 ml/min per 1.73 m 2 (88% versus 54%; OR, 6.05 [2.35 to 15.0]) but similar when the eGFR was ≥15 ml/min per 1.73 m 2 (90% versus 75%; OR, 3.00 [0.48 to 34.9]). Patients undergoing an AV fistula were more likely to undergo an angioplasty (11% versus 0%, P < 0.001), surgical access revision (26% versus 8%, P < 0.001), a second access placement (16% versus 6%, P = 0.02), and a catheter insertion (32% versus 11%, P < 0.001). CONCLUSIONS: Among patients with CKD undergoing vascular access surgery when their eGFR was <15 ml/min per 1.73 m 2 , catheter use at dialysis initiation was much less likely when an AV graft, rather than an AV fistula, was placed.

Trends in Vascular Access Among Patients Initiating Hemodialysis in the US.

This cohort study uses the US Renal Data System database to analyze trends in vascular access among more than 600 000 patients who initiated hemodialysis from 2015 to 2020.

Effects of a More Selective Arteriovenous Fistula Strategy on Vascular Access Outcomes.

SIGNIFICANCE STATEMENT: The optimal choice of vascular access for patients undergoing hemodialysis-arteriovenous fistula (AVF) or arteriovenous graft (AVG)-remains controversial. In a pragmatic observational study of 692 patients, the authors found that among patients who initiated hemodialysis with a central vein catheter (CVC), a strategy that maximized AVF placement resulted in a higher frequency of access procedures and greater access management costs for patients who initially received an AVF than an AVG. A more selective policy that avoided AVF placement if an AVF was predicted to be at high risk of failure resulted in a lower frequency of access procedures and access costs in patients receiving an AVF versus an AVG. These findings suggest that clinicians should be more selective in placing AVFs because this approach improves vascular access outcomes. BACKGROUND: The optimal choice of initial vascular access-arteriovenous fistula (AVF) or graft (AVG)-remains controversial, particularly in patients initiating hemodialysis with a central venous catheter (CVC). METHODS: In a pragmatic observational study of patients who initiated hemodialysis with a CVC and subsequently received an AVF or AVG, we compared a less selective vascular access strategy of maximizing AVF creation (period 1; 408 patients in 2004 through 2012) with a more selective policy of avoiding AVF creation if failure was likely (period 2; 284 patients in 2013 through 2019). Prespecified end points included frequency of vascular access procedures, access management costs, and duration of catheter dependence. We also compared access outcomes in all patients with an initial AVF or AVG in the two periods. RESULTS: An initial AVG placement was significantly more common in period 2 (41%) versus period 1 (28%). Frequency of all access procedures per 100 patient-years was significantly higher in patients with an initial AVF than an AVG in period 1 and lower in period 2. Median annual access management costs were significantly higher among patients with AVF ($10,642) versus patients with AVG ($6810) in period 1 but significantly lower in period 2 ($5481 versus $8253, respectively). Years of catheter dependence per 100 patient-years was three-fold higher in patients with AVF versus patients with AVG in period 1 (23.3 versus 8.1, respectively), but only 30% higher in period 2 (20.8 versus 16.0, respectively). When all patients were aggregated, the median annual access management cost was significantly lower in period 2 ($6757) than in period 1 ($9781). CONCLUSIONS: A more selective approach to AVF placement reduces frequency of vascular access procedures and cost of access management.

Biomimetic cardiac tissue chip and murine arteriovenous fistula models for recapitulating clinically relevant cardiac remodeling under volume overload conditions.

Cardiovascular events are the primary cause of death among dialysis patients. While arteriovenous fistulas (AVFs) are the access of choice for hemodialysis patients, AVF creation can lead to a volume overload (VO) state in the heart. We developed a three-dimensional (3D) cardiac tissue chip (CTC) with tunable pressure and stretch to model the acute hemodynamic changes associated with AVF creation to complement our murine AVF model of VO. In this study, we aimed to replicate the hemodynamics of murine AVF models in vitro and hypothesized that if 3D cardiac tissue constructs were subjected to "volume overload" conditions, they would display fibrosis and key gene expression changes seen in AVF mice. Mice underwent either an AVF or sham procedure and were sacrificed at 28 days. Cardiac tissue constructs composed of h9c2 rat cardiac myoblasts and normal adult human dermal fibroblasts in hydrogel were seeded into devices and exposed to 100 mg/10 mmHg pressure (0.4 s/0.6 s) at 1 Hz for 96 h. Controls were exposed to "normal" stretch and experimental group exposed to "volume overload". RT-PCR and histology were performed on the tissue constructs and mice left ventricles (LVs), and transcriptomics of mice LVs were also performed. Our tissue constructs and mice LV both demonstrated cardiac fibrosis as compared to control tissue constructs and sham-operated mice, respectively. Gene expression studies in our tissue constructs and mice LV demonstrated increased expression of genes associated with extracellular matrix production, oxidative stress, inflammation, and fibrosis in the VO conditions vs. control conditions. Our transcriptomics studies demonstrated activated upstream regulators related to fibrosis, inflammation, and oxidative stress such as collagen type 1 complex, TGFB1, CCR2, and VEGFA and inactivated regulators related to mitochondrial biogenesis in LV from mice AVF. In summary, our CTC model yields similar fibrosis-related histology and gene expression profiles as our murine AVF model. Thus, the CTC could potentially play a critical role in understanding cardiac pathobiology of VO states similar to what is present after AVF creation and may prove useful in evaluating therapies.

Study protocol of a randomized controlled trial of fistula vs. graft arteriovenous vascular access in older adults with end-stage kidney disease on hemodialysis: the AV access trial.

BACKGROUND: Treatment of end-stage kidney disease (ESKD) with hemodialysis requires surgical creation of an arteriovenous (AV) vascular access-fistula (AVF) or graft (AVG)-to avoid (or limit) the use of a central venous catheter (CVC). AVFs have long been considered the first-line vascular access option, with AVGs as second best. Recent studies have suggested that, in older adults, AVGs may be a better strategy than AVFs. Lacking evidence from well-powered randomized clinical trials, integration of these results into clinical decision making is challenging. The main objective of the AV Access Study is to compare, between the two types of AV access, clinical outcomes that are important to patients, physicians, and policy makers. METHODS: This is a prospective, multicenter, randomized controlled trial in adults ≥ 60 years old receiving chronic hemodialysis via a CVC. Eligible participants must have co-existing cardiovascular disease, peripheral arterial disease, and/or diabetes mellitus; and vascular anatomy suitable for placement of either type of AV access. Participants are randomized, in a 1:1 ratio, to a strategy of AVG or AVF creation. An estimated 262 participants will be recruited across 7 healthcare systems, with average follow-up of 2 years. Questionnaires will be administered at baseline and semi-annually. The primary outcome is the rate of CVC-free days per 100 patient-days. The primary safety outcome is the cumulative incidence of vascular access (CVC or AV access)-related severe infections-defined as access infections that lead to hospitalization or death. Secondary outcomes include access-related healthcare costs and patients' experiences with vascular access care between the two treatment groups. DISCUSSION: In the absence of studies using robust and unbiased research methodology to address vascular access care for hemodialysis patients, clinical decisions are limited to inferences from observational studies. The goal of the AV Access Study is to generate evidence to optimize vascular access care, based on objective, age-specific criteria, while incorporating goals of care and patient preference for vascular access type in clinical decision-making. TRIAL REGISTRATION: This study is being conducted in accordance with the tenets of the Helsinki Declaration, and has been approved by the central institutional review board (IRB) of Wake Forest University Health Sciences (approval number: 00069593) and local IRB of each participating clinical center; and was registered on Nov 27, 2020, at ClinicalTrials.gov (NCT04646226).

Cardiac changes following arteriovenous fistula creation in a mouse model.

BACKGROUND: Arteriovenous fistula (AVF) creation may negatively affect cardiac structure and function and impact cardiovascular mortality. The objective of this study was to develop and characterize the cardiac changes following AVF creation in a murine AVF model. METHODS: AVFs were constructed using the carotid artery and jugular vein in C57BL/6 mice. Sham-operated AVF mice served as the control group. 2D-echocardiography was performed prior to AVF creation (baseline) and at 7 and 21 days after creation in AVF and sham-operated mice. Picrosirius red was used to stain the left ventricle for collagen production. RESULTS: The cardiac output (CO), left ventricular end diastolic (LVEDD) and systolic (LVESD) diameter, and end-diastolic (LVEDV) and systolic (LVESV) volume was significantly increased at 7 and 21 days in AVF compared to sham-operated mice. There was also a significant increase in CO, LVEDD, LVESD, LVEDV, and LVESV from baseline to 21 days within the AVF group, but not the sham-operated mice. There was a significant decrease in ejection fraction and fractional shortening at 21 days in AVF compared to sham-operated mice. Picrosirius red was significantly more prominent around both the perivascular and interstitial areas of the cardiac tissue from AVF mice compared to sham-operated AVF mice at 21 days. CONCLUSIONS: The creation of an AVF in our murine model leads to cardiac changes such as increased cardiac output, left ventricular dilation, and cardiac fibrosis, while showing reductions of ejection fraction and fractional shortening.

Study protocol for Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) : A multi-center, multinational validation study to assess the accuracy and feasibility of measuring vascular access function in clinical practice.

BACKGROUND: A functioning vascular access (VA) is crucial to providing adequate hemodialysis (HD) and considered a critically important outcome by patients and healthcare professionals. A validated, patient-important outcome measure for VA function that can be easily measured in research and practice to harvest reliable and relevant evidence for informing patient-centered HD care is lacking. Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) aims to assess the accuracy and feasibility of measuring a core outcome for VA function established by the international Standardized Outcomes in Nephrology (SONG) initiative. METHODS: VALID is a prospective, multi-center, multinational validation study that will assess the accuracy and feasibility of measuring VA function, defined as the need for interventions to enable and maintain the use of a VA for HD. The primary objective is to determine whether VA function can be measured accurately by clinical staff as part of routine clinical practice (Assessor 1) compared to the reference standard of documented VA procedures collected by a VA expert (Assessor 2) during a 6-month follow-up period. Secondary outcomes include feasibility and acceptability of measuring VA function and the time to, rate of, and type of VA interventions. An estimated 612 participants will be recruited from approximately 10 dialysis units of different size, type (home-, in-center and satellite), governance (private versus public), and location (rural versus urban) across Australia, Canada, Europe, and Malaysia. Validity will be measured by the sensitivity and specificity of the data acquisition process. The sensitivity corresponds to the proportion of correctly identified interventions by Assessor 1, among the interventions identified by Assessor 2 (reference standard). The feasibility of measuring VA function will be assessed by the average data collection time, data completeness, feasibility questionnaires and semi-structured interviews on key feasibility aspects with the assessors. DISCUSSION: Accuracy, acceptability, and feasibility of measuring VA function as part of routine clinical practice are required to facilitate global implementation of this core outcome across all HD trials. Global use of a standardized, patient-centered outcome measure for VA function in HD research will enhance the consistency and relevance of trial evidence to guide patient-centered care. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03969225. Registered on 31st May 2019.

Racial Disparities in Arteriovenous Fistula Use Among Hemodialysis Patients: The Role of Surgeon Supply.

Introduction: Factors contributing to racial disparities in arteriovenous fistula (AVF) use among hemodialysis (HD) patients remain poorly defined. We evaluated whether the Black/White race disparity in AVF use is affected by vascular access surgeon supply. Methods: Using Consolidated Renal Operations in a Web-Enabled Network (CROWNWeb) and Medicare claims data from the US Renal Data System (USRDS), competing risk analyses of all US patients initiating HD with a central venous catheter (CVC) from 2016 to 2017 (n = 100,227) were performed. The likelihood of successful AVF use was compared between Black and White patients after adjusting for vascular access surgeon supply. Results: Compared with the first (lowest) quartile of surgeon supply, higher supply levels were associated with modestly increased adjusted likelihoods of overall AVF use: 4% (95% CI 1.4%-7.2%), 4% (95% CI 1.4%-7.1%), and 3% (0.0%-6.1%) for second, third, and fourth quartiles, respectively. Although areas with lower surgeon supply had a higher proportion of Black patients, residing in areas with a greater surgeon supply was not significantly associated with a mitigation in racial disparity. Specifically, compared with White patients, Black patients were 10% (95% CI 7%-13%) and 8% (95% CI 5%-11%) less likely to have successful AVF use in lower and higher surgeon supply areas, respectively. Conclusion: Regions with lower surgeon supply had a higher proportion of Black dialysis patients. However, racial disparities in AVF use among patients initiating HD with a CVC were similar in regions with a high and low surgeon supply. Other patient, provider, and practice factors should be evaluated toward mitigating lower rates of AVF use among Black HD patients.

Nitric oxide releasing nanomatrix gel treatment inhibits venous intimal hyperplasia and improves vascular remodeling in a rodent arteriovenous fistula.

Vascular access is the lifeline for hemodialysis patients and the single most important component of the hemodialysis procedure. Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients, but nearly 60% of AVFs created fail to successfully mature due to early intimal hyperplasia development and poor outward remodeling. There are currently no therapies available to prevent AVF maturation failure. First, we showed the important regulatory role of nitric oxide (NO) on AVF development by demonstrating that intimal hyperplasia development was reduced in an overexpressed endothelial nitric oxide synthase (NOS3) mouse AVF model. This supported the rationale for the potential application of NO to the AVF. Thus, we developed a self-assembled NO releasing nanomatrix gel and applied it perivascularly at the arteriovenous anastomosis immediately following rat AVF creation to investigate its therapeutic effect on AVF development. We demonstrated that the NO releasing nanomatrix gel inhibited intimal hyperplasia formation (more than 70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress approaching the preoperative level and less vorticity). Therefore, direct application of the NO releasing nanomatrix gel to the AVF anastomosis immediately following AVF creation may enhance AVF development, thereby providing long-term and durable vascular access for hemodialysis.

Analysis of Geometric and Hemodynamic Profiles in Rat Arteriovenous Fistula Following PDE5A Inhibition.

Arteriovenous fistula (AVF) is essential for chronic kidney disease (CKD) patients on hemodialysis, but treatment for AVF maturation failure remains an unmet clinical need. Successful AVF remodeling occurs through sufficient lumen expansion to increase AVF blood flow and lumen area. Aberrant blood flow is thought to impair AVF remodeling, but previous literature has largely focused on hemodynamics averaged over the entire AVF or at a single location. We hypothesized that hemodynamics is heterogeneous, and thus any treatment's effect size is heterogeneous in the AVF. To test our hypothesis, we used the PDE5A inhibitor sildenafil to treat AVFs in a rat model and performed magnetic resonance imaging (MRI) based computational fluid dynamics (CFD) to generate a detailed spatial profile of hemodynamics in AVFs. 90 mg/kg of sildenafil was administered to rats in their drinking water for 14 days. On day 14 femoral AVFs were created in rats and sildenafil treatment continued for another 21 days. 21 days post-AVF creation, rats underwent non-contrast MRI for CFD and geometrical analysis. Lumen cross-sectional area (CSA) and flow rate were used to quantify AVF remodeling. Parameters used to describe aberrant blood flow include velocity magnitude, wall shear stress (WSS), oscillatory shear index (OSI), and vorticity. Geometrical parameters include arterial-venous (A-V) distance, anastomosis angle, tortuosity, and nonplanarity angle magnitude. When averaged across the entire AVF, sildenafil treated rats had significantly higher CSA, flow rate, velocity, WSS, OSI, and vorticity than control rats. To analyze heterogeneity, the vein was separated into zones: 0-5, 5-10, 10-15, and 15-20 mm from the anastomosis. In both groups: 1) CSA increased from the 0-5 to 15-20 zone; 2) velocity, WSS, and vorticity were highest in the 0-5 zone and dropped significantly thereafter; and 3) OSI increased at the 5-10 zone and then decreased gradually. Thus, the effect size of sildenafil on AVF remodeling and the relationship between hemodynamics and AVF remodeling depend on location. There was no significant difference between control and sildenafil groups for the other geometric parameters. Rats tolerated sildenafil treatment well, and our results suggest that sildenafil may be a safe and effective therapy for AVF maturation.

The geometry of arteriovenous fistulas using endothelial nitric oxide synthase mouse models.

BACKGROUND: Arteriovenous fistula (AVF) maturation failure is a significant clinical problem in the hemodialysis population. Geometric parameters of human AVFs were associated with AVF development, but causative studies are lacking. We characterized mouse AVF geometry using endothelial nitric oxide synthase (NOS3) mouse models. METHODS: Carotid-jugular AVFs were created in NOS3 overexpression (OE), knockout (KO), and wild type (WT) mice. At 7 and 21 days postcreation, black-blood magnetic resonance images of AVFs were acquired and used to build three-dimensional reconstructions of AVF lumens. We used these reconstructions to calculate the lumen area, lumen centerline, and centerline-derived parameters: anastomosis angle, tortuosity, nonplanarity angle, and location of maximal distance between the feeding artery and AVF vein. Inter- and intrauser variabilities were also determined. RESULTS: When all mice were considered, increased minimum AVF venous lumen area was accompanied by increased venous tortuosity and increased distance between the artery and vein, with both remaining in-plane with the anastomosis. At day 7, the lumen area of AVFs from all strains was 1.5- to 2.5-fold larger than native veins. Furthermore, at day 21, AVF lumen in NOS3 OE (4.04±1.43 mm2) was significantly larger than KO (2.74±1.34 mm2) (P<0.001) and WT (2.94±1.30 mm2) mice (p<0.001). At day 21, the location of maximal artery-vein distance on the vein was further away from the anastomosis in OE (4.49±0.66 mm) than KO (2.87±0.38 mm) (p=0.001). Other geometric parameters were not significantly different between mouse strains or time points. Inter- and intrauser variabilities were small, indicating the reliability and reproducibility of our protocol. CONCLUSIONS: Our study presents a detailed characterization of mouse AVF geometry, and a robust protocol for future mechanistic studies to investigate the role of molecular pathways in AVF geometry. Identifying a geometry related to desired AVF remodeling can help inform surgery to enhance AVF maturation.

Racial Disparities in the Arteriovenous Fistula Care Continuum in Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Arteriovenous fistulas are the optimal vascular access type for patients on hemodialysis. However, arteriovenous fistulas are used less frequently in Black than in White individuals. The arteriovenous fistula care continuum comprises a series of sequential steps. A better understanding is needed of where disparities exist along the continuum in order to mitigate racial differences in arteriovenous fistula use. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using Medicare claims data from the United States Renal Data System, longitudinal analyses of patients ≥67 years initiating hemodialysis with a central venous catheter between July 1, 2010 and June 30, 2012 were performed. Three patient cohorts were identified: patients initiating hemodialysis with a catheter (n=41,814), patients with arteriovenous fistula placement within 6 months of dialysis initiation (n=14,077), and patients whose arteriovenous fistulas were successfully used within 6 months of placement (n=7068). Three arteriovenous fistula processes of care outcomes were compared between Blacks and Whites: (1) arteriovenous fistula creation, (2) successful arteriovenous fistula use, and (3) primary arteriovenous fistula patency after successful use. RESULTS: An arteriovenous fistula was placed within 6 months of dialysis initiation in 37% of patients initiating dialysis with a catheter. Among the patients with arteriovenous fistula placement, the arteriovenous fistula was successfully used for dialysis within 6 months in 48% of patients. Among patients with successful arteriovenous fistula use, 21% maintained primary arteriovenous fistula patency at 3 years. After adjusting for competing risks, Black patients on hemodialysis were 10% less likely to undergo arteriovenous fistula placement (adjusted subdistribution hazard ratio, 0.90; 95% confidence interval, 0.87 to 0.94); 12% less likely to have successful arteriovenous fistula use after placement (adjusted subdistribution hazard ratio, 0.88; 95% confidence interval, 0.83 to 0.93); and 22% less likely to maintain primary arteriovenous fistula patency after successful use (subdistribution hazard ratio, 0.78; 95% confidence interval, 0.74 to 0.84). CONCLUSIONS: Lower arteriovenous fistula use among Blacks older than 67 years of age treated with hemodialysis was attributable to each step along the continuum of arteriovenous fistula processes of care.

Perspectives in Individualizing Solutions for Dialysis Access.

The vascular access is the lifeline for the hemodialysis patient. Previous national vascular access guidelines have emphasized placement of arteriovenous fistulas in most hemodialysis patients. However, the new Kidney Disease Outcomes Quality Initiative guidelines for vascular access, soon to be published, will focus on a patient's end-stage kidney disease "life plan" and take a patient "first" approach. One of the major themes of the new Kidney Disease Outcomes Quality Initiative guidelines is selecting the "right access, for the right patient, at the right time, for the right reason". Given the availability of new advances in biomedical technologies, techniques, and devices in the vascular access field, this shift to a more patient-centered vascular access approach presents unique opportunities to individualize the solutions and care for patients requiring a dialysis vascular access. This review article will address 3 potential areas where there is an unmet need to individualize solutions for dialysis vascular access care: (1) biological approaches to improve vascular access selection and selection of therapies, (2) vascular access care for the post-transplant patient, and (3) vascular access disparities in race, gender, and the elderly patient.

KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update.

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) has provided evidence-based guidelines for hemodialysis vascular access since 1996. Since the last update in 2006, there has been a great accumulation of new evidence and sophistication in the guidelines process. The 2019 update to the KDOQI Clinical Practice Guideline for Vascular Access is a comprehensive document intended to assist multidisciplinary practitioners care for chronic kidney disease patients and their vascular access. New topics include the end-stage kidney disease "Life-Plan" and related concepts, guidance on vascular access choice, new targets for arteriovenous access (fistulas and grafts) and central venous catheters, management of specific complications, and renewed approaches to some older topics. Appraisal of the quality of the evidence was independently conducted by using a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, and interpretation and application followed the GRADE Evidence to Decision frameworks. As applicable, each guideline statement is accompanied by rationale/background information, a detailed justification, monitoring and evaluation guidance, implementation considerations, special discussions, and recommendations for future research.

Vasoreactivity of the Murine External Jugular Vein and Carotid Artery.

INTRODUCTION: Impaired venous reactivity has potential to contribute to clinically significant pathologies such as arteriovenous fistula (AVF) maturation failure. Vascular segments commonly used in murine preclinical models of AVF include the carotid artery and external jugular vein. Detailed descriptions of isometric procedures to evaluate function of murine external jugular vein ex vivo have not been previously published. OBJECTIVE: To establish isometric procedures to measure naive murine external jugular vein reactivity ex vivo. METHODS: Vasomotor responses of external jugular veins and ipsilateral common carotid arteries from C57BL/6 mice were evaluated using isometric tension procedures. RESULTS: External jugular veins developed tension (p < 0.05) to potassium chloride and U-46619, but not to phenylephrine, whereas common carotid arteries responded to all 3 agents (p < 0.05). While maximal responses to acetylcholine (ACh) were similar between the venous and arterial segments, the dose required to achieve this value was lower (p < 0.05) in the artery versus vein. Nitric oxide synthase inhibition attenuated (p < 0.05) but did not abolish ACh-evoked vasorelaxation in both vascular segments, whereas cyclooxygenase blockade had no effect. Endothelium-independent vasorelaxation to sodium nitroprusside was similar in the artery and vein. CONCLUSION: Vasorelaxation and vasocontraction can be reliably assessed in the external jugular vein in C57BL/6 mice using isometric procedures.

A Novel Model of Balloon Angioplasty Injury in Rat Arteriovenous Fistula.

BACKGROUND: There are very few animal models of balloon angioplasty injury in arteriovenous fistula (AVF), hindering insight into the pathophysiologic processes following angioplasty in AVF. The objective of the study was to develop and characterize a rat model of AVF angioplasty injury. METHODS: Balloon angioplasty in 12- to 16-week-old Sprague-Dawley rats was performed at the arteriovenous anastomosis 14 days post-AVF creation with a 2F Fogarty balloon catheter. Morphometry and protein expression of endothelial nitric oxide synthase (eNOS), monocyte-chemoattractant protein-1 (MCP-1), alpha-smooth muscle actin (α-SMA), CD68 (macrophage marker), and collagen expression in AVFs with and without angioplasty were assessed. RESULTS: In AVFs with angioplasty versus without angioplasty: (1) angioplasty increased AVF-vein and artery intimal hyperplasia, (2) angioplasty decreased eNOS protein expression in AVF-vein and artery at 21 days post-AVF creation and remained decreased in the AVF-vein angioplasty group at 35 days, (3) angioplasty increased AVF-vein and artery α-SMA expression within the intimal region at 35 days, (4) angioplasty increased the expression of AVF-vein MCP-1 at 21 days and CD68 at 21 and 35 days, and (5) angioplasty increased AVF-vein and artery collagen expression at 35 days. CONCLUSION: Our findings describe a reproducible rat model to better understand the pathophysiologic mechanisms that ensue following AVF angioplasty.