Intraoperative transit time flow measurement predicts maturation of radiocephalic arteriovenous fistulas.

OBJECTIVE: The arteriovenous fistula (AVF) is the first choice for gaining vascular access for hemodialysis. However, 20% to 50% of AVFs fail within 4 months after creation. Although demographic risk factors have been described, there is little evidence on the intraoperative predictors of AVF maturation failure. The aim of this study was to assess the predictive value of intraoperative transit time flow measurements (TTFMs) on AVF maturation failure. METHODS: In this retrospective cohort study, intraoperative blood flow, measured using TTFM, was compared with AVF maturation after 6 weeks in 55 patients. Owing to its significantly higher prevalence and risk of nonmaturation, the radiocephalic AVF (RCAVF) was the main focus of this study. A recommended cutoff point for high vs low intraoperative blood flow was determined for RCAVFs, using a receiver operating characteristic curve. RESULTS: The average intraoperative blood flow in RCAVFs was 156 mL/min. Patients with an intraoperative blood flow equal or lower than the determined cutoff point of 160 mL/min, showed a 3.03 times increased risk of AVF maturation failure after 6 weeks, compared with patients with a higher intraoperative blood flow (P < .001). CONCLUSIONS: The intraoperative blood flow in RCAVFs measured by TTFM provides an adequate means of predicting AVF nonmaturation 6 weeks after surgery. For RCAVFs, a cutoff point for intraoperative blood flow of 160 mL/min is recommended for maximum sensitivity and specificity to predict AVF maturation failure after 6 weeks.

Systematic review and meta-analysis of preoperative interventions to support the maturation of arteriovenous fistulae in patients with advanced kidney disease.

BACKGROUND: There is great potential to improve outcomes of arteriovenous fistulas (AVFs) by focusing more on the preoperative period of AVF creation. We aim to systematically review the evidence on safety and efficacy of various preoperative interventions that have been tried to improve AVF maturation and success rate. METHODS: We searched five databases: PubMed, Embase, CINAHL, Cochrane Library and King's Fund Library. Experimental studies that investigated the effect of various preoperative interventions to improve AVF outcomes among advanced chronic kidney disease (CKD) patients were searched. The effect size for primary outcome was calculated as the weighted mean difference in the final vessel calibre, rate of AVF maturation or primary failure between the intervention and control arm. We also assessed adverse effects and dropout rates. This review was preregistered in the International Prospective Register of Systematic Reviews (CRD42020193257). RESULTS: Eight eligible studies were identified involving three types of intervention: hand exercise (n = 6), cholecalciferol supplementation (n = 1) and pneumatic compression of the arm using a Fist Assist device (n = 1). The overall effect size of hand exercise on distal cephalic vein calibre was 0.24 mm [95% confidence interval (CI) 0.03-0.45] on meta-analysis of hand exercise studies. On restricting analysis to two randomized controlled trials (RCTs) that had independent control groups, the effect size was higher, at 0.29 mm (95% CI 0.11-0.47). Hand exercise was a well-tolerated intervention, especially when confined to the first 4 weeks. DISCUSSION: Hand exercise is the predominant intervention tried in the preoperative period of AVF creation, although there is methodological heterogeneity. Intermittent pneumatic compression using a Fist Assist device is a novel intervention that has shown some promise. Well-designed prospective RCTs are needed on preoperative interventions among advanced CKD patients, aimed at improving AVF outcomes.

Building a Scaffold for Arteriovenous Fistula Maturation: Unravelling the Role of the Extracellular Matrix.

Vascular access is the lifeline for patients receiving haemodialysis as kidney replacement therapy. As a surgically created arteriovenous fistula (AVF) provides a high-flow conduit suitable for cannulation, it remains the vascular access of choice. In order to use an AVF successfully, the luminal diameter and the vessel wall of the venous outflow tract have to increase. This process is referred to as AVF maturation. AVF non-maturation is an important limitation of AVFs that contributes to their poor primary patency rates. To date, there is no clear overview of the overall role of the extracellular matrix (ECM) in AVF maturation. The ECM is essential for vascular functioning, as it provides structural and mechanical strength and communicates with vascular cells to regulate their differentiation and proliferation. Thus, the ECM is involved in multiple processes that regulate AVF maturation, and it is essential to study its anatomy and vascular response to AVF surgery to define therapeutic targets to improve AVF maturation. In this review, we discuss the composition of both the arterial and venous ECM and its incorporation in the three vessel layers: the tunica intima, media, and adventitia. Furthermore, we examine the effect of chronic kidney failure on the vasculature, the timing of ECM remodelling post-AVF surgery, and current ECM interventions to improve AVF maturation. Lastly, the suitability of ECM interventions as a therapeutic target for AVF maturation will be discussed.

Patient Frailty and Functional Use of Hemodialysis Vascular Access: A Retrospective Study of the US Renal Data System.

RATIONALE & OBJECTIVE: Despite the high prevalence of frailty among dialysis patients, it is unknown whether frailty is associated with dialysis vascular access failure. This study examined the association between frailty and functional use of vascular access. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Patients who initiated hemodialysis through a tunneled catheter in the US Renal Data System database from 2012 through 2017 and underwent subsequent creation of an arteriovenous fistula or graft. PREDICTORS: The "claims-based frailty indicator" (CFI) was calculated using a validated claims-based disability status model anchored to a well-described frailty phenotype. OUTCOMES: Time to functional use for fistulas and grafts defined as the time from initiation of hemodialysis to treatments using the index vascular access with 2 needles. ANALYTICAL APPROACH: Fine and Gray competing risk models separately examining fistula and graft outcomes. Patient survival was modeled for the entire cohort using Cox proportional hazards regression. RESULTS: A total of 41,471 patients met inclusion criteria, including 33,212 who underwent fistula creation and 8,259 who underwent graft placement. Higher CFI quartiles were associated with a greater rate of mortality. Patients in the highest CFI quartile had more than 2 times the rate of mortality compared with patients in the lowest CFI quartile (hazard ratio [HR], 2.49 [95% CI, 2.41-2.58]). In multivariable analyses, the highest CFI quartile was significantly associated with longer time to functional use of fistulas (HR, 0.65 [95% CI, 0.62-0.69]) and grafts (HR, 0.88 [95% CI, 0.79-0.98]). LIMITATIONS: Generalizability may be limited by the requirement of 12 months of Medicare claims availability before initiation of dialysis. There were no data on patient anatomic characteristics or surgeon characteristics and limited patient-specific sociodemographic data. CONCLUSIONS: Higher degrees of frailty are associated with longer times to vascular access functional use. Frailty may be useful for informing clinical decision-making regarding choice of vascular access.

Innate and adaptive immune cells associate with arteriovenous fistula maturation and failure.

Creation of arteriovenous fistula (AVF) causes local injury, resulting in immune response of the body and infiltration of immune cells. Acute inflammation is favorable to control inflammation and proceed AVF toward maturation while chronic inflammation in AVF leads to AVF maturation failure. Chronic inflammation in AVF is due to chronic infiltration of immune cells and secretion of inflammatory cytokines. A balance between proinflammatory and anti-inflammatory response is a must for AVF maturation and an overwhelmed proinflammatory infiltrate causes chronic inflammation and AVF failure. As immune cell infiltration plays a critical role in maturation and failure of AVF, it is important to investigate the role of immune cells as well as their density in early and late phase of AVF maturation. The role of inflammation has been discussed in the literature and this review article focuses on the role of pro- and anti-inflammatory immune cells, including macrophages, dendritic cells (DCs), T-cells, and T-regulatory (Treg) cells in AVF maturation and maturation failure.

Targeting the Crosstalk of Immune Response and Vascular Smooth Muscle Cells Phenotype Switch for Arteriovenous Fistula Maturation.

Plaque formation, thrombosis, and embolism are the underlying causes of acute cardiovascular events such as myocardial infarction and stroke while early thrombosis and stenosis are common pathologies for the maturation failure of arteriovenous fistula (AVF). Chronic inflammation is a common underlying pathogenesis mediated by innate and adaptive immune response involving infiltration of immune cells and secretion of pro- and anti-inflammatory cytokines. Impaired immune cell infiltration and change in vascular smooth muscle cell (VSMC) phenotype play a crucial role in the underlying pathophysiology. However, the change in the phenotype of VSMCs in a microenvironment of immune cell infiltration and increased secretion of cytokines have not been investigated. Since change in VSMC phenotype regulates vessel remodeling after intimal injury, in this study, we investigated the effect of macrophages and pro-inflammatory cytokines, IL-6, IL-1ß, and TNF-α, on the change in VSMC phenotype under in vitro conditions. We also investigated the expression of the markers of VSMC phenotypes in arteries with atherosclerotic plaques and VSMCs isolated from control arteries. We found that the inhibition of cytokine downstream signaling may mitigate the effect of cytokines on the change in VSMCs phenotype. The results of this study support that regulating or targeting immune cell infiltration and function might be a therapeutic strategy to mitigate the effects of chronic inflammation to attenuate plaque formation, early thrombosis, and stenosis, and thus enhance AVF maturation.

Catheter Dependence After Arteriovenous Fistula or Graft Placement Among Elderly Patients on Hemodialysis.

RATIONALE & OBJECTIVE: Creation of an arteriovenous fistula (AVF), compared with an arteriovenous graft (AVG), is associated with longer initial catheter dependence after starting hemodialysis (HD) but longer access survival and lower long-term catheter dependence. The extent of these potential long-term benefits in elderly patients is unknown. We assessed catheter dependence after AVF or AVG placement among elderly patients who initiated HD without a permanent access in place. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients≥67 years of age identified in the US Renal Data System who had a first AVF (n=14,532) or AVG (n=3,391) placed within 1 year after HD initiation between May 2012 and May 2017. EXPOSURE: AVF versus AVG placement in the first year of HD. OUTCOME: Catheter dependence after AVF or AVG placement assessed using CROWNWeb data. ANALYTICAL APPROACH: Generalized estimating equations and negative binomial regression for catheter use over time and Cox proportional hazards models for mortality. RESULTS: Creation of an AVF versus AVG placement was associated with greater catheter dependence at 1 month (95.6% vs 92.5%) and 3 months (82.8% vs 41.2%), but lower catheter dependence at 12 months (14.2% vs 15.8%) and 36 months (8.2% vs 15.0%). Creation of an AVF, however, remained significantly associated with greater cumulative catheter-dependent days (80.1 vs 54.6 days per person-year) and a lower proportion of catheter-free survival time (78.1% vs 85.1%) after 3 years of follow-up. LIMITATIONS: Potential for unmeasured confounding and analyses limited to elderly patients. CONCLUSIONS: Creation of an AVF was associated with significantly greater cumulative catheter dependence than placement of an AVG in an elderly population initiating HD without a permanent access. As the long-term benefits in terms of catheter dependence of an AVF are not realized in many elderly patients, specific patient characteristics should be considered when making decisions regarding vascular access.

International Comparisons of Native Arteriovenous Fistula Patency and Time to Becoming Catheter-Free: Findings From the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Optimizing vascular access use is crucial for long-term hemodialysis patient care. Because vascular access use varies internationally, we examined international differences in arteriovenous fistula (AVF) patency and time to becoming catheter-free for patients receiving a new AVF. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,191 AVFs newly created in 2,040 hemodialysis patients in 2009 to 2015 at 466 randomly selected facilities in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from the United States, Japan, and EUR/ANZ (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom, Australia, and New Zealand). PREDICTORS: Demographics, comorbid conditions, dialysis vintage, body mass index, AVF location, and country/region. OUTCOMES: Primary/cumulative AVF patency (from creation), primary/cumulative functional patency (from first use), catheter dependence duration, and mortality. ANALYTICAL APPROACH: Outcomes estimated using Cox regression. RESULTS: Across regions, mean patient age ranged from 61 to 66 years, with male preponderance ranging from 55% to 66%, median dialysis vintage of 0.3 to 3.2 years, with 84%, 54%, and 32% of AVFs created in the forearm in Japan, EUR/ANZ, and United States, respectively. Japan displayed superior primary and cumulative patencies due to higher successful AVF use, whereas cumulative functional patency was similar across regions. AVF patency associations with age and other patient characteristics were weak or varied considerably between regions. Catheter-dependence following AVF creation was much longer in EUR/ANZ and US patients, with nearly 70% remaining catheter dependent 8 months after AVF creation when AVFs were not successfully used. Not using an arteriovenous access within 6 months of AVF creation was related to 53% higher mortality in the subsequent 6 months. LIMITATIONS: Residual confounding. CONCLUSIONS: Our findings highlight the need to reevaluate practices for optimizing long-term access planning and achievable AVF outcomes, especially AVF maturation. New AVFs that are not successfully used are associated with long-term catheter exposure and elevated mortality risk. These findings highlight the importance of selecting the best access type for each patient and developing effective clinical pathways for when AVFs fail to mature successfully.

Effect of far infrared therapy on arteriovenous fistula maturation, survival and stenosis in hemodialysis patients, a randomized, controlled clinical trial: the FAITH on fistula trial.

BACKGROUND: An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis treatment. After creation many of the AVFs will never mature or if functioning will need an intervention within 1 year due to an AVF stenosis. Studies investigating possible therapies that improves the AVF maturation and survival are scarce. Far infrared therapy (FIR) has shown promising results. In minor single centre and industry supported trials FIR has shown improved AVF maturation and survival. There is a need of a randomized multicentre controlled trial to examine the effect of FIR on the AVF maturation and survival and to explore the possible AVF protective mechanism induced by the FIR treatment. METHODS: This investigator initiated, randomized, controlled, open-labeled, multicenter clinical trial will examine the effect of FIR on AVF maturation in patients with a newly created AVF (incident) and AVF patency rate after 1 year of treatment in patients with an existing AVF (prevalent) compared to a control group. The intervention group will receive FIR to the skin above their AVF three times a week for 1 year. The control group will be observed without any treatment. The primary outcome for incident AVFs is the time from surgically creation of the AVF to successful cannulation. The primary outcome for the prevalent AVFs is the difference in number of AVFs without intervention and still functioning in the treatment and control group after 12 months. Furthermore, the acute changes in inflammatory and vasodilating factors during FIR will be explored. Arterial stiffness as a marker of long term AVF patency will also be examined. DISCUSSION: FIR is a promising new treatment modality that may potentially lead to improved AVF maturation and survival. This randomized controlled open-labelled trial will investigate the effect of FIR and its possible mechanisms. TRIAL REGISTRATION: Clinicaltrialsgov NCT04011072 (7th of July 2019).

Surgeon Characteristics and Dialysis Vascular Access Outcomes in the United States: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: An arteriovenous fistula (AVF) is the preferred access for most patients receiving maintenance hemodialysis, but maturation failure remains a challenge. Surgeon characteristics have been proposed as contributors to AVF success. We examined variation in AVF placement and AVF outcomes by surgeon and surgeon characteristics. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: National Medicare claims and web-based data submitted by dialysis facilities on maintenance hemodialysis patients from 2009 through 2015. EXPOSURES: Patient characteristics, including demographics and comorbid conditions; surgeon characteristics, including specialty, prior volume of AVF placements, and years since medical school graduation. OUTCOMES: Percent of access placements that were an AVF from 2009 to 2015 (designated AVF placement), and percent of AVFs with successful use within 6 months of placement (maturation) from 2013 to 2014. ANALYTICAL APPROACH: Multilevel logistic regression models examining the association of surgeon characteristics with the outcomes, adjusted for patient characteristics and dialysis facilities as random effects. RESULTS: Among 4,959 surgeons placing 467,827 accesses, median AVF placement was 71% (IQR, 59%-84%). More recent year of medical school graduation and general surgery specialty (vs vascular, cardiothoracic, or transplantation surgery) were associated with higher odds of AVF placement. Among 2,770 surgeons placing 49,826 AVFs, the median AVF maturation rate was 59% (IQR, 44%-71%). More recent year of medical school graduation, but not surgical specialty, was associated with higher odds of AVF maturation. Greater prior volume of AVF placement was associated with higher odds of AVF maturation: OR of 1.46 (95% CI, 1.37-1.57) for highest (>84 AVF placements in 2years) versus lowest (<14) volume quintile. LIMITATIONS: The study relied on administrative data, limiting capture of some factors affecting access outcomes. CONCLUSIONS: There is substantial surgeon-level variation in AVF placements and AVF maturation. Surgeons' prior volume of AVF placements is strongly associated with AVF maturation.

Arteriovenous Fistula Maturation in Prevalent Hemodialysis Patients in the United States: A National Study.

BACKGROUND: Arteriovenous fistulas (AVFs) are the preferred form of hemodialysis vascular access, but maturation failures occur frequently, often resulting in prolonged catheter use. We sought to characterize AVF maturation in a national sample of prevalent hemodialysis patients in the United States. STUDY DESIGN: Nonconcurrent observational cohort study. SETTING & PARTICIPANTS: Prevalent hemodialysis patients having had at least 1 new AVF placed during 2013, as identified using Medicare claims data in the US Renal Data System. PREDICTORS: Demographics, geographic location, dialysis vintage, comorbid conditions. OUTCOMES: Successful maturation following placement defined by subsequent use identified using monthly CROWNWeb data. MEASUREMENTS: AVF maturation rates were compared across strata of predictors. Patients were followed up until the earliest evidence of death, AVF maturation, or the end of 2014. RESULTS: In the study period, 45,087 new AVFs were placed in 39,820 prevalent hemodialysis patients. No evidence of use was identified for 36.2% of AVFs. Only 54.7% of AVFs were used within 4 months of placement, with maturation rates varying considerably across end-stage renal disease (ESRD) networks. Older age was associated with lower AVF maturation rates. Female sex, black race, some comorbid conditions (cardiovascular disease, peripheral artery disease, diabetes, needing assistance, or institutionalized status), dialysis vintage longer than 1 year, and catheter or arteriovenous graft use at ESRD incidence were also associated with lower rates of successful AVF maturation. In contrast, hypertension and prior AVF placement at ESRD incidence were associated with higher rates of successful AVF maturation. LIMITATIONS: This study relies on administrative data, with monthly recording of access use. CONCLUSIONS: We identified numerous associations between AVF maturation and patient-level factors in a recent national sample of US hemodialysis patients. After accounting for these patient factors, we observed substantial differences in AVF maturation across some ESRD networks, indicating a need for additional study of the provider, practice, and regional factors that explain AVF maturation.

A new method to determine anastomosis angle configuration for arteriovenous fistula maturation.

Background: The kidneys of patients with chronic kidney disease (CKD) do not function well enough and those in end-stage renal disease (ESRD) of CKD need hemodialysis (HD) as a common renal replacement therapy (RRT) procedure. HD requires a vascular access (VA), and arteriovenous fistula (AVF) is the common VA choice in the world due to its very few complications. Despite the widespread use of AVFs, some risk factors maximize AVF failure, which is accompanied by complications of the patient such as repeating VA surgeries and hospitalization. Therefore, finding effective factors in the success of surgery is highly important and, thus, this study aimed at measuring the effect of anastomosis angle on the success of AVF surgery. Methods: This study evaluated the effect of conducted angle in an AVF anastomosis on AVF maturation. The images of 48 created AVFs for CKD patients was provided over a one-year period (from May 2016 to April 2017). Cross-tab analysis was used, and significance level was considered meaningful at p-value≤0.001. A centralized database was designed to integrate data. A method for image processing was developed and geometrical characteristics of the vessels (such as anastomosis angle) and also the diameter of artery and vein were measured via AutoCAD 2017 software and exported to the database along with other data. Results: The rate of the AVF failure in the studied patients was 8.96%. The anastomosis angle ≤ 30° is preferable from the AVF status point of view because most AVF maturation (or least AVF failure) rates are detected at this range. Conclusion: This study was performed based on a new approach without the need to measure hemodynamic parameters. Moreover, it signified the important role of anastomosis angle in the function of AVF, showing that the anastomosis angle ≤ 30° is a preferable intraoperative recommendation for AVF surgery.

Immune-Related Genes and Immune Cell Infiltration Characterize the Maturation Status of Arteriovenous Fistulas: An Integrative Bioinformatics Study and Experimental Validation Based on Transcriptome Sequencing.

Purpose: Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis, but the low maturation rate is concerning. Immune cells' impact on AVF maturation lacks bioinformatics research. The study aims to investigate the potential predictive role of immune-related genes and immune cell infiltration characteristics in AVF maturation. Patients and Methods: We analyzed the high-throughput sequencing dataset to identify differentially expressed genes (DEGs). Then, we performed enrichment analyses (GO, KEGG, GSEA) on immune-related genes and pathways in mature AVF. We focused on differentially expressed immune-related genes (DEIRGs) and constructed a PPI network to identify hub genes. These hub genes were validated in other databases and experiments, including qPCR and immunohistochemistry (IHC). The immune cell infiltration characteristics in native veins, failed AVFs, and matured AVFs were analyzed by cibersortX. Partial experimental validation was conducted using clinical samples. Results: Our results showed that immune-related genes and signaling pathways are significantly enriched in mature AVF. We validated this in other databases and ultimately identified three hub genes (IL1B, IL6, CXCR4) in combination with experiments. Significant differences in immune cell infiltration characteristics were observed among native veins, failed AVFs, and matured AVFs. Immune cell infiltration analysis revealed that accumulation of CD4+ T cells, dendritic cells, mast cells and M2 macrophages contribute to AVF maturation. These immune-related genes and immune cells have the potential to serve as predictive factors for AVF maturation. We partially validated this experimentally. Conclusion: From a bioinformatics perspective, our results have identified, for the first time, a set of immune-related genes and immune cell infiltration features that can characterize the maturation of AVF and significantly impact AVF maturation. These features hold potential as predictive indicators for AVF maturation outcomes.

Study on prediction of arterio-venous fistula maturation by flow mediated dilatation and AVF blood flow.

BACKGROUND: The physiology and pathology of AVF maturation depends on the vessels characteristics and its ability to remodel. Outcome of AVF using flow mediated dilatation (FMD), AVF blood flow and diameter has been studied. METHODOLOGY: Present observational study included single stage AVF (both Radiocephalic and Brachiocephalic) in consecutive CKD five patients (n = 158) prospectively over 1 year. Demographic and Doppler ultrasound parameters of upper limb (for vessel diameter and FMD) at baseline were recorded. Blood flow, diameter and depth of AVF were studied at 2, 6 and 12 weeks and their association with clinical maturation (usage of fistula with two needles for 75% of dialysis sessions during 15 day period) was studied (n = 129, after excluding lost to followup and expired patients; accordingly cohort was divided in matured (M) or non-matured (NM) groups. Clinical and radiological parameters between both groups were compared; receiver operator curve (ROC) and correlation of Doppler parameters were analysed. RESULTS: Of 129 AVF, 67.4% were matured and 32.5% non-matured. Mean age was 40 years with male predominance75% in both the groups. The mean arterial diameter for distal (NM = 1.96 ± 0.58 and M = 2.02 ± 0.41) and proximal AVF (NM = 3.37 ± 0.82 and M = 3.36 ± 0.75) was not statistically different in both the groups. The matured fistula group had a mean FMD of 11.67 ± 4.09 as against FMD value of 9.365 ± 3.55 in the failed fistula group (p value 0.01). For maturation prediction, sensitivity and specificity of blood flow at 2 weeks were 86.2% and 59.5% and at 6 weeks 96.6% and 64.3%, respectively. In multivariate analysis predictors for AVF maturation were FMD (adjusted odds ratio (AOR) = 1.15) and blood flow (AOR = 1.67). CONCLUSION: Second and Sixth week AVF blood flow was found to be predicting AVF maturation. Higher baseline FMD correlated with the AVF maturation, but not with vessel diameter.

Heterogeneous Population of Immune cells Associated with Early Thrombosis in Arteriovenous Fistula.

End-Stage Renal Disease (ESRD) is a growing cause of morbidity and mortality in the practice of modern medicine. Advances in medicine have elongated the average life span and subsequently made chronic diseases prevalent. Hemodialysis is the main treatment that is used to treat ESRD and is a clinical procedure that is being re-imagined with novel approaches to improve patient and clinic practicality and effectiveness. Arteriovenous Fistulas (AVF) are now used in place of catheters due to their higher success and lower co-morbidities. The main drawback of AVF is the time gap that is needed from the surgical creation of AVF to its use. During this time, the AVF is susceptible to thrombosis and occlusion rendering the fistula ineffective for treatment. Immune cells play a major role in vascular pathologies and macrophages, dendritic cells, and T-regulatory cells are the main cells seen during the inflammatory and anti-inflammatory phases. However, the role of immune response and immune cells in AVF maturation is poorly understood. This study aimed to investigate the immune response and immune cell expression in femoral vessels after AVF creation in a miniswine model of AVF using immunohistochemistry and qRT-PCR. The results of this study revealed an increased expression of immune cells in AVF vessels and suggest an association of immune response with AVF creation and maturation.

von Willebrand Factor: A Central Regulator of Arteriovenous Fistula Maturation Through Smooth Muscle Cell Proliferation and Outward Remodeling.

Background Arteriovenous fistula (AVF) maturation failure is a main limitation of vascular access. Maturation is determined by the intricate balance between outward remodeling and intimal hyperplasia, whereby endothelial cell dysfunction, platelet aggregation, and vascular smooth muscle cell (VSMC) proliferation play a crucial role. von Willebrand Factor (vWF) is an endothelial cell-derived protein involved in platelet aggregation and VSMC proliferation. We investigated AVF vascular remodeling in vWF-deficient mice and vWF expression in failed and matured human AVFs. Methods and Results Jugular-carotid AVFs were created in wild-type and vWF-/- mice. AVF flow was determined longitudinally using ultrasonography, whereupon AVFs were harvested 14 days after surgery. VSMCs were isolated from vena cavae to study the effect of vWF on VSMC proliferation. Patient-matched samples of the basilic vein were obtained before brachio-basilic AVF construction and during superficialization or salvage procedure 6 weeks after AVF creation. vWF deficiency reduced VSMC proliferation and macrophage infiltration in the intimal hyperplasia. vWF-/- mice showed reduced outward remodeling (1.5-fold, P=0.002) and intimal hyperplasia (10.2-fold, P<0.0001). AVF flow in wild-type mice was incremental over 2 weeks, whereas flow in vWF-/- mice did not increase, resulting in a two-fold lower flow at 14 days compared with wild-type mice (P=0.016). Outward remodeling in matured patient AVFs coincided with increased local vWF expression in the media of the venous outflow tract. Absence of vWF in the intimal layer correlated with an increase in the intima-media ratio. Conclusions vWF enhances AVF maturation because its positive effect on outward remodeling outweighs its stimulating effect on intimal hyperplasia.

TLR-4 Inhibition Attenuates Inflammation, Thrombosis, and Stenosis in Arteriovenous Fistula in Yucatan Miniswine.

Arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis patients; however, it is afflicted with a high failure rate. Chronic inflammation, excessive neointimal hyperplasia (NIH), vessel stenosis, early thrombosis, and failure of outward remodeling are the major causes of AVF maturation failure. Inflammatory mediator toll-like receptor (TLR)-4 plays a critical role in NIH, arterial thrombosis, and stenosis. We investigated the effect of TLR-4 inhibition on early thrombosis. Yucatan miniswine were used to create AVF involving femoral artery and femoral vein and treated with TLR-4 inhibitor TAK-242 with ethanol as the vehicle. The vessels were assessed after 12 weeks using histomorphometry, immunostaining, ultrasound, angiography, and optical coherence tomography. Inhibition of TLR-4 attenuated inflammation and early thrombosis in 50% of animals, and blood flow was present through AVF in 25% of animals. Thus, targeting TLR-4 to attenuate inflammation and early thrombosis might be a therapeutic approach to keep AVF patent and maintain blood flow through the outflow vein.

Sterile inflammation in the pathogenesis of maturation failure of arteriovenous fistula.

Chronic kidney disease is a widespread terminal illness that afflicts millions of people across the world. Hemodialysis is the predominant therapeutic management strategy for kidney failure and involves the external filtration of metabolic waste within the circulation. This process requires an arteriovenous fistula (AVF) for vascular access. However, AVF maturation failures are significant obstacles in establishing long-term vascular access for hemodialysis. Appropriate stimulation, activation, and proliferation of smooth muscle cells, proper endothelial cell orientation, adequate structural changes in the ECM, and the release of anti-inflammatory markers are associated with maturation. AVFs often fail to mature due to inadequate tissue repair and remodeling, leading to neointimal hyperplasia lesions. The transdifferentiation of myofibroblasts and sterile inflammation are possibly involved in AVF maturation failures; however, limited data is available in this regard. The present article critically reviews the interplay of various damage-associated molecular patterns (DAMPs) and the downstream sterile inflammatory signaling with a focus on the NLRP3 inflammasome. Improved knowledge concerning AVF maturation pathways can be unveiled by investigating the novel DAMPs and the mediators of sterile inflammation in vascular remodeling that would open improved therapeutic opportunities in the management of AVF maturation failures and its associated complications.

The role of venous diameter in predicting arteriovenous fistula maturation: when not to expect an AVF to mature according to pre-operative vein diameter measurements? A best evidence topic.

This best evidence topic was investigated according to a described protocol. We asked the question: what is the minimal vein diameter that can successfully predict maturation of an arteriovenous fistula (AVF) in patients undergoing dialysis. Using the reported search 804 papers were found, of which five represented the best evidence to answer the clinical question. All studies assessed the association between successful AVF maturation and the size of vein used. The strongest evidence came from a nonrandomised controlled follow-up study in which 76% of fistulas created using >2 mm cephalic vein successfully matured compared to 16% when the vein measured ≤2 mm. Another prospective, multicentre study showed 65% successful maturation using veins >4 mm compared to 45% with veins <3 mm. Vein diameter was found to be an independent predictor of maturation in multivariate regression analysis in two retrospective observational studies. Another retrospective observational study found that using venous measurements of ≥2.5 mm following tourniquet application resulted in more fistulas been created that would have otherwise been denied based on venous ultrasound mapping. A large multicentre randomised clinical trial assessing the use of different vein sizes both with and without tourniquet application using proper statistical tools - such as receiver operating characteristic - is required to make a final recommendation. Until then, a vein diameter of <2.5 mm should be considered inadequate for formation of an AVF, particularly if those measurements remain unchanged following the use of tourniquet.