Arteriovenous Fistula Maturation Failure Research Articles

Intraoperative transit time flow measurement predicts maturation of radiocephalic arteriovenous fistulas

ObjectiveThe 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. MethodsIn 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. ResultsThe 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). ConclusionsThe 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.

Intimal CD31-Positive Relative Surfaces Are Associated with Systemic Inflammatory Markers and Maturation of Arteriovenous Fistula in Dialysis Patients.

Arteriovenous fistula dysfunction is a widely disputed subject in the scientific literature on end-stage kidney disease (ESKD). The main cause of mortality and morbidity in these patients is the non-maturation or dysfunction of the arteriovenous fistula. Despite the many complications, the native arteriovenous fistula remains the gold standard in the treatment of these patients requiring renal replacement. This study aims to discuss the predictive role of some systemic inflammatory biomarkers (NLR, PLR, SII, IL-6), intimal hyperplasia, and neoangiogenesis (characterized by intimal-media CD31-positive relative surface) in arteriovenous fistula maturation failure. The present study was designed as an observational, analytical, and prospective study which included patients diagnosed with ESKD with indications of radio-cephalic arteriovenous fistula (RCAVF). Demographic data, comorbidities, preoperative laboratory data and histological/digital morphometry analysis results were processed. The patients included were divided into two groups based on their AVF maturation status at 8 weeks: "Maturation" (Group 1) and "Failed Maturation" (Group 2). There was no difference in the demographic data. In terms of comorbidities, the second group had a greater incidence of heart failure (p = 0.03), diabetes (p = 0.04), peripheral artery disease (p = 0.002), and obesity (p = 0.01). Additionally, regarding the laboratory findings, these patients had higher levels of serum uric acid (p = 0.0005), phosphates (p < 0.0001), and creatinine (p = 0.02), as well as lower levels of total calcium (p = 0.0002), monocytes (p = 0.008), and lymphocytes (p < 0.0001). Moreover, all inflammatory markers (p = 0.001; p < 0.0001; p = 0.006, and p = 0.03) and Ca-P product (p < 0.0001) had higher baseline values in Group 2. Upon immunohistochemical analysis, regarding the density of neoformed vessels, there was a higher incidence of CD31-positive surfaces (p = 0.006) and CD31-positive relative surfaces (p = 0.001); the NLR (r = 0.323; p = 0.03), PLR (r = 0.381; p = 0.04), SII (r = 0.376; p = 0.03), and IL-6 (r = 0.611; p < 0.001) are all significantly correlated with vascular density, as evidenced by CD31. Heart failure, peripheral artery disease, obesity, and diabetes, as well as the systemic inflammatory markers (NLR, PLR, SII, IL-6), intimal hyperplasia, and CD31-positive relative surfaces are predictors of arteriovenous fistula maturation failures.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

Rates of arteriovenous fistula maturation failure are still high, especially when suboptimal size veins are used. During successful maturation, the vein undergoes lumen dilatation and medial thickening, adapting to the increased hemodynamic forces. The vascular extracellular matrix plays an important role in regulating these adaptive changes and may be a target for promoting fistula maturation. In this study, we tested whether a device-enabled photochemical treatment of the vein prior to fistula creation facilitates maturation. Sheep cephalic veins were treated using a balloon catheter coated by a photoactivatable molecule (10-8-10 Dimer) and carrying an internal light fiber. As a result of the photochemical reaction, new covalent bonds were created during light activation among oxidizable amino acids of the vein wall matrix proteins. The treated vein lumen diameter and media area became significantly larger than the contralateral control fistula vein at 1 week (p = 0.035 and p = 0.034, respectively). There was also a higher percentage of proliferating smooth muscle cells in the treated veins than in the control veins (p = 0.029), without noticeable intimal hyperplasia. To prepare for the clinical testing of this treatment, we performed balloon over-dilatation of isolated human veins and found that veins can tolerate up to 66% overstretch without notable histological damage.

Brachiocephalic arteriovenous fistula maturity in end stage renal disease: The role of intraoperative brachial artery blood flow rate and peak systolic velocity.

Arteriovenous fistula (AVF) is the preferred vascular access option due to its lower risk of complications and better long-term outcomes. However, AVF maturation failure is still quite high. Achieving an adequate blood flow rate (BFR) through the AVF is essential for maintaining hemodialysis adequacy. This study aims to investigate brachial artery intraoperative BFR and peak systolic velocity (PSV) increase as a predictor of brachiocephalic AVF maturation. A multicenter retrospective cohort study was conducted on patients with end stage renal disease undergoing brachiocephalic AVF creation from July 2019 to February 2022 from five hospitals. Doppler ultrasound examinations of BFR and PSV were collected. BFR and PSV increases were calculated by comparing pre-operative and intraoperative results. Maturity was determined at 6 weeks postoperatively. This study included 83 patients, with 50 patients (60.24%) achieving maturity at 6 weeks. Brachial artery BFR difference has an excellent diagnostic value to predict brachiocephalic AVF maturation with an area under the curve (AUC) of 97%. BFR increase of 184.58 ml/min predicts brachiocephalic AVF maturity with a sensitivity of 100%, specificity of 84.8%, and accuracy of 93.98%. Meanwhile, brachial artery PSV increase has a low diagnostic value to predict brachiocephalic AVF with an AUC of 71.2%. PSV increase of 8.97 cm/s predicts brachiocephalic AVF maturity with a sensitivity of 82%, specificity of 51.5%, and accuracy of 69.9%. The increase in intraoperative brachial artery BFR and PSV in brachiocephalic AVF can be used as a useful parameter to predict AVF maturation.

Oncostatin M, Serpins, and Oxidative Stress in Extracellular Matrix Remodeling and Arteriovenous Fistula Maturation.

End-stage renal disease is a crippling diagnosis that generally requires dialysis to prolong life. To facilitate filtration of patient's blood in dialysis, surgical formation of an arteriovenous fistula (AVF) is commonly performed. Maturation of the AVF is required to allow for successful dialysis. However, AVFs commonly fail to mature, leading to the fistula closure, the necessity for another fistula site, and markedly increased morbidity and mortality. The current literature concerning molecular mechanisms associated with AVF maturation failure supports the role of inflammatory mediators involving immune cells and inflammatory cytokines. However, the role of oncostatin M (OSM), an inflammatory cytokine, and its downstream targets are not well investigated. Through inflammation, oxidative stress, and hypoxic conditions, the vascular tissue surrounding the AVF undergoes fibrosis, stenosis, and wall thickening, leading to complete occlusion and nonfunctional. In this report, first we critically review the existing literature on the role of OSM in the most common causes of early AVF failure - vascular inflammation, thrombosis, and stenosis. We next consider the potential of using OSM as a therapeutic target, and finally discuss therapeutic agents targeting inflammatory mediators involved in OSM signaling to potentiate successful maturation of the AVF.

Brachial artery and cephalic vein diameter as maturation predictors of brachiocephalic arteriovenous fistula in end-stage renal diseases with type 2 diabetes mellitus

Introduction: Arteriovenous fistula (AVF) is the gold standard for vascular access for hemodialysis in end-stage renal disease (ESRD) patients. There is a high rate of AVF maturation failure, especially in DM patients, and it takes longer for maturation in diabetes mellitus (DM) patients. This study aimed to obtain the recommendations for the minimum diameter of the brachial artery and cephalic vein as a predictor of brachiocephalic AVF maturation in ESRD patients with type 2 diabetes mellitus after six weeks to eight weeks of AVF creation. Methods: This study is a retrospective cohort study using secondary data from patients with brachiocephalic arteriovenous fistula. The examined variables were brachial artery diameter, cephalic vein diameter, and brachiocephalic arteriovenous fistula maturation. Comparative analysis and ROC curve analysis were performed. Results: A total of 72 patients met the inclusion and exclusion criteria. Forty-four (61,11%) patients were mature at six weeks, while 47 (65,28%) were mature at eight weeks postoperatively. At week six, the mature group had a significantly larger cephalic vein diameter (3,20±0,94 vs. 2,65±1,02, p=0,002). At week eight there was a significantly larger brachial artery (4,22±0,70 vs 3,78±0,60, p=0,012), and cephalic vein diameter (3,28±0,98 vs 2,43±0,82, p=0,000) in the mature group. Conclusion: The best threshold value for preoperative brachial artery diameter predicting AVF maturation eighth week was 3.85 mm. The best threshold value for preoperative cephalic vein diameter predicting AVF maturation at the sixth week was 2.45 mm, and at the eighth week, it was 2.45 mm.

The Predictive Value of Systemic Inflammatory Markers, the Prognostic Nutritional Index, and Measured Vessels' Diameters in Arteriovenous Fistula Maturation Failure.

Background: An arteriovenous fistula (AVF) is the first-line vascular access pathway for patients diagnosed with end-stage renal disease (ESRD). In planning vascular access, it is necessary to check the diameters of the venous and arterial components for satisfactory long-term results. Furthermore, the mechanism underlying the maturation failure and short-term patency in cases of AVFs is not fully known. This study aims to verify the predictive role of inflammatory biomarkers (the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), systemic inflammatory index (SII), and C-reactive protein (CRP)), Ca-P product, the prognostic nutritional index (PNI), and the diameters of the venous and arterial components in the failure of AVF maturation. Methods: The present study was designed as an observational, analytical, and retrospective cohort study with a longitudinal follow-up, and included all patients with a diagnosis of ESRD that were admitted to the Vascular Surgery Clinic of the Targu Mures Emergency County Hospital, Romania, between January 2019 and December 2021. Results: The maturation of AVF at 6 weeks was clearly lower in cases of patients in the high-NLR (31.88% vs. 91.36%; p < 0.0001), high-PLR (46.94% vs. 85.55%; p < 0.0001), high-SII (44.28% vs. 88.89%; p < 0.0001), high-CRP (46.30% vs. 88.73%; p < 0.0001), high-Ca-P product (40.43% vs. 88.46%; p < 0.0001), and low-PNI (34.78% vs. 91.14%; p < 0.0001) groups, as well as in patients with a lower radial artery (RA) diameter (40% vs. 94.87%; p = 0.0009), cephalic vein (CV) diameter (44.82% vs. 97.14%; p = 0.0001) for a radio-cephalic AVF (RC-AVF), and brachial artery (BA) diameter (30.43% vs. 89.47%; p < 0.0001) in addition to CV diameter (40% vs. 94.59%; p < 0.0001) for a brachio-cephalic AVF (BC-AVF), respectively. There was also a significant increase in early thrombosis and short-time mortality in the same patients. A multivariate analysis showed that a baseline value for the NLR, PLR, SII, CRP, Ca-P product, and PNI was an independent predictor of adverse outcomes for all of the recruited patients. Furthermore, for all patients, a high baseline value for vessel diameter was a protective factor against any negative events during the study period, except for RA diameter in mortality (p = 0.16). Conclusion: Our findings concluded that higher NLR, PLR, SII, CRP, Ca-P product, and PNI values determined preoperatively were strongly predictive of AVF maturation failure, early thrombosis, and short-time mortality. Moreover, a lower baseline value for vessel diameter was strongly predictive of AVF maturation failure and early thrombosis.

Effect of primary balloon angioplasty on draining vein diameter and volume flow in patients with arteriovenous fistula: A cohort study

BackgroundChronic kidney disease (CKD) and end-stage kidney disease (ESKD) cause major morbidity and mortality in 10% of the global population with CKD. The most common renal replacement therapy is hemodialysis with arteriovenous fistula (AVF) access. AVF often undergoes maturation failure due to feeding artery and draining vein inadequacy. Mechanical dilatation, such as primary balloon angioplasty (PBA), can overcome AVF maturation failure. The volume flow (VF) and diameter of the draining veins in AVF patients must be known to evaluate the effect of PBA on AVF maturation. This study aims to analyze the impact of PBA on VF and draining vein diameter in ESKD patients undergoing AVF surgery. MethodsA retrospective cohort clinical trial was conducted at our institution. A total of 75 participants had AVF with an arterial diameter >1.5 mm or vein diameter at the AVF creation site of 2–4 mm. The subjects were divided into 2 groups: the intervention group undergoing PBA (n = 36) and the control group, without PBA (n = 39). PBA was performed using a Mustang ballon (3–6 mm, Medtronic). Follow-ups were conducted at 1 week, 2 weeks, and 6 weeks after AVF creation. ResultsBased on the data, the diameter and VF of the draining veins were significantly larger in the intervention group than in the control group (p < 0.001). Furthermore, we found significant differences in the mean diameter and VF of the draining veins between the control and intervention groups at all stages of examination, from preoperatively to 6 weeks postoperatively (p < 0.001). The strength of the analysis was more than 80%. ConclusionPBA can increase the diameter and VF of the draining veins in patients with AVF.

Role of platelet factor 4 in arteriovenous fistula maturation failure: What do we know so far?

The rate of arteriovenous fistula (AVF) maturation failure remains unacceptably high despite continuous efforts on technique improvement and careful pre-surgery planning. In fact, half of all newly created AVFs are unable to be used for hemodialysis (HD) without a salvage procedure. While vascular stenosis in the venous limb of the access is the culprit, the underlying factors leading to vascular narrowing and AVF maturation failure are yet to be determined. We have recently demonstrated that AVF non-maturation is associated with post-operative medial fibrosis and fibrotic stenosis, and post-operative intimal hyperplasia (IH) exacerbates the situation. Multiple pathological processes and signaling pathways are underlying the stenotic remodeling of the AVF. Our group has recently indicated that a pro-inflammatory cytokine platelet factor 4 (PF4/CXCL4) is upregulated in veins that fail to mature after AVF creation. Platelet factor 4 is a fibrosis marker and can be detected in vascular stenosis tissue, suggesting that it may contribute to AVF maturation failure through stimulation of fibrosis and development of fibrotic stenosis. Here, we present an overview of the how PF4-mediated fibrosis determines AVF maturation failure.

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.

Contact Laxative Use and the Risk of Arteriovenous Fistula Maturation Failure in Patients Undergoing Hemodialysis: A Multi-Center Cohort Study.

Laxatives are commonly prescribed for constipation management; however, they are recognized as an independent factor associated with cardiovascular diseases. Arteriovenous fistula (AVF) is the closest to the ideal model of hemodialysis (HD) vascular access and part of the cardiovascular system. Our study aims to explore the association of contact laxative use with AVF maturation outcomes in patients undergoing HD. We conducted a multi-center cohort study of 480 contact laxative users and 472 non-users who had undergone initial AVF creation. All patients were followed until the outcomes of AVF maturation were confirmed. Multivariable logistic regression models were performed to evaluate the risk of AVF maturation failure imposed by laxatives. Here, we found that patients who used contact laxatives were significantly associated with an increased risk of AVF maturation failure compared to non-users (adjusted odds ratio, 1.64; p = 0.003). Notably, the risk of AVF maturation failure increased when increasing their average daily doses and cumulative treatment days. In conclusion, our study found a significant dose- and duration-dependent relationship between contact laxative use and an increased risk of AVF maturation failure. Thus, laxatives should be prescribed with caution in this population. Further studies are needed to validate these observations and investigate the potential mechanisms.

Systemic Profile of Cytokines in Arteriovenous Fistula Patients and Their Associations with Maturation Failure.

Systemic cytokines are elevated in patients with chronic kidney disease (CKD) and on hemodialysis compared with the general population. However, whether cytokine levels interfere with vascular remodeling, increasing the risk of arteriovenous fistula (AVF) failure, remains unknown. This is a case-control study of 64 patients who underwent surgery for AVF creation (32 with AVF maturation failure and 32 matching controls with successful maturation). A total of 74 cytokines, including chemokines, interferons, interleukins, and growth factors, were measured in preoperative plasma samples using multiplex assays. Sixty-two patients were included in the statistical analyses. Associations with AVF failure were assessed using paired comparisons and conditional logistic regressions accounting for paired strata. Seven cytokines were significantly higher in patients with AVF maturation failure than in matching controls (G-CSF, IL-6, MDC, RANTES, SDF-1α/β, TGFα, and TPO). Of these, G-CSF (odds ratio [OR]=1.71; 95% confidence interval [95% CI], 1.05 to 2.79 per 10 pg/ml), MDC (OR=1.60, 95% CI, 1.08 to 2.38 per 100 pg/ml), RANTES (OR=1.55, 95% CI, 1.10 to 2.17 per 100 pg/ml), SDF-1α/β (OR=1.18, 95% CI, 1.04 to 1.33 per 1000 pg/ml), and TGFα (OR=1.39, 95% CI 1.003, 1.92 per 1 pg/ml) showed an incremental association by logistic regression. This study identified a profile of plasma cytokines associated with adverse maturation outcomes in AVFs. These findings may open the doors for future therapeutics and markers for risk stratification.

Transcriptomic Analysis Identifies Differentially Expressed Genes Associated with Vascular Cuffing and Chronic Inflammation Mediating Early Thrombosis in Arteriovenous Fistula.

Arteriovenous fistula (AVF) is vascular access created for hemodialysis in end-stage renal disease patients. AVF creation causes increased blood flow in the outflow vein with increased pressure. Increased blood flow, blood volume, and shear stress causes outward remodeling so that the outflow vein can withstand the increased pressure. Outward remodeling of the vein involved in AVF is necessary for AVF maturation, however, inward remodeling due to excessive neointimal hyperplasia (NIH) and chronic inflammation may end up with vessel thrombosis and AVF maturation failure. Early thrombosis of the vessel may be due to the luminal factors including NIH and chronic inflammation or due to chronic inflammation of the adventitial due to perivascular cuffing. Inflammation may either be due to an immune response to the vascular injury during AVF creation or injury to the surrounding muscles and fascia. Several studies have discussed the role of inflammation in vascular thrombosis due to intimal injury during AVF creation, but there is limited information on the role of inflammation due to surrounding factors like a muscle injury. The concept of perivascular cuffing has been reported in the nervous system, but there is no study of perivascular cuffing in AVF early thrombosis. We performed the bulk RNA sequencing of the femoral arterial tissue and contralateral arteries as we found thrombosed arteries after AVF creation. RNA sequencing revealed several significantly differentially expressed genes (DEGs) related to chronic inflammation and perivascular cuffing, including tripartite motif-containing protein 55 (TRIM55). Additionally, DEGs like myoblast determination protein 1 (MYOD1) increased after muscle injury and relates to skeletal muscle differentiation, and network analysis revealed regulation of various genes regulating inflammation via MYOD1. The findings of this study revealed multiple genes with increased expression in the AVF femoral artery and may provide potential therapeutic targets or biomarkers of early thrombosis in AVF maturation failure. Thus, not only the luminal factors but also the surrounding factors mediating vascular cuffing contribute to vessel thrombosis and AVF failure via early thrombosis, and targeting the key regulatory factors may have therapeutic potential.

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.

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.

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.

Early Adventitial Activation and Proliferation in a Mouse Model of Arteriovenous Stenosis: Opportunities for Intervention.

Background: Arteriovenous fistula (AVF) stenosis remains an important cause of AVF maturation failure, for which there are currently no effective therapies. We examined the pattern and phenotype of cellular proliferation at different timepoints in a mouse model characterized by a peri-anastomotic AVF stenosis. Methods: Standard immunohistochemical analyses for cellular proliferation and macrophage infiltration were performed at 2, 7 and 14 d on our validated mouse model of AVF stenosis to study the temporal profile, geographical location and cellular phenotype of proliferating and infiltrating cells in this model. Results: Adventitial proliferation and macrophage infiltration (into the adventitia) began at 2 d, peaked at 7 d and then declined over time. Surprisingly, there was minimal macrophage infiltration or proliferation in the neointimal region at either 7 or 14 d, although endothelial cell proliferation increased rapidly between 2 d and 7 d, and peaked at 14 d. Conclusions: Early and rapid macrophage infiltration and cellular proliferation within the adventitia could play an important role in the downstream pathways of both neointimal hyperplasia and inward or outward remodelling.

Maturation and survival of arteriovenous fistula: The challenge starts from the preoperative assessment stage.

It is necessary to assess the association between the preoperative indicators and the maturation and survival of arteriovenous fistula (AVF). We retrospectively identified 236 patients with a new AVF created between 2016 and 2018 in our Dialysis Center. Multivariate Logistic regression showed that preoperative arterial diameter (odds ratio [OR] = 1.452, 95% confidence interval [CI] [1.233, 1.710], p < 0.001), preoperative venous diameter (OR = 1.296, 95% CI [1.166, 1.477], p < 0.001), left ventricular ejection fraction (LVEF) (OR = 1.187, 95% CI [1.103, 1.277], p < 0.001), and diabetes mellitus (OR = 0.245, 95% CI [0.107, 0.560], p = 0.01) were independent influential factors for AVF maturation. Two years after the AVF surgery follow-up, multivariate Cox proportional-hazards model showed that the preoperative arterial diameter (OR = 0.510, 95% CI [0.320, 0.813], p = 0.005), preoperative venous diameter (OR = 0.940, 95% CI [0.897, 0.985], p = 0.010) and diabetes mellitus (OR = 1.785, 95% CI [1.117, 2.855], p = 0.016) was prognostic factors of AVF survival. The Kaplan-Meier method showed that the primary survival of AVF in patients with different preoperative arterial diameter was statistically significant (log-rank χ2 = 15.415, p < 0.001), while the secondary survival was not statistically significant (log-rank χ2 = 0.131, p = 0.717). In our cohort, the preoperative arterial and venous diameter and diabetes mellitus were independent influential factors for AVF maturation and prognostic factors of AVF survival. However, the preoperative LVEF only associated with the maturation of AVF. Meanwhile, smaller arterial diameter (≤2.15 mm) was associated with AVF maturation failure, but did not impact secondary survival of AVF.

Natural Vascular Scaffolding Treatment Promotes Outward Remodeling During Arteriovenous Fistula Development in Rats.

Following creation, an arteriovenous fistula (AVF) must mature (i.e., enlarge lumen to allow high blood flow) before being used for hemodialysis. AVF maturation failure rates are high, and currently, there are no effective therapy to treat this problem. The maturation process is likely affected by the integrity of the vascular extracellular matrix (ECM). Natural Vascular Scaffolding (NVS) Therapy is a new technology that interlinks collagen and elastin via photoactivation of a locally delivered small molecule (4-amino-1,8-naphtalamide). We hypothesized that NVS Therapy may improve AVF remodeling by preserving ECM integrity. AVFs were created in Wistar male rats by connecting the femoral vein (end) to femoral artery (side) in the same limb. Immediately after blood flow was restored to dilate the femoral vein by arterial pressure, a 10 μl-drop of the NVS compound (2 mg/ml) was placed on the anastomosis perivascularly. Following 5-min incubation, the NVS treated area was exposed to 1-min illumination by 450-nm light. The control group received 10 μl-drop of phosphate buffered saline (PBS) and the same light activation. The skin was closed, and rats were euthanized 4 weeks (n = 6–9 per group) post-AVF creation for histology, morphometry, immunohistochemistry (IHC), and multiphoton microscopy for second-harmonic-generation evaluation of collagen fibers. The vascular thickness was similar in both groups. The AVF vein’s open lumen area and % open lumen area in NVS-treated rats were significantly larger than in PBS-treated rats (4.2-fold p = 0.014 and 2-fold p = 0.009, respectively). The inflammatory markers IL-6 and MMP-9 in the AVF walls were significantly decreased in the NVS group than the PBS group. Collagen fibers in the vascular wall trended toward perpendicular alignment to the lumen circumference in the NVS-treated AVFs, with more defined shape but less area than in the PBS-treated AVFs. These results indicate that the NVS Therapy exerted changes in collagen, which may influence AVF maturation. Rats tolerated the NVS treatment well, and the lack of cell death by the treatment was confirmed in cell culture experiments. These results suggest that NVS treatment is safe and may have therapeutic potential by facilitating lumen expansion to enhanced AVF maturation in patients.

Analyses of hemodialysis arteriovenous fistula geometric configuration and its associations with maturation and reintervention

ObjectiveAn arteriovenous fistula (AVF) is the preferred vascular access for chronic hemodialysis; however, the rates of AVF maturation failure and reintervention remain high. We investigated the AVF geometric parameters and their associations with AVF physiologic maturation and reintervention in a prospective multicenter study. MethodsFrom 2011 to 2016, patients undergoing vein end-to-artery side upper extremity AVF creation surgery were recruited. Contrast-free dark blood and phase-contrast magnetic resonance imaging (MRI) scans were performed using 3.0T scanners to obtain the AVF lumen geometry and flow rates, respectively, at postoperative day 1, week 6, and month 6. The arteriovenous anastomosis angle, nonplanarity, and tortuosity of the fistula were calculated according to the lumen centerlines. AVFs were considered physiologically matured if, using the week 6 MRI data, the flow rate was ≥500 mL/min and the minimum vein lumen diameter was ≥5 mm. The associations of these geometric parameters with AVF maturation and reintervention due to perianastomotic and mid-vein stenosis within 1 year were assessed. ResultsA total of 111 patients had a usable day 1 MRI scan, with most having upper arm AVFs (n = 73). Compared with the forearm AVFs, upper arm AVFs had greater anastomosis angles (P < .001), larger deviations from a plane (nonplanarity; P = .002), and more prominent tortuosity (P = .038) at day 1. These parameters significantly increased between day 1 and week 6 in upper arm AVFs. In contrast, significant changes in these parameters in forearm AVFs were not observed. The rate of maturation was 54% and 86% for forearm and upper arm AVFs, respectively. None of the geometric parameters at day 1 were associated with AVF maturation in either location. The rate of reintervention was 24% and 30% for forearm and upper arm AVFs, respectively, with a larger nonplanarity angle at day 1 associated with less reintervention (30° ± 15° vs 21° ± 10°; P = .034) in upper arm AVFs only. This relationship was unchanged after adjusting for age, sex, race, dialysis status, or diabetes. ConclusionsIn our study, upper arm fistulas had a larger anastomosis angle, were more nonplanar, and had more tortuous veins than forearm fistulas. For upper arm fistulas, a larger nonplanarity angle is associated with a lower rate of reintervention within 1 year. Once confirmed, vascular surgeons could consider increasing the nonplanarity angle by incorporating a tension-free gentle curvature in the proximal segment of the mobilized vein to reduce reinterventions when creating an upper arm fistula.