Arteriovenous Fistula Maturation Failure Research Articles

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.

Hypoxia-inducible factors in arteriovenous fistula maturation: A prospective cohort study.

Neointimal hyperplasia is the main cause of arteriovenous fistula (AVF) failure. Hypoxia-inducible factors (HIFs) factors are associated with neointimal hyperplasia. Thus, we investigated the association between HIF-2 alpha (HIF-2α) and AVF maturation in end-stage kidney disease (ESKD) patients. This prospective cohort study was conducted in 21 voluntary healthy subjects and 50 patients with ESKD who were eligible for AVF creation. Inclusion criteria were being ESKD patients without a history of AVF surgery and dialysis. Eight patients excluded from the study due to having unavailable veins six patients were excluded due to acute thrombosis after surgery. One patient lost to follow-up. A total of 35 patients were included in final analysis. The blood samples were collected a day before the AVF surgery for biochemical parameters and HIF-2α measurement. HIF-2α levels were measured by the ELISA method. Compared with healthy subjects, ESKD patients had a significantly higher level of HIF-2α. [1.3 (1.0-1.9) vs 2.2 (1.6-3.0)] (P=.002). Patients were divided into two groups after the evaluation of AVF maturation, as the mature group (n=19) and the failure group (n=16). Serum HIF-2α level was 1.7 (1.1-1.8) in the mature group; however, it was 3.1 (2.8-3.3 in failure group (P<.001). Multiple logistic regression analyses showed that HIF-2α independently predicted AVF maturation. The ROC curve analysis showed that HIF-2α>2.65 predicted AVF maturation failure with the 87% sensitivity and 94% specificity [AUC:0.947, 95% CI (0.815-0.994), P<.001]. HIF-2-α levels were higher in ESKD patients than healthy subjects. HIF-2-α could be a marker of AVF maturation failure.

Arteriovenous fistula maturation rate is not affected by ipsilateral tunneled dialysis catheter

ObjectiveThe effect that ipsilateral tunneled dialysis catheters (TDC) have on arteriovenous fistula (AVF) maturation is unclear. We sought to define this association by comparing AVF maturation rates in patients with contralateral TDC with those with ipsilateral TDC. MethodsA review of a prospectively maintained database including all AVF creation procedures between 2009 and 2016 was performed. All patients with a TDC in place at the time of AVF creation were included in this study. Clinical and functional maturation rates were compared in patients with contralateral vs ipsilateral dialysis catheters. Categorical variables were analyzed by a two-tailed Fisher's exact test. A P value of less than .05 was considered statistically significant. ResultsThere were 187 patients who underwent fistula creation with a TDC in place during the study period. Of those, 137 patients had a contralateral TDC and 50 had an ipsilateral TDC. A greater proportion of contralateral patients were first-time dialysis access patients at the time of index AVF creation (67% vs 48%; P = .03). There was no difference in clinical (contralateral 73% vs ipsilateral 78%; P = .57) and functional (contralateral 64% vs ipsilateral 74%) maturation rates between the two groups. The rate of TDC removal after AVF maturation was also not different (contralateral 64% vs ipsilateral 72%; P = .30). There was also no statistical difference in the rates of thrombosis at less than 30 days, outflow stenosis, central stenosis, and steal syndrome. ConclusionsThere was no association between TDC sidedness and AVF maturation or early failure in our cohort. Planning for AVF creation should not be influenced by attempts to avoid an ipsilateral TDC.

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation

The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

Baseline characteristics of arm vessels by preoperative duplex ultrasonography in Korean patients for hemodialysis vascular access.

Preoperative mapping with duplex ultrasonography is crucial for successful vascular access creation for hemodialysis. The aims of this study are to assess the baseline characteristics of arm vessels by preoperative duplex ultrasonography in Korean patients, to find out a preoperative duplex ultrasonography parameter precluding distal arteriovenous fistula creation, to assess the maturation failure rate of arteriovenous fistulas, and to identify associated risk factors. Preoperative duplex ultrasonography mapping for vascular access creation was done in all patients with end-stage renal diseases during the year 2015. The baseline data of duplex ultrasonography were retrospectively analyzed with follow-up clinical data. A total of 299 end-stage renal disease patients (mean age = 62 years, 62% male) were included. On preoperative duplex ultrasonography, mean diameters of radial artery and cephalic vein at wrist were 2.03 and 2.40 mm in the non-dominant arm and 2.10 and 2.26 mm in the dominant arm, respectively. The most common reason for precluding radial-cephalic arteriovenous fistula at wrist was small-sized cephalic vein. Multivariate logistic regression analysis revealed that the risk factors for inadequate vessels were warfarin treatment, old age (⩾75 years), and peripheral arterial occlusive disease. The rate of arteriovenous fistula maturation failure was 21% and vein diameter <2.5 mm was the only risk factor for arteriovenous fistula maturation failure by multivariate logistic regression analysis. Preoperative duplex ultrasonography evaluation is important to find out inadequate vessels for native arteriovenous fistula and to determine the location of vascular access.

The effect of endothelial nitric oxide synthase on the hemodynamics and wall mechanics in murine arteriovenous fistulas

Creation of a hemodialysis arteriovenous fistula (AVF) causes aberrant vascular mechanics at and near the AVF anastomosis. When inadequately regulated, these aberrant mechanical factors may impede AVF lumen expansion to cause AVF maturation failure, a significant clinical problem with no effective treatments. The endothelial nitric oxide synthase (NOS3) system is crucial for vascular health and function, but its effect on AVF maturation has not been fully characterized. We hypothesize that NOS3 promotes AVF maturation by regulating local vascular mechanics following AVF creation. Here we report the first MRI-based fluid-structure interaction (FSI) study in a murine AVF model using three mouse strains: NOS3 overexpression (NOS3 OE) and knockout (NOS3−/−) on C57BL/6 background, with C57BL/6 as the wild-type control (NOS3+/+). When compared to NOS3+/+ and NOS3−/−, AVFs in the OE mice had larger lumen area. AVFs in the OE mice also had smoother blood flow streamlines, as well as lower blood shear stress at the wall, blood vorticity, inner wall circumferential stretch, and radial wall thinning at the anastomosis. Our results demonstrate that overexpression of NOS3 resulted in distinct hemodynamic and wall mechanical profiles associated with favorable AVF remodeling. Enhancing NOS3 expression may be a potential therapeutic approach for promoting AVF maturation.

Correlation between preoperative vein and artery diameters and arteriovenous fistula outcome in patients with end-stage renal disease.

Background and aimsArteriovenous fistula (AVF) maturation failure rates remain high in patients with end-stage renal disease (ESRD). Although preoperative morphological and functional assessment of blood vessels by duplex ultrasonography (DUS) has been shown to improve AVF maturation, there is no consensus regarding the optimal vein (VD) and artery (AD) diameters to be universally used for AVF creation. To improve patient selection, set out to investigate if there is a correlation between preoperative VD/AD and clinical covariates, and postoperative AVF outcome.MethodsThis was a prospective cohort study conducted during January–August 2014. ESRD patients referred to “Niculae Stăncioiu” Heart Institute Cluj-Napoca, who had a VD ≥1.9 mm and AD ≥1.5 mm, as measured by DUS, and underwent AVF creation were enrolled. We assessed whether preoperative VD/AD and clinical covariates were associated with AVF maturation rate and primary patency at 2 years after AVF creation.ResultsOf 115 patients referred for AVF creation, 93 were included in the study. Mean (± standard deviation) VD was 3.3 ± 1.1 mm and VDs were distributed in quartile Q1 <2.55 mm, Q2: 2.56–3.10 mm, Q3: 3.11–3.70 mm and Q4: >3.71 mm. Mean AD was 3.3 ± 1.4 mm and ADs were distributed in Q1 <2.55 mm, Q2: 2.56–3.10 mm, Q3: 3.11–3.70 mm, and Q4, >3.71 mm. AVF maturation rate increased proportionally with VD from Q1 (62%) to Q2 (70%), Q3 (82%) to Q4 (96%) (p=0.03). Based on AD, a higher AVF maturation rate was observed in Q3 (86%), Q4 (83%) vs Q1 (71%) and Q2 (67%). Long-term primary patency of AVFs seemed not to be influenced by VD and AD. In older patients and those with peripheral arterial disease, AVF maturation failure tended to be higher.ConclusionsOur findings suggest that a preoperative VD ≥1.9 mm and AD ≥1.5 mm have a successful maturation rate of AVF greater than 60% in ESRD patients. The maturation rate of surgical AVF increases proportionally with the size of VD used for AVF creation.

Effect of Anti-Hypertensive Medication History on Arteriovenous Fistula Maturation Outcomes

Background: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. However, approximately half of AVFs fail to mature. The use of angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) exerts favorable endothelial effects and may promote AVF maturation. We tested associations of ACE-I and ARBs, CCBs, beta-blockers, and diuretics with the maturation of newly created AVFs. Methods: We evaluated 602 participants from the Hemodialysis Fistula Maturation Study, a multi-center, prospective cohort study of AVF maturation. We ascertained the use of each medication class within 45 days of AVF creation surgery. We defined maturation outcomes by clinical use within 9 months of surgery or 4 weeks of initiating hemodialysis. Results: Unassisted AVF maturation failure without intervention occurred in 54.0% of participants, and overall AVF maturation failure (with or without intervention) occurred in 30.1%. After covariate adjustment, CCB use was associated with a 25% lower risk of overall AVF maturation failure (95% CI 3%–41% lower) but a non-significant 10% lower risk of unassisted maturation failure (95% CI 23% lower to 5% higher). ACE-I/ARB, beta-blocker, and diuretic use was not significantly associated with AVF maturation outcomes. None of the antihypertensive medication classes were associated with changes in AVF diameter or blood flow over 6 weeks following surgery. Conclusions: CCB use may be associated with a lower risk of overall AVF maturation failure. Further studies are needed to determine whether CCBs might play a causal role in improving AVF maturation outcomes.

Arteriovenous Fistula Maturation Failure in a Large Cohort of Hemodialysis Patients in the Netherlands

ObjectivesRadiocephalic arteriovenous fistulas (RCAVF) are the preferred vascular access (VA) for hemodialysis (HD). Cohort studies from North America revealed that nonmaturation is a significant disadvantage of RCAVFs compared to other VAs. DESIGN: This present retrospective study describes the incidence of nonmaturation of AVFs and functional failure of arteriovenous grafts (AVG) in a multicentre cohort in the Netherlands and attempts to create a prediction model for nonmaturation of RCAVFs. Furthermore, the efficacy of interventions to promote maturation as well as the variability between hemodialysis centers was evaluated.MaterialsMedical records from 8 hospitals from 1997 to 2016 were retrospectively evaluated for VA type, maturation/primary success and demographics and comorbidities.MethodsA prediction model was created for RCAVF nonmaturation using multivariate logistic regression analysis, selecting significant predictors using backward selection. Discrimination and calibration of the model were assessed.Results1383 AVFs and 273 AVGs were included in 1221 patients. Overall nonmaturation was 24% for RCAVFs, and 11% for upper arm AVFs. The functional failure rate for AVGs was 6%. The nonmaturation rate of contralateral RCAVFs after failure of an RCAVF was 22%. Procedures to improve RCAVF maturation were successful in 98/142 cases (69%). Predictors for nonmaturation were female gender, peripheral vascular disease, cerebrovascular disease and a cephalic vein diameter <2.5 mm, but the prediction model lacked sensitivity and specificity predicting individual RCAVF nonmaturation (C-statistic 0.629).ConclusionNonmaturation rates are highest for RCAVFs, but nonmaturation could not be predicted with demographic parameters.

Pre-existing arterial pathologic changes affecting arteriovenous fistula patency and cardiovascular mortality in hemodialysis patients.

The radiocephalic arteriovenous fistula (AVF) provides optimal vascular access for hemodialysis; it has a higher long-term patency rate and fewer complications than other vascular access methods. However, the AVF has a high primary failure rate. The presence of small-diameter vessels at anastomosis sites is an important risk factor for AVF failure. However, in a recent study, despite selecting an adequate artery and vein for creating an AVF by routine preoperative vascular mapping, AVF maturation and primary failure occurred. Thus, pre-existing arteriosclerosis at AVF anastomosis sites likely contributes to AVF failure. In this review, we discuss the relationship between pathologic changes and AVF patency in hemodialysis patients. Because arteriosclerosis of the major arteries such as the coronary and carotid arteries is associated with cardiovascular mortality, we also review the impact of arteriosclerosis of upper arm arteries at AVF anastomosis sites on cardiovascular mortality in hemodialysis patients.

Contribution of monoamine oxidases to vascular oxidative stress in patients with end-stage renal disease requiring hemodialysis.

Arteriovenous fistula (AVF) is the "lifeline" for patients with end-stage renal disease (ESRD) undergoing hemodialysis. AVF maturation failure is a poorly understood process, one of the contributors being endothelial dysfunction due to oxidative stress. Monoamine oxidases (MAOs) A and B were recently identified as novel sources of vascular oxidative stress. The aim of the present study was to assess the contribution of MAOs to the endothelial dysfunction in patients with ESDR with indication of hemodialysis. Fragments of brachial artery collaterals were harvested from ESRD patients during the surgical procedure aimed at creating the vascular access in the cubital fossa. The effect of increasing concentrations (10, 30, 100 μmol/L) of the irreversible MAO-A inhibitor, clorgyline, and MAO-B inhibitor, selegiline, on endothelial-dependent relaxation (EDR) in response to cumulative doses of acetylcholine was studied in isolated phenylephrine-preconstricted vascular rings. Hydrogen peroxide (H2O2) production was assessed using ferrous oxidation xylenol orange assay. We showed that incubation of brachial rings with MAO inhibitors significantly improved EDR and attenuated H2O2 generation in patients with ESRD. MAO-related oxidative stress might contribute to the primary dysfunction/non-maturation of the AVF and MAO inhibitors could improve maturation and long-term patency of the vascular access in dialysis patients.

Intimal Hyperplasia, Stenosis, and Arteriovenous Fistula Maturation Failure in the Hemodialysis Fistula Maturation Study.

Intimal hyperplasia and stenosis are often cited as causes of arteriovenous fistula maturation failure, but definitive evidence is lacking. We examined the associations among preexisting venous intimal hyperplasia, fistula venous stenosis after creation, and clinical maturation failure. The Hemodialysis Fistula Maturation Study prospectively observed 602 men and women through arteriovenous fistula creation surgery and their postoperative course. A segment of the vein used to create the fistula was collected intraoperatively for histomorphometric examination. On ultrasounds performed 1 day and 2 and 6 weeks after fistula creation, we assessed fistula venous stenosis using pre-specified criteria on the basis of ratios of luminal diameters and peak blood flow velocities at certain locations along the vessel. We determined fistula clinical maturation using criteria for usability during dialysis. Preexisting venous intimal hyperplasia, expressed per 10% increase in a hyperplasia index (range of 0%-100%), modestly associated with lower fistula blood flow rate (relative change, -2.5%; 95% confidence interval [95% CI], -4.6% to -0.4%; P=0.02) at 6 weeks but did not significantly associate with stenosis (odds ratio [OR], 1.07; 95% CI, 1.00 to 1.16; P=0.07) at 6 weeks or failure to mature clinically without procedural assistance (OR, 1.07; 95% CI, 0.99 to 1.15; P=0.07). Fistula venous stenosis at 6 weeks associated with maturation failure (OR, 1.98; 95% CI, 1.25 to 3.12; P=0.004) after controlling for case mix factors, dialysis status, and fistula location. These findings suggest that postoperative fistula venous stenosis associates with fistula maturation failure. Preoperative venous hyperplasia may associate with maturation failure but if so, only modestly.

Applicability of an entry flow model of the brachial artery for flow models of the hemodialysis fistula.

The native arteriovenous fistula creates a shunt that provides the high blood flow that is needed for dialysis. Lumped parameter hemodynamic models of the arteriovenous fistula can be used to predict shear stresses and pressure losses and can be applied to help understand unsolved problems such as the high rate of arteriovenous fistula maturation failure. These models combine together flow components, such as arteries, stenosis, anastomoses, arterial compliance, and blood inertia, and each component must be modeled with an appropriate pressure-flow relationship. Poiseuille flow is generally assumed for straight vessels, but the unique high flow rates within the brachial artery of an arteriovenous fistula are expected to induce entry flow effects that are neglected in this model. To estimate the importance of these effects, brachial artery flow was modeled in a low-resistance network, such as the one that occurs when an arteriovenous fistula is constructed, through the lumped parameter model, and the predicted flow rates and pressures were compared to those predicted by computational fluid dynamics. When Poiseuille flow was assumed, the flow rate from the lumped parameter model was consistently larger than that from computational fluid dynamics, with a cycle-averaged error of 36.8%. When an entry flow model (Shah) was assumed, the lumped parameter-based flow was 6% lower than the computational fluid dynamics model at the peak of the flow waveform, and the cycle-averaged error was reduced to 7.8%. Thus, in a low-resistance (high flow) arteriovenous fistula circuit, an entry flow model can account for steeper near-wall velocity gradients. This result can provide a useful guide for designing engineering models of the arteriovenous fistula.

Leptin, pre-existing vascular disease, and increased arteriovenous fistula maturation failure in dialysis patients

The adipocytokine leptin is an independent cardiovascular risk factor and exerts proatherogenic effect. Pre-existing vascular disease is an important cause of arteriovenous fistula (AVF) maturation failure. We explored the association between serum leptin, pre-existing vascular disease, and AVF maturation failure in incident hemodialysis patients. Vein samples from 62 patients were collected at the time of AVF creation. Pre-existing vascular disease was evaluated with histologic changes and immunohistochemical characteristics of cellular phenotypes in intima. AVF maturation failure was defined as an AVF that could not be used successfully by the third month after its creation. The prevalence of body mass index ≥30kg/m2 was 17%, and AVF maturation failure occurred in 28 (45%) patients. Patients within the highest leptin tertile showed significantly higher maturation failure rate, independent of age, gender, diabetes, and body mass index. On histologic examination, significant differences in intimal hyperplasia (13.3± 4.5 vs 18.2± 5.2 vs 30.3± 14.3μm) and medial thickening (76.8± 23.7 vs 103.9± 33.6 vs 109.3± 36.5μm) were observed across leptin tertiles. Similarly, medial fibrosis was most severe in the highest tertile. According to the immunohistochemical staining, most intimal cells were α-smooth muscle actin-positive, vimentin-positive, desmin-negative myofibroblasts. However, in the lowest tertile, desmin-positive contractile smooth muscle cells were also frequently observed, suggesting relatively slow phenotypic changes in this group. Furthermore, as leptin tertiles increased, the expression of leptin receptor in the luminal border of intima was significantly decreased. Obesity-related higher fistula maturation failure rate may be partly mediated by higher leptin level-associated pre-existing vascular diseases in end-stage renal disease patients. Decreased expression of leptin receptor may be related to this association.

Balloon-assisted maturation for arteriovenous fistula maturation failure: an early period experience.

PurposeBalloon-assisted maturation (BAM) is emerging as a salvage management for arteriovenous fistula maturation failure (AVF MF). However, BAM is a relatively new, yet controversial technique for AVF maturation. Therefore, we evaluated the effectiveness of BAM for AVF MF.MethodsBetween January 2012 and December 2014, 249 AVFs were created. The total MF rate was 24.8%. But, only 110 AVFs were enrolled, including 74 brachiocephalic (BC) AVFs and 36 radiocephalic (RC) AVFs. The follow-up period was 12 months. Among those, there were 42 MFs (22 BC AVFs and 20 RC AVFs) and 68 maturation successes (MS) (52 BC AVFs and 16 RC AVFs). BAM was involved in MF group. We compared the clinical characteristics, AVF flows, and AVF flow ratios of MF and MS groups. Also, we evaluated the etiology, management, and result of MF.ResultsThere was no difference in clinical characteristics between MF and MS groups. In MF group, 39 balloon angioplasties (BAs) for 42 AVF MFs were performed. Number of BA was 1.45 ± 0.57 and duration of BA was 21.30 ± 21.24 weeks. BAM rate was 46.2%. For 1 year after AVF creation, AVF flows of MS group were significantly larger than those of MF group (P < 0.05) but there was no difference in AVF flow ratio between MF and MS groups (P > 0.05).ConclusionBA for AVF MF is a relatively applicable and effective modality. Although a large volume study is necessary, we suggest BAM is an effective salvage management for AVF MF.

Oral prostacycline analog and clopidogrel combination provides early maturation and long-term survival after arteriovenous fistula creation: A randomized controlled study.

Vascular access is used as a lifeline for hemodialysis in patients with end stage renal disease failure (ESRD). Failure of arteriovenous fistula (AVF) maturation is still high. The purpose of this study was to research the effects of clopidogrel in combination with oral iloprost, a synthetic analog of prostacyclin PGI2. Ninety-six diabetic ESRD patients were divided into two groups. In the first group (Group 1, N = 50), clopidogrel (75 mg daily dose) and an oral prostacycline analog (200 mg daily dose) were administered. In the second group (Group 2, N = 46), placebo was given. All patients took study medication 7–10 days prior to surgery. A Doppler ultrasound (USG) was performed for measurement of arterial and venous diameters, and peak systolic velocity of arterial flow based on subsequent fistula adequacy. Autogenous AVFs were constructed in forearm as distally as possible in all patients. Both groups were followed-up for a year. In the placebo group, early AVF thrombosis was detected in two patients (4.3%). AVF maturation failure was noted in 14 patients (30.4%) in placebo group and in four patients (8%) in clopidogrel plus oral prostacycline analog group in the early postoperative period (P = 0.001). The mean maturation time was 38 ± 6.5 and 53 ± 12.8 days in study and placebo groups, respectively (P = 0.023). The mean blood flow was 352 ± 94 mL/min in placebo group and 604 ± 125 mL/min in study group (P = 0.001). The arterial end diastolic velocity was 116 ± 14 cm/s in study group and 72 ± 21 cm/s in placebo group (P = 0.036) 1 year after the surgery. Our data indicated that clopidogrel and oral prostacycline analog combination is effective and safe for the prevention of primary AVF failure in hemodialysis patients and decreased acute and chronic thrombotic events.

Proliferation patterns in a pig model of AV fistula stenosis: can we translate biology into novel therapies?

Arteriovenous fistula (AVF) stenosis remains an important cause of AVF maturation failure for which there are currently no effective therapies. To understand the mechanisms involved, we have examined the pattern of cellular proliferation at different time points in a pig model of AVF stenosis. Immunohistochemical analysis of cellular proliferation was performed at 2, 7, 28, and 42days. The distribution of cellular proliferation within the different layers of the vessel wall was also studied. An ANOVA analysis was used to identify differences between the magnitude of cellular proliferation at different time points and within different layers of the vessel wall. Adventitial proliferation occurred at 2days and declined over time. Intimal and medial proliferation peaked at 7days and then decreased over time. There was minimal proliferation in all three layers at the 28- and 42-day time points. An important finding was the presence of active myofibroblast proliferation within "neointimal buds" at the 7-day time point. Results suggest that there could be early adventitial activation, followed by a passage of these cells into the medial and intimal layers. These suggest that the application of perivascular antiproliferative (adventitial) therapies at the time of surgery could potentially reduce AVF maturation failure.

Arteriovenous Fistula Failure: Is There a Role for Epigenetic Regulation?

Epigenetics is the study of heritable changes in gene expression or cellular phenotype that occur without alterations in the DNA sequence. In the past decade, epigenetics has been identified as a key regulator of gene expression and therefore is likely to play a major role in multiple disease processes. More importantly, we now recognize epigenetics to be a sensitive, dynamic, and reversible process that has opened the door to multiple novel diagnostic, prognostic, and therapeutic strategies for human diseases. The focus of this review, however, is to explore the potential role of epigenetics in arteriovenous fistula (AVF) maturation. AVF maturation failure is currently the single most important cause of dialysis vascular access dysfunction and most important is the result of a peri-anastomotic stenosis thought to be caused by a combination of neointimal hyperplasia and inadequate outward remodeling. At a pathogenetic level, however, AVF maturation failure is likely the end result of the interaction between hemodynamic stressors (injury) and the vascular response to these stressors; the latter being influenced by uremia, oxidative stress, and inflammation. Interestingly, these same factors (hemodynamic shear stress, oxidative stress, inflammation, and uremia) are also important mediators of epigenetic modifications. We therefore believe that epigenetic factors potentially could play an important role in the pathogenesis of AVF maturation failure. The current review therefore tries to unravel some of these critical biological connections, with an emphasis on the future development of epigenetic-based diagnostic and therapeutic strategies for AVF maturation failure (a clinical problem for which there are currently no effective therapeutic interventions).

Influence of Temporal Variation in Wall Shear Stress on Intima‐Media Thickening in Arteriovenous Fistulae

Arteriovenous fistula (AVF) failure is mainly due to venous stenosis characterized by significant amount of intima-media thickening (IMT), probably in the presence of negative (inward) remodeling. Our hypothesis is that the longitudinal changes in wall shear stress (WSS) within different configurations of AVF can influence remodeling factors (changes in luminal diameter (ΔDh ) and IMT) during its maturation process. Dh is an equivalent diameter for a noncircular conduit. A total of six AVFs with curved (C-AVF; n = 3) and straight (S-AVF; n = 3) configurations were created between the femoral artery and vein of three pigs, bilaterally. CT scans and ultrasounds were utilized to calculate local WSS at 2D (D: days), 7D, and 28D postsurgery. For each AVF, IMT was measured at four regions along the vein using morphometric analyses. At these regions, repeated measurements of WSS and luminal diameter of each AVF were obtained over time. The ΔD(h) between 7D and 28D was significantly larger for C-AVF than for S-AVF (2.27 ± 0.67 mm vs. 0.02 ± 0.55 mm; p < 0.05). Also, at 28D the amount of IMT in C-AVF (77.46 ± 7.10 units) was significantly greater (p < 0.05) when compared with S-AVF (53.71 ± 8.23 units). These structural changes were accompanied by significantly different gradients of WSS over time (τ') for C-AVF (-0.56 ± 0.60 dyne/cm(2)/day) in comparison with S-AVF (0.71 ± 0.39 dyne/cm(2)/day). Negative τ' for C-AVF corresponded to reduction in WSS level over time resulting in a physiological level of WSS at 28D (4.08 ± 5.08 dyne/cm(2)). In contrast, a positive τ' for S-AVF was associated with the increase in WSS levels over time causing high levels of WSS at 28D (36.68 ± 5.32 dyne/cm(2)). The decrease in WSS levels for the C-AVF over time was associated with outward remodeling of the venous wall (favorable to maturation). In contrast, for S-AVF, the increase in WSS levels over time was associated with inward remodeling and subsequently, venous stenosis. Thus, temporal gradients of WSS, which could be altered by the surgical configuration of AVF, may provide important information on the remodeling behavior of AVFs. Identification of an optimal AVF configuration, which results in a temporal decrease in WSS and an outward remodeling of the venous wall, may reduce AVF maturation failure.

Serial analysis of lumen geometry and hemodynamics in human arteriovenous fistula for hemodialysis using magnetic resonance imaging and computational fluid dynamics

The arteriovenous fistula (AVF) is the preferred form of vascular access for maintenance hemodialysis, but it often fails to mature to become clinically usable, likely due to aberrant hemodynamic forces. A robust pipeline for serial assessment of hemodynamic parameters and subsequent lumen cross-sectional area changes has been developed and applied to a data set from contrast-free MRI of a dialysis patient's AVF collected over a period of months after AVF creation surgery. Black-blood MRI yielded images of AVF lumen geometry, while cine phase-contrast MRI provided volumetric flow rates at the in-flow and out-flow locations. Lumen geometry and flow rates were used as inputs for computational fluid dynamics (CFD) modeling to provide serial wall shear stress (WSS), WSS gradient, and oscillatory shear index (OSI) profiles. The serial AVF lumen geometries were co-registered at 1mm intervals using respective lumen centerlines, with the anastomosis as an anatomical landmark. Lumen enlargement was limited at the vein region near the anastomosis and a downstream vein valve, potentially attributed to the physical inhibition of wall expansion at those sites. This work is the first serial and detail study of lumen and hemodynamic changes in human AVF using MRI and CFD. This novel protocol will be used for a multicenter prospective study to identify critical hemodynamic factors that contribute to AVF maturation failure.