Hemodialysis Fistula Maturation Study Research Articles

Association between anaesthesia type and arteriovenous fistula maturation.

Background:Whereas general anaesthesia is commonly used for haemodialysis fistula creation, regional or local anaesthesia has been posited to lead to better fistula maturation outcomes. We sought to measure the association between anaesthesia type and arteriovenous fistula maturation.Methods:We performed a secondary analysis of data from the Hemodialysis Fistula Maturation study, a multicentre prospective cohort study of advanced chronic kidney disease patients who underwent single-stage upper extremity fistula creation between 2010 and 2013. We evaluated the relationship between anaesthesia type and unassisted (without maturation-facilitating interventions) or overall (unassisted or assisted) fistula maturation using multivariable logistic regression.Results:Among 602 participants, 336 (55.8%) received regional/local anaesthesia and 266 (44.2%) received general anaesthesia. Unassisted maturation occurred in 164/309 patients (53.1%) after regional/local vs 91/226 patients (40.3%) after general anaesthesia (P=0.003). After adjustment for patient factors and fistula type, regional/local anaesthesia was associated with greater odds of unassisted maturation than general anaesthesia (odds ratio 1.72, 95% confidence interval 1.24–2.39; P=0.001). However, after further adjustment for clinical centre fixed effects, odds of unassisted maturation did not differ by anaesthesia type (odds ratio 1.03, 95% confidence interval 0.78–1.36; P=0.830). Similar findings were observed for overall maturation and composite endpoints accounting for potential survivorship bias.Conclusions:Regional/local anaesthesia was associated with increased odds of fistula maturation when adjusting for patient factors and fistula type. However, this association did not persist after adjusting for centre fixed effects. Future research is needed to better understand the relationship between anaesthesia type and centre factors to optimise outcomes after fistula surgery.

Arteriovenous Fistula Maturation, Functional Patency, and Intervention Rates

National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

The Impact of Intervention on Arteriovenous Fistula Maturation and Functional Patency in the Hemodialysis Fistula Maturation Study

National initiatives have emphasized the use of arteriovenous fistulas (AVF) for hemodialysis, but this has been associated with high maturation failure rates. This study describes intervention outcomes to facilitate AVF maturation and maintain post-maturation patency among patients enrolled in the Hemodialysis Fistula Maturation study.

Prediction of Arteriovenous Fistula Clinical Maturation from Postoperative Ultrasound Measurements: Findings from the Hemodialysis Fistula Maturation Study.

The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

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.

Alteration of HDL Protein Composition with Hemodialysis Initiation.

HDL particles obtained from patients on chronic hemodialysis exhibit lower cholesterol efflux capacity and are enriched in inflammatory proteins compared with those in healthy individuals. Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways. We compared HDL-associated proteins in 143 participants who initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to total HDL protein using targeted mass spectrometry assays that included a stable isotope-labeled internal standard. We used linear regression to compare the relative abundances of HDL-associated proteins after adjustment and required a false discovery rate q value ≤10% to control for multiple testing. We further assessed the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants. After adjustment for demographics, comorbidities, and other clinical characteristics, eight HDL-associated proteins met the prespecified false discovery threshold for association. Recent hemodialysis initiation was associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-β; haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals with advanced CKD did not reach statistical significance. Compared with advanced CKD, hemodialysis initiation within the previous year is associated with higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_07_25_CJASNPodcast_18_8_W.mp3.

Local Adipose-Associated Mediators and Adaptations Following Arteriovenous Fistula Creation

IntroductionLocal inflammation is an important regulator of vascular remodeling. We hypothesized that adipose tissue adjacent to hemodialysis arteriovenous fistulae modulates maturation.MethodsDuring fistula creation, perivenous adipose was collected from 111 participants in the Hemodialysis Fistula Maturation Study. Nine adipose-associated mediators were measured. Duplex ultrasound was performed at 4 time points postoperatively from 1 day to first cannulation (10–26 weeks). Associations between logarithmically transformed biomarker levels and fistula remodeling were evaluated using mixed effects regression.ResultsElevated interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 were associated with a reduction in the fractional vein diameter during the early time frame of 1 day to 2 weeks (diameter change of 26.6% and 20.4% at the 25th and 75th percentile for IL-6, P = 0.01; 27.8% and 21.1% at the 25th and 75th percentile for MCP-1, P = 0.02), but not in later stages of remodeling. Local leptin levels showed a significant negative correlation with fractional venous flow increase between 2 and 6 weeks (percent flow change 31.4% and 11.3% at the 25th and 75th percentile for leptin, P = 0.03).ConclusionThus, impaired fistula vein dilation and reduced capacity for flow augmentation associate with specific local adipose phenotypic signatures in a time-dependent manner. In view of adipose tissue plasticity, these findings raise the possibility of novel adipose-based strategies to facilitate fistula maturation.

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.

Access-related hand ischemia and the Hemodialysis Fistula Maturation Study

Access-related hand ischemia (ARHI) is a major complication after hemodialysis access construction. This study was designed to prospectively describe its incidence, predictors, interventions, and associated access maturation. The Hemodialysis Fistula Maturation Study is a multicenter prospective cohort study designed to identify predictors of autogenous arteriovenous access (arteriovenous fistula [AVF]) maturation. Symptoms and interventions for ARHI were documented, and participants who received interventions for ARHI were compared with other participants using a nested case-control design. Associations of ARHI with clinical, ultrasound, vascular function, and vein histologic variables were each individually evaluated using conditional logistic regression; the association with maturation was assessed by relative risk, Pearson χ(2) test, and multiple logistic regression. The study cohort included 602 participants with median follow-up of 2.1years (10th-90th percentiles, 0.7-3.5years). Mean age was 55.1± 13.4 (standard deviation) years; the majority were male (70%), white (47%), diabetic (59%), smokers (55%), and on dialysis (64%) and underwent an upper arm AVF (76%). Symptoms of ARHI occurred in 45 (7%) participants, and intervention was required in 26 (4%). Interventions included distal revascularization with interval ligation (13), ligation (7), banding (4), revision using distal inflow (1), and proximalization of arterial inflow (1). Interventions were performed ≤7days after AVF creation in 4 participants (15%), between 8 and 30days in 6 (23%), and >30days in 16 (63%). Female gender (odds ratio, 3.17; 95% confidence interval, 1.27-7.91; P= .013), diabetes (13.62 [1.81-102.4]; P= .011), coronary artery disease (2.60 [1.03-6.58]; P= .044), higher preoperative venous capacitance (per %/10mm Hg, 2.76 [1.07-6.52]; P= .021), and maximum venous outflow slope (per [mL/100mL/min]/10mm Hg, 1.13 [1.03-1.25]; P= .011) were significantly associated with interventions; a lower carotid-femoral pulse wave velocity and the outflow vein diameter in the early postoperative period (days 0-3) approached significance (P< .10). Intervention for ARHI was not associated with AVF maturation failure (unadjusted risk ratio, 1.18 [0.69-2.04], P=.56; adjusted odds ratio, 0.97 [0.41-2.31], P= .95). Remedial intervention for ARHI after AVF construction is uncommon. Diabetes, female gender, capacitant outflow veins, and coronary artery disease are all associated with an increased risk of intervention. These higher risk patients should be counseled preoperatively, their operative plans should be designed to reduce the risk of hand ischemia, and they should be observed closely.

Vascular Function at Baseline in the Hemodialysis Fistula Maturation Study.

BackgroundEnd‐stage renal disease is accompanied by functional and structural vascular abnormalities. The objective of this study was to characterize vascular function in a large cohort of patients with end‐stage renal disease, using noninvasive physiological measurements, and to correlate function with demographic and clinical factors.Methods and ResultsWe analyzed cross‐sectional baseline data from the Hemodialysis Fistula Maturation Study, a multicenter prospective observational cohort study of 602 patients with end‐stage renal disease from 7 centers. Brachial artery flow‐ and nitroglycerin‐mediated dilation, carotid‐femoral and ‐radial pulse wave velocity, and venous occlusion plethysmography were performed prior to arteriovenous fistula creation. Relationships of these vascular function measures with demographic, clinical, and laboratory factors were evaluated using linear mixed‐effects models. Arterial function, as assessed by flow‐ and nitroglycerin‐mediated dilation and carotid‐femoral pulse wave velocity, worsened with increasing age and diabetes mellitus. Venous capacitance decreased with diabetes mellitus but not with age. Flow‐mediated dilation was higher among patients undergoing maintenance dialysis than for those at predialysis, and a U‐shaped relationship between serum phosphorus concentration and flow‐mediated dilation was evident. Partial correlations among different measures of vascular function, adjusting for demographic factors, diabetes mellitus, and clinical center, were modest or essentially nonexistent.ConclusionsMultiple demographic and clinical factors were associated with the functions of vessels of different sizes and types in this large cohort of patients with end‐stage renal disease. Low correlations between the different measures, controlling for demographic factors, diabetes mellitus, and center, indicated that these different types of vascular function otherwise vary heterogeneously across patients.

Association between Preoperative Vascular Function and Postoperative Arteriovenous Fistula Development.

Arteriovenous fistula (AVF) maturation failure is the primary cause of dialysis vascular access dysfunction. To evaluate whether preoperative vascular functional properties predict postoperative AVF measurements, patients enrolled in the Hemodialysis Fistula Maturation Study underwent up to five preoperative vascular function tests (VFTs): flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NMD), carotid-femoral pulse wave velocity, carotid-radial pulse wave velocity, and venous occlusion plethysmography. We used mixed effects multiple regression analyses to relate each preoperative VFT to ultrasound measurements of AVF blood flow rate and venous diameter at 1 day, 2 weeks, and 6 weeks after AVF placement. After controlling for AVF location, preoperative ultrasound measurements, and demographic factors (age, sex, race, and dialysis status), greater NMD associated with greater 6-week AVF blood flow rate and AVF diameter (per absolute 10% difference in NMD: change in blood flow rate =14.0%; 95% confidence interval [95% CI], 3.7% to 25.3%; P<0.01; change in diameter =0.45 mm; 95% CI, 0.25 to 0.65 mm; P<0.001). Greater FMD also associated with greater increases in 6-week AVF blood flow rate and AVF diameter (per absolute 10% difference in FMD: change in blood flow rate =11.6%; 95% CI, 0.6% to 23.9%; P=0.04; change in diameter =0.31 mm; 95% CI, 0.05 to 0.57 mm; P=0.02). None of the remaining VFT parameters exhibited consistent statistically significant relationships with both postoperative AVF blood flow rate and diameter. In conclusion, preoperative NMD and FMD positively associated with changes in 6-week AVF blood flow rate and diameter, suggesting that native functional arterial properties affect AVF development.

Multiple preoperative and intraoperative factors predict early fistula thrombosis in the Hemodialysis Fistula Maturation Study

Early thrombosis (ET) contributes to autogenous arteriovenous fistula (AVF) failure. We studied patients undergoing AVF placement in the Hemodialysis Fistula Maturation Study, a prospective, observational cohort study, using a nested case-control analysis to identify preoperative and intraoperative predictors of ET. ET cases were compared with controls, who were matched for gender, age, diabetes, dialysis status, and surgeon fistula volume. ET was defined as thrombosis diagnosed by physical examination or ultrasound within 18 days of AVF creation. Conditional logistic regression models were fit to identify risk factors for ET. Thirty-two ET cases (5.3%) occurred among 602 study participants; 198 controls were matched. ET was associated with female gender (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.19-6.38; P = .018), fistula location (forearm vs upper arm; OR, 2.76; 95% CI, 1.05-7.23; P = .039), feeding artery (radial vs brachial; OR, 2.64; 95% CI, 1.03-6.77; P = .043) and arterial diameter (OR, 1.52; 95% CI, 1.02-2.26; P = .039, per mm smaller). The draining vein diameter was nonlinearly associated with ET, with highest risk in 2- to 3-mm veins. Surprisingly, ET risk was lower in diabetics (OR, 0.19; 95% CI, 0.07-0.47; P = .0004), lower with less nitroglycerin-mediated brachial artery dilation (OR, 0.42; 95% CI, 0.20-1.92; P = .029 for each 10% lower) and higher with lower carotid-femoral pulse wave velocity (OR, 1.49; 95% CI, 1.02-2.20; P = .041, for each m/s lower). Intraoperative protamine use was associated with a higher ET risk (OR, 3.26; 95% CI, 1.28-∞; P = .038). Surgeon's intraoperative perceptions were associated with ET: surgeons' greater concern about maturation success (likely, marginal, unlikely) was associated with higher thrombosis risk (OR, 8.09; 95% CI, 4.03-∞; P < .0001, per category change), as were absence vs presence of intraoperative thrill (OR, 21.0; 95% CI, 5.07-∞; P = .0001) and surgeons' reported frustration during surgery (OR, 6.85; 95% CI, 2.70-∞; P = .0004). Decreased extent of intraoperative thrill (proximal, mid or distal third of the forearm or upper arm, based on AVF placement) was also associated with ET (OR, 2.91; 95% CI, 1.31-∞; P = .007, per diminished level). Oral antithrombotic medication use was not significantly associated with ET. ET was found to be associated with female gender, forearm AVF, smaller arterial size, draining vein diameter of 2 to 3 mm, and protamine use. Paradoxically, diabetes and stiff, noncompliant feeding arteries were associated with a lower frequency of ET. Absent or attenuated intraoperative thrill, and both surgeon frustration and concern about successful maturation during surgery, were correlated strongly with ET.

Objectives and Design of the Hemodialysis Fistula Maturation Study

A large proportion of newly created arteriovenous fistulas cannot be used for dialysis because they fail to mature adequately to support the hemodialysis blood circuit. The Hemodialysis Fistula Maturation (HFM) Study was designed to elucidate clinical and biological factors associated with fistula maturation outcomes. Multicenter prospective cohort study. Approximately 600 patients undergoing creation of a new hemodialysis fistula will be enrolled at 7 centers in the United States and followed up for as long as 4 years. Clinical, anatomical, biological, and process-of-care attributes identified pre-, intra-, or postoperatively. The primary outcome is unassisted clinical maturation, defined as successful use of the fistula for dialysis for 4 weeks without maturation-enhancing procedures. Secondary outcomes include assisted clinical maturation, ultrasound-based anatomical maturation, fistula procedures, fistula abandonment, and central venous catheter use. Preoperative ultrasound arterial and venous mapping, flow-mediated and nitroglycerin-mediated brachial artery dilation, arterial pulse wave velocity, and venous distensibility; intraoperative vein tissue collection for histopathologic and molecular analyses; postoperative ultrasounds at 1 day, 2 weeks, 6 weeks, and prior to fistula intervention and initial cannulation. Assuming complete data, no covariate adjustment, and unassisted clinical maturation of 50%, there will be 80% power to detect ORs of 1.83 and 1.61 for dichotomous predictor variables with exposure prevalences of 20% and 50%, respectively. Exclusion of 2-stage transposition fistulas limits generalizability. The requirement for study visits may result in a cohort that is healthier than the overall population of patients undergoing fistula creation. The HFM Study will be of sufficient size and scope to: (1) evaluate a broad range of mechanistic hypotheses, (2) identify clinical practices associated with maturation outcomes, (3) assess the predictive utility of early indicators of fistula outcome, and (4) establish targets for novel therapeutic interventions to improve fistula maturation.

Smooth muscle nitric oxide responsiveness predicts clinical maturation of hemodialysis fistulae

The arteriovenous fistula is the preferred type of hemodialysis vascular access for patients with end‐stage renal disease, but 50% of newly created fistulas fail to mature adequately for use. Stenosis due to neointimal hyperplasia is present in a large proportion of fistulae with maturation failure suggesting that local mechanisms controlling vascular smooth muscle cell (SMC) migration are important contributors to maturation failure. Our objective is to manipulate local factors present in the vein at the time of fistula surgery in order to prevent maturation failure. Using SMC explants from vein tissue obtained at the time of fistula creation from patients enrolled in the NIH Hemodialysis Fistula Maturation Study, we find that among patients with subsequent fistula maturation failure, •NO inhibits SMC migration significantly less. Using strategies initially developed in animal models, we find that impaired •NO inhibition is associated with oxidation of the calcium regulatory protein, sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and can be reversed by overexpressing SERCA or by down‐regulating Nox4 NADPH oxidase. Our data suggest that SMC •NO responsiveness may be predictive of fistula maturation outcome and that therapeutic restoration of •NO responsiveness through manipulation of local factors may prevent fistula maturation failure.Funding: R21DK084390 and R01 HL31607