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Importance: National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned., Objective: 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., Design, Setting, and Participants: 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., Interventions: All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation., Main Outcomes and Measures: 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., Results: 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., Conclusions and Relevance: 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.

Background: 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., Methods: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH) 2 D, 24,25(OH) 2 D, 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., Results: 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) 2 D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups., Conclusions: 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., (Copyright © 2019 European Society for Vascular Surgery. All rights reserved.)

Background: The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2018 by the American Society of Nephrology.)

Background: Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation., Study Design: Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study., Setting & Participants: 491 patients with single-stage AVFs who had neither thrombosis nor AVF intervention before a 6-week postoperative ultrasonographic examination and who required maintenance hemodialysis., Predictors: Postoperative care processes and complications., Outcomes: Attempted cannulation, successful cannulation, and unassisted and overall clinical maturation as defined by the HFM Study criteria., Results: AVF cannulation was attempted in 443 of 491 (90.2%) participants and was eventually successful in 430 of these 443 (97.1%) participants. 263 of these 430 (61.2%) reached unassisted and 118 (27.4%) reached assisted AVF maturation (overall maturation, 381/430 [88.6%]). Attempted cannulation was less likely in patients of surgeons with policies for routine 2-week versus later-than-2-week first postoperative visits (OR, 0.21; 95% CI, 0.06-0.70), routine second postoperative follow-up visits (OR, 0.39; 95% CI, 0.15-0.97), and a routine clinical postoperative ultrasound (OR, 0.28; 95% CI, 0.14-0.55). Attempted cannulation was also less likely among patients undergoing procedures to assist maturation (OR, 0.51; 95% CI, 0.27-0.98). Unassisted maturation was more likely for patients treated in facilities with access coordinators (OR, 1.91; 95% CI, 1.17-3.12), but less likely after precannulation nonstudy ultrasounds (OR per ultrasound, 0.42 [95% CI, 0.26-0.68]) and initial unsuccessful cannulation attempts (OR per each additional attempt, 0.90 [95% CI, 0.83-0.98]). Overall maturation was less likely with infiltration before successful cannulation (OR, 0.44; 95% CI, 0.22-0.89). Among participants receiving maintenance hemodialysis before AVF surgery, unassisted and overall maturation were less likely with longer intervals from surgery to initial cannulation (ORs for each additional month of 0.81 [95% CI, 0.76-0.88] and 0.93 [95% CI, 0.89-0.98], respectively) and from initial to successful cannulation (ORs for each additional week of 0.87 [95% CI, 0.81-0.94] and 0.88 [95% CI, 0.83-0.94], respectively)., Limitations: Surgeons' management policies were assessed only by questionnaire at study onset. Most participants received upper-arm AVFs, planned 2-stage AVFs were excluded, and maturation time windows were imposed. Some care processes may have been missed and the observational design limits causal attribution., Conclusions: Multiple processes of care and complications are associated with AVF maturation outcomes., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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., (© 2018 S. Karger AG, Basel.)

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., (Copyright © 2017 by the American Society of Nephrology.)

Stenosis from venous neointimal hyperplasia is common in native arteriovenous fistulas (AVFs). However, the preexisting histologic characteristics of veins at fistula creation, and associations thereof with baseline patient factors, have not been well characterized. In this study, we conducted histologic analysis of a segment of the vein used for anastomosis creation, obtained during AVF creation from 554 of the 602 participants in the multicenter Hemodialysis Fistula Maturation Cohort Study. We quantified intimal and medial areas and lengths of the internal and external elastic lamina by morphometry and assessed venous wall cells by immunohistochemistry, extracellular matrix with Movat stain, and calcium deposition by alizarin red stain. We also studied a representative subset of veins for markers of monocyte/macrophage content, cell proliferation, apoptosis, and neoangiogenesis. Neointima occupied >20% of the lumen in 57% of fully circumferential vein samples, and neointimal hyperplasia associated positively with age and inversely with black race. The neointima was usually irregularly thickened, sometimes concentric, and contained α -smooth muscle actin-expressing cells of smooth muscle or myofibroblast origin. Proteoglycans admixed with lesser amounts of collagen constituted the predominant matrix in the neointima. In 82% of vein samples, the media of vessel walls contained large aggregates of collagen. A minority of veins expressed markers of inflammation, cell proliferation, cell death, calcification, or neoangiogenesis. In conclusion, we observed preexisting abnormalities, including neointimal hyperplasia and prominent accumulation of extracellular matrix, in veins used for AVF creation from a substantial proportion of this cohort., (Copyright © 2017 by the American Society of Nephrology.)

Background and Objectives: In individuals undergoing in-center hemodialysis (HD), use of central venous catheters (CVCs) is associated with worse clinical outcomes compared with use of arteriovenous access. However, it is unclear whether a similar difference in risk by vascular access type is present in patients undergoing home HD., Design, Setting, Participants, & Measurements: Our study examined the associations of vascular access type with all-cause mortality, hospitalization, and transfer to in-center HD in patients who initiated home HD from 2007 to 2011 in 464 facilities in 43 states in the United States. Patients were followed through December 31, 2011. Data were analyzed using competing risks hazards regression, with vascular access type at the start of home HD as the primary exposure in a propensity score-matched cohort (1052 patients; 526 with CVC and 526 with arteriovenous access)., Results: Over a median follow-up of 312 days, 110 patients died, 604 had at least one hospitalization, and 202 transferred to in-center hemodialysis. Compared with arteriovenous access use, CVC use was associated with higher risk for mortality (hazard ratio, 1.73; 95% confidence interval, 1.18 to 2.54) and hospitalization (hazard ratio, 1.19; 95% confidence interval, 1.02 to 1.39). CVC use was not associated with increased risk for transfer to in-center HD. The results of analyses in the entire unmatched cohort (2481 patients), with vascular access type modeled as a baseline exposure at start of home HD or a time-varying exposure, were similar. Analyses among a propensity score-matched cohort of patients undergoing in-center HD also showed similar risks for death and hospitalization with use of CVCs., Conclusions: In a large cohort of patients on home HD, CVC use was associated with higher risk for mortality and hospitalization. Additional studies are needed to identify interventions which may reduce risk associated with use of CVCs among patients undergoing home HD., (Copyright © 2016 by the American Society of Nephrology.)

Background: 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., Study Design: Multicenter prospective cohort study., Setting & Participants: 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., Predictors: Clinical, anatomical, biological, and process-of-care attributes identified pre-, intra-, or postoperatively., Outcomes: 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., Measurements: 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., Results: 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., Limitations: 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., Conclusions: 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., (Copyright © 2013 National Kidney Foundation, Inc. All rights reserved.)

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P=0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA., (Copyright © 2011 by the American Society of Nephrology)

Efforts to increase the number of functioning arteriovenous fistulas in chronic kidney disease (CKD) stages 4 and 5 have been impacted by concerns about the risk for contrast-induced nephropathy during diagnostic and interventional procedures for poorly developed fistulas. We conducted a prospective observational study of low volume iodinated contrast administration for fistulography and angioplasty in a CKD stage 4 and stage 5 population pretreated with a sodium bicarbonate protocol. Acute kidney injury was assessed by change in serum creatinine and urinary neutrophil-gelatinase associated lipocalcin (NGAL). Only 1/18 patients (5.5%) developed acute kidney injury as defined by change in serum creatinine 48 hours after contrast exposure. No patients demonstrated significant change in urinary NGAL at 3 or 48 hours after procedure, nor did any require acute initiation of dialysis. Fistulography alone, or with angioplasty, utilizing a low volume of iodinated contrast and sodium bicarbonate solution for prophylaxis, appears to be safe in the CKD stages 4 and 5 population., (© 2010 Wiley Periodicals, Inc.)

Eighty-two percent (82%) of patients initiating hemodialysis in the United States in 2006 did so with a catheter as the functioning access. Even in patients who have been followed by nephrologists for 6 months or more, 74% of patients initiated dialysis with a catheter. This is a multifactoral problem that requires attention and solutions from all stakeholders, including the nephrologist, the vascular surgeon, the hospital, and the insurance industry, as well as the patient and family. We propose a series of specific proposals that include a process for the timely referral and timely placement of a permanent access based on the patient's estimated or measured glomerular filtration rate (GFR), and a 'pay-for-performance' measure for vascular surgeons and nephrologists who admit patients with functional permanent accesses; such pay for performance would place a higher value for patients who are admitted with a functional arteriovenous (AV) fistula than for patients who are admitted with an AV graft. We also propose that hospitals develop a less permissive process for placement of PICC (peripherally inserted central catheters) lines in patients with GFR <60 ml/min and to consider surgery for access placement as 'urgent'. Finally, a more proactive educational process for patients and their families, including an 'informed non-consent' for patients who defer placement of a permanent access needs to be considered. The morbidity, mortality, and health-care costs associated with prolonged catheter use mandate urgent attention to this problem.

Context: The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas., Objective: To determine whether clopidogrel reduces early failure of hemodialysis fistulas., Design, Setting, and Participants: Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later., Intervention: Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation., Main Outcome Measures: The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions., Results: Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40)., Conclusion: Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

The success of Fistula First nationwide has been accompanied by an unplanned increase in hemodialysis catheters. Complications related to prolonged hemodialysis catheter use include increased morbidity, mortality, and cost. We hypothesize that the national focus on increasing fistulas may have inadvertently diverted attention away from initiatives to decrease dependence on hemodialysis catheters. Based on a synthesis of guidelines, reviews, published evidence, and the authors' opinions, we propose that the national vascular access initiative be revised to have a dual goal of Fistula First and "Catheters Last." These goals are not mutually exclusive, but rather complementary. We recommend a systematic refocus on interventions that not only increase fistulas, but help avoid extended catheter use. Clearly, the ideal practice for hemodialysis vascular access remains early placement of fistulas with enough maturation time such that they can be used for initiating long-term hemodialysis therapy when the need arises. To effect this change, a reimbursement policy covering the costs associated with permanent access placement before the need for dialysis is essential. Individualized patient management strategies may consider such innovative approaches as initiating patients on peritoneal dialysis therapy or using nonautogenous grafts as bridge accesses in lieu of catheters. For patients who are dialyzing using catheters, immediate active planning for permanent access placement and removal of the catheter is necessary. In the same vein as Fistula First, the renal community should once again be galvanized in working together toward controlling the catheter epidemic in our dialysis population.

Background: The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery., Purpose: The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure., Methods: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis., Results: This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention., Conclusions: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

Background: Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts., Methods: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis., Results: This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints., Conclusions: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Background: Vascular access thrombosis accounts for at least $1 billion dollars in annual expenses and 25% of hospitalizations for chronic hemodialysis patients. Low vascular access blood flow (less than 800 ml/min) has been shown to modestly increase the relative risk for thrombosis in the subsequent three months. In this study, it is hypothesized that a time-dependent decrease in vascular access blood flow may be more predictive of subsequent thrombosis especially in vascular accesses with flows more than 800 ml/min, since it would indicate the development of a critical outlet stenosis in the graft., Methods: Ninety-five accesses in 91 CHD patients were prospectively followed over 18 months. Vascular access blood flow was measured every six months by the ultrasound dilution technique. Thrombotic events were recorded during the three study periods., Results: A total of 34 thrombotic events in 95 accesses were documented through the total study duration. Accesses that thrombosed had a 22% decrease in vascular access blood flow during the first observation period and a further 41% decrease during the second observation period as compared to 4% drop and 15% increase during the first and second observation periods, respectively, for accesses that did not thrombose. There was an estimated 13.6-fold (95%, confidence interval 2.68 to 69.16) increase in the relative risk of thrombosis for accesses with more than 35% decrease in vascular access blood flow compared to those accesses with no change in blood flow. There was no statistical difference in the average vascular access blood flow of all patients over the study period., Conclusions: Accesses that show a large (>15%) decrement in vascular access blood flow are associated with a high risk of thrombosis. Serial measurements of vascular access blood flow predict access thrombosis.

Recent evidence suggests that the cost as well as the morbidity associated with the maintenance of hemodialysis access is increasing rapidly; currently, the cost exceeds 1 billion dollars and access related hospitalization accounts for 25% of all hospital admissions in the U.S.A. This increase in cost and morbidity has been associated with several epidemiological trends that may contribute to access failure. These include late patient referral to nephrologists and surgeons, late planning of vascular access as well as a shift from A-V fistulaes to PTFE grafts and temporary catheters, which have a higher failure rate. The reasons for this shift in the types of access is multifactorial and is not explained by changes in the co-morbidities of patients presenting to dialysis. Surgical preference and training also appear to play an important role in the large regional variation and patency rate of these PTFE grafts. We propose a program for early placement of A-V fistulae, a continuous quality improvement, multidisciplinary program to monitor access outcome, the development of new biomaterials, and a research plan to investigate pharmacological intervention to reduce development of stenosis and clinical interventions to treat those that do develop, prior to thrombosis.

Malfunction of permanent vascular accesses remains a cause of frequent and costly morbidity in patients receiving chronic hemodialysis (CHD). Several recommendations for routine monitoring of these permanent vascular accesses for incipient failure have been proposed. In this study, multiple indicators of incipient vascular access dysfunction, including "venous" and "arterial" pressures at serial blood flows (200 ml/min, 300 ml/min, and 400 ml/min), percent urea recirculation, Doppler ultrasound, and access blood flow by ultrasound dilution technique were simultaneously evaluated in a total of 220 vascular accesses in 170 chronic hemodialysis patients in two separate study periods (6 months apart). The rate of thrombosis was determined within the subsequent 12 weeks of each study period to assess the short-term predictive power of access thrombosis. During the period of follow-up, there were 34 thrombotic events in 172 polytetrafluoroethylene (PTFE) grafts and only one thrombotic event in 48 arterio-venous fistulas (AVF). Therefore, the statistical analysis was limited to the PTFE grafts. When grafts with thromboses were compared to those without thrombosis by univariate analysis, access blood flow measured either by ultrasound dilution technique (875 +/- 426 ml/min with thrombosis vs. 1193 +/- 677 ml/min without thrombosis, P = 0.001) or by Doppler ultrasound (762 +/- 420 ml/min with thrombosis vs. 1171 +/- 657 ml/min without thrombosis, P = 0.001) were significantly different in the two groups. There was good correlation (r = 0.79, P = 0.0001) between the blood flows determined by both techniques. The grade of stenosis determined by ultrasound was also a statistically significant predictor (P = 0.02). "Venous" and "arterial" pressures were numerically similar and were not statistically different between the accesses that did and those that did not thrombose. When multivariate analysis was used, there was a significantly increased risk of thrombosis only with decreasing access blood flow determined by ultrasound dilution techniques after adjusting for other confounding variables. When the average blood flow of all grafts (1134 ml/min) is considered as the reference access blood flow (relative risk of 1.0), the relative risk of a PTFE thrombotic event within the subsequent 12 weeks was 1.23 at a blood flow 950 ml/min, 1.67 at a blood flow of 650 ml/min and to 2.39 at a blood flow of 300 ml/min. In summary, access blood flow measured by either Dilution or Doppler is a reliable indicator of subsequent short-term thrombosis risk. Other proposed methods of evaluating access dysfunction were not useful in our patients. If simple to use, cost-effective devices to measure dialysis access blood flow become readily available, the measurement of access blood flow will likely become the method of choice for screening of PTFE vascular access dysfunction in hemodialysis patients.