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Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider evolving priorities over time, deconstruction of language and meaning for conceptual consistency and clarity, understanding of potential overlap and associations between outcomes, and an assessment of applicability to the range of interventions in hemodialysis. For implementation, they proposed that core outcomes must have simple, inexpensive, and validated outcome measures that could be used in clinical care (quality indicators) and trials (including pragmatic trials) and endorsement by regulatory agencies. Integrating these recommendations may foster acceptance and optimize the uptake and translation of core outcomes in hemodialysis, leading to more informative research, for better treatment and improved patient outcomes.

In accordance with the recently released Kidney Disease Outcomes Quality Initiative  (KDOQI) guidelines, there is a significant need for focused efforts on improving hemodialysis cannulation outcomes. Toward this, structured and meaningful training of our clinical personnel who cannulate in dialysis clinics is a priority. With the availability of advanced sensors and computing methods, simulators could be indispensable tools for standardized skills assessment and training. In this article we present ways in which sensor data could be used to quantify cannulation skill. As with many other medical specialties, implementation of simulator-based training holds the promise of much-needed improvement in end-stage kidney disease patient outcomes. [ABSTRACT FROM AUTHOR]

In patients receiving hemodialysis, the provision of safe and effective vascular access using an arteriovenous fistula or graft is regarded as a critical priority by patients and health professionals. Vascular access failure is associated with morbidity and mortality, such that strategies to prevent these outcomes are essential. Inadequate vascular remodeling and neointimal hyperplasia resulting in stenosis and frequently thrombosis are critical to the pathogenesis of access failure. Systemic medical therapies with pleiotropic effects including antiplatelet agents, omega-3 polyunsaturated fatty acids (fish oils), statins, and inhibitors of the renin-angiotensin-aldosterone system (RAAS) may reduce vascular access failure by promoting vascular access maturation and reducing stenosis and thrombosis through antiproliferative, antiaggregatory, anti-inflammatory and vasodilatory effects. Despite such promise, the results of retrospective analyses and randomized controlled trials of these agents on arteriovenous fistula and graft outcomes have been mixed. This review describes the current understanding of the pathogenesis of arteriovenous fistula and graft failure, the biological effects of antiplatelet agents, fish oil supplementation, RAAS blockers and statins that may be beneficial in improving vascular access survival, results from clinical trials that have investigated the effect of these agents on arteriovenous fistula and graft outcomes, and it explores future therapeutic approaches combining these agents with novel treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: Hemodialysis (HD) in end-stage renal disease (ESRD) patients requires vascular access (VA) through an arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG), or a central venous catheter. While AVF or AVG is commonly used for HD, the economic implications of AVF versus AVG use have not been fully established. We describe the healthcare resource utilization and costs of AVF and AVG use for incident ESRD patients in the United States.Methods: This observational cohort study of AVF and AVG placements used data from the United States Renal Data System to identify and follow access placements. AVF and AVG placements after ESRD onset for incident patients from 2012 to 2014 with continuous Medicare primary coverage were included. All-cause and access-related Medicare costs were averaged over the placement lifetime and expressed as per dialysis-month costs.Results: The analysis included 38,035 AVF placements and 12,789 AVG placements. Total all-cause monthly costs for AVF averaged USD 8,508; mean monthly costs were USD 3,027 for inpatient (IP), USD 3,139 for outpatient (OP), USD 1,572 for physician services, and USD 770 for other care settings. Access-related monthly costs averaged USD 1,699 and represented 20% of all-cause charges for AVFs. Mean all-cause monthly costs for AVG were USD 9,605; by setting monthly costs were USD 3,811 for IP, USD 3,034 for OP, USD 1,881 for physician services and USD 879 for other care settings. Access-related monthly costs averaged USD 2,656 and represented 28% of all-cause charges for AVGs.Discussion/conclusions: This study indicates that costs due to VA are a significant burden on Medicare budgets and on patients. The factors driving access-related utilization and costs merit attention in future research. Both optimizing process of care and discovery innovation may significantly accelerate better stewardship of available healthcare resources. [ABSTRACT FROM AUTHOR]

Background: Chronic hemodialysis requires a mode of vascular access through an arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG), or a central venous catheter (CVC). AVF is recommended over AVG or CVC due to increased patency and decreased intervention rates for those that mature. AVG are preferred over CVC due to decreased infection and mortality risk. The aims of this study were to evaluate the lifespan of AVF and AVG in maturation, sustained access use, and abandonment.Methods: The United States Renal Data System (USRDS), Medicare claims, and CROWNWeb were used to identify access placements. Patients with a first end-stage renal disease (ESRD) service from January 1, 2012 to June 30, 2014 with continuous coverage with Medicare as primary payer and ≥1 AVF or AVG placed after ESRD onset were included. Maturation was defined as the first use of the access for hemodialysis recorded in CROWNWeb. Sustained access use was defined as 3 consecutive months of use without catheter placement or replacement. Accesses that were never used at any time post-placement were considered abandoned.Results: The cohort included 38,035 AVF placements and 12,789 AVG placements. Sixty-nine percent of AVF and 72% of AVG matured. Fifty-two percent of AVF and 51% of AVG achieved sustained access use. One quarter of AVF and 14% of AVG were abandoned without use as recorded in CROWNWeb.Conclusion: Although considered the gold standard for vascular access, only half of AVF and AVG placements achieved sustained access use. The USRDS database has inherent limitations but provides useful clinical insight into maturation, sustained use, and abandonment. [ABSTRACT FROM AUTHOR]

Hemodialysis vascular access is at the same time both the 'Lifeline' and the 'Achilles Heel' of hemodialysis. This review will initially summarize the vascular biology of dialysis vascular access dysfunction and then use this information to describe some novel and innovative ways (including advances in the process of care for vascular access) to prevent this problem. [ABSTRACT FROM AUTHOR]

Remodeling in the arteriovenous fistulas (AVFs) is believed to be a hemodynamic-driven process, which results in extreme changes in the diameter and intima-media thickening (IMT) of vessels over time. This study aims to describe the successful development of techniques that enabled correlation of changes in local and longitudinal wall shear stress (WSS) with the temporal variations of the diameter and IMT in the venous segment of AVFs. An AVF was created between the femoral artery and vein of a 50-kg pig. We have previously shown the successful use of CT-scan and ultrasound techniques for anatomical and flow measurements in AVFs, respectively. In this study, we developed new techniques involving markers (both in vivo and ex vivo), casting (ex vivo), and micro-MRI (ex vivo; 7 Tesla). A radiopaque marker (ROM) was sutured to the AVF at the day of surgery, which was visible in the CT-scan images, micro-MRI, and histology sections. Therefore, ROM served as a fixed local reference for both in vivo and ex vivo states of AVFs. Immediately after sacrificing the pig, a procedure was developed to create a cast from the AVF and thus, maintaining the in vivo state of the AVF during the histology process. Then, micro-MRI and histology techniques were conducted on the AVF to measure IMT in the vein. Along the ROM, the local changes in WSS levels for two cross-sections were tracked at 2D (D: days) and 28D post surgery. WSS levels reduced from 2D to 28D for both cross-sections. Also, the recirculation zones, which formed at 2D for both sections, became smaller in size at 28D. These hemodynamic changes were then mapped onto the corresponding IMT measurements from histology and micro-MRI. It was observed that the recirculation zones at 2D and 28D corresponded to the largest IMT in the two sections. In summary, the new methodologies allowed us to define a fixed local reference at all time points in the AVF, which enabled accurate tracking of local changes in hemodynamics (WSS), configuration (diameter), and structure (IMT) of the venous segment over time. This also empowered study of the interactions between these parameters, which could improve our understanding about the hemodynamic-driven remodeling in AVFs. From a clinical point of view, this information could be translated into local and early therapeutic interventions for dialysis patients. [ABSTRACT FROM AUTHOR]

Arteriovenous fistulas (AVFs) used for hemodialysis fail because of venous neointimal hyperplasia (VNH). There are 1,500,000 patients that have end stage renal disease worldwide and the majority requires hemodialysis. In the present study, the role of the intermediate early response gene X-1 (IEX-1), also known as IER-3 in the pathogenesis of VNH was evaluated. In human samples removed from failed AVF, there was a significant increase in IEX-1 expression localized to the adventitia. In Iex-1−/− mice and wild type (WT) controls, chronic kidney disease was induced and an AVF placed 28 days later by connecting the carotid artery to jugular vein. The outflow vein was removed three days following the creation of the AVF and gene expression analysis demonstrated a significant decrease in vascular endothelial growth factor-A (Vegf-A) and monocyte chemoattractant protein-1 (Mcp-1) gene expression in Iex-1−/− mice when compared to WT mice (P<0.05). At 28 days after AVF placement, histomorphometric and immune-histochemical analyses of the outflow vein demonstrated a significant decrease in neointimal hyperplasia with an increase in average lumen vessel area associated with a decrease in fibroblast, myofibroblast, and Ly6C staining. There was a decrease in proliferation (Ki-67) and an increase in the TUNEL staining in Iex-1 KO mice compared to WT. In addition, there was a decrease in Vegf-A, Mcp-1, and matrix metalloproteiniase-9 (Mmp-9) staining. Iex-1 expression was reduced in vivo and in vitro using nanoparticles coated with calcitriol, an inhibitor of Iex-1 that demonstrated that Iex-1 reduction results in decrease in Vegf-A. In aggregate, these results indicate that the absence of IEX-1 gene results in reduced VNH accompanied with a decrease in proliferation, reduced fibroblast, myofibroblast, and Ly6C staining accompanied with increased apoptosis mediated through a reduction in Vegf-A/Mcp-1 axis and Mmp-9. Adventitial delivery of nanoparticles coated with calcitriol reduced Iex-1 and VNH. [ABSTRACT FROM AUTHOR]

Despite all the progress achieved since Scribner first introduced the arteriovenous (AV) shunt in 1960 and Cimino and Brescia introduced the native AV fistula in 1962, we have continued to face a conundrum in vascular access for dialysis, in that dialysis vascular access is at the same time both the 'lifeline' and the 'Achilles' heel' of haemodialysis. Indeed, findings from a multitude of published articles in this area, unfortunately mainly observational studies, reflect both our frustration and our limited knowledge in this area. Despite improved understanding of the pathophysiology of stenosis and thrombosis of the vascular access, we have unfortunately not been very successful in translating these advances into either improved therapies or a superior process of care. As a result, we continue to face an epidemic of arteriovenous fistula (AVF) maturation failure, a proliferation of relatively ineffective interventions such as angioplasty and stent placement, an extremely high incidence of catheter use, and more doubts rather than guidance with regard to the role (or lack thereof) of surveillance. An important reason for these problems is the lack of focused translational research and robust randomized prospective studies in this area. In this Review, we will address some of these critical issues, with a special emphasis on identifying the best process of care pathways that could reduce morbidity and mortality. We also discuss the potential use of novel therapies to reduce dialysis vascular access dysfunction. [ABSTRACT FROM AUTHOR]

Summary: Arteriovenous fistula (AVF) maturation failure is currently a huge clinical problem. One approach to enhance the AVF maturation rate is an aggressive sequence of balloon angioplasty procedures, often known as balloon-assisted maturation. The goal of the current paper is to explore the pros and cons of this procedure and to try and better identify its impact on AVF maturation. [ABSTRACT FROM AUTHOR]

Objectives: Arteriovenous fistula (AVF) is the preferred type of vascular access for hemodialysis to treat end-stage renal disease. A high proportion of AVF are never used for dialysis because the vein fails to mature adequately. We have previously described the safety and feasibility of Vascugel (Genzyme BioSurgery, Cambridge, Mass) (allogeneic aortic endothelial cells in a gelatin matrix) when placed around the anastomotic and venous outflow sites of AVFs (Vascular intimal Hyperplasia: Extending Arterial and venous patency, Limiting vascular Trauma, and inhibiting Hyperplasia while re-establishing vascular health [V-HEALTH] clinical study). In this retrospective analysis, we investigated factors that influenced AVF remodeling in patients from the V-HEALTH study. We hypothesized that providing healthy endothelial cells and their secreted factors immediately after surgery could enhance venous remodeling in the setting of vascular injury. Methods: Thirty-one AVF patients from the V-HEALTH study were randomized 2:1 to receive either Vascugel or control matrices (placebo) at surgery and were followed for 24 weeks. Venous lumen diameter was measured by ultrasound at 1, 3, and 5 cm from the anastomosis. Vein remodeling (change in lumen diameter at 4, 12, and 24 weeks compared with baseline diameter at 2 weeks) was analyzed using a multiple regression mixed model. Results: The results indicated that diabetes was a significant, negative predictor of venous remodeling over the 24-week study (P = .02). The model-predicted change in lumen diameter from 2 to 24 weeks was −0.7 mm in diabetic patients (n = 11) and +2.4 mm in nondiabetic patients (n = 15), a difference of 3.1 mm, 95% confidence interval [CI] (1.4-4.9), P = .0014. Patient race, baseline vein diameter, and time post-AVF creation were also significant factors that affected remodeling (P < .05). Compared with placebo, there was a strong suggestion that Vascugel treatment improved the rate of venous enlargement in diabetic patients (P = .05). The model-predicted change in lumen diameter at 24 weeks was −1.9 mm for placebo-treated diabetic patients and +0.4 mm for Vascugel-treated diabetic patients, a difference of 2.3 mm, 95% CI (−0.1-4.8), P = .06, suggesting that treatment with Vascugel may mitigate the negative influence of diabetes on AVF remodeling. Conclusions: Diabetes negatively impacts AVF remodeling and targeted local therapy with perivascular, allogeneic endothelial cells may ameliorate this effect. A phase II trial designed specifically to evaluate AVF remodeling is needed to determine if Vascugel can increase AVF maturation and use and to support larger randomized trials. [ABSTRACT FROM AUTHOR]

Background. Haemodialysis vascular access dysfunction (due to venous stenosis and thrombosis) is a leading cause of hospitalization and morbidity. The aim of the current study was to identify the specific cell types present within stenotic tissue samples from patients with AV fistula and graft failure. [ABSTRACT FROM PUBLISHER]

Background: Hemodialysis patients have high rates of sudden death, but relationships between serum electrolytes, the dialysis prescription, and intra-dialytic shifts in fluid and electrolyte with arrhythmia are uncertain.Methods: We analyzed sixty-six hemodialysis patients who underwent loop recorder implantation with continuous electrocardiographic monitoring, weekly to bi-weekly testing of pre- and post-dialysis electrolytes, and detailed capture of dialysis prescription and flow sheet data for 6 months. The incidence rate ratio (IRR) of reviewer confirmed arrhythmias (RCA) during dialysis through 8 h after dialysis and associations with serum chemistries and dialytic parameters were assessed using adjusted, negative-binomial regression.Results: Among 66 individuals with a mean age of 56 years, 12,480 events were detected in 64 (97%) patients. RCA nadired 12-24 h after dialysis and increased during the final 12 h of the inter-dialytic interval through the first 8 h after dialysis. Higher pre-dialysis serum magnesium concentration was associated with lower incidence rate ratio for arrythmia (IRR per 1 mg/dL increase 0.49, 95% CI; 0.25, 0.94), as was dialysate calcium concentration > 2.5 mEq/L vs. 2.5 mEq/L (IRR 0.52, 95% CI: 0.39, 0.70). Neither intradialytic serum potassium nor weight change were significantly associated with RCA rate. However, there was effect modification such that arrhythmia rate was maximal with concurrently high intradialytic volume and potassium removal (Pinteraction = 0.01).Conclusions: Intra and post-dialytic arrhythmias are common in hemodialysis. Additional studies designed to further elucidate whether modification of the serum magnesium concentration, dialysate calcium concentration, and the extent of intradialytic potassium and fluid removal reduces the risk of per-dialytic arrhythmia are warranted.Trial Registration: Clinicaltrials.gov NCT01779856. Prospectively registered on January 22, 2013. [ABSTRACT FROM AUTHOR]

Haemodialysis vascular access is a 'life line' for almost 2 million patients worldwide; yet given the substantial problems associated with access dysfunction, vascular access is also the Achilles heel of haemodialysis. Recent data suggest that use of novel bioengineered human a cellular vessels for haemodialysis access might help to overcome these problems. [ABSTRACT FROM AUTHOR]

Advances in standards of care have extended the life expectancy of patients with kidney failure. However, options for chronic vascular access for haemodialysis - an essential part of kidney replacement therapy - have remained unchanged for decades. The high morbidity and mortality associated with current vascular access complications highlights an unmet clinical need for novel techniques in vascular access and is driving innovation in vascular access care. The development of devices, biological approaches and novel access techniques has led to new approaches to controlling fistula geometry and manipulating the underlying cellular and molecular pathways of the vascular endothelium, and influencing fistula maturation and formation through the use of external mechanical methods. Innovations in arteriovenous graft materials range from small modifications to the graft lumen to the creation of completely novel bioengineered grafts. Steps have even been taken to create new devices for the treatment of patients with central vein stenosis. However, these emerging therapies face difficult hurdles, and truly creative approaches to vascular access need resources that include well-designed clinical trials, frequent interaction with regulators, interventionalist education and sufficient funding. In addition, the heterogeneity of patients with kidney failure suggests it is unlikely that a 'one-size-fits-all' approach for effective vascular access will be feasible in the current environment. [ABSTRACT FROM AUTHOR]

BACKGROUND Use of vascular allografts could obviate the cost and complications of polytetrafluoroethylene (PTFE) grafts in patients who require hemodialysis but have poor vascular status. OBJECTIVE To investigate the outcomes of formaldehyde-fixed cadaveric arterial allografts as vascular access for hemodialysis. DESIGN AND INTERVENTION Patients with end-stage renal disease (ESRD) requiring chronic hemodialysis were recruited at the Jinan Central Hospital, Jinan, China for this prospective, non-randomized study. Inclusion criteria were poor vascular condition of the forearm, multiple failed attempts at creation of an arteriovenous fistula, lack of availability of native vessels for vascular access, or pseudoaneurysm or insufficient blood flow of an arteriovenous fistula. Femoral arterial allografts were obtained from donors who had died of trauma or brain tumor; donors with other types of malignancy, or infectious or vascular disease were excluded. Arteries were removed aseptically, fixed with 20% formaldehyde at room temperature for 4 h, and then stored in alcohol at 4°C until required. Transplantation was performed under local anesthesia, and cefazolin was administered perioperatively. No immunosuppressants were given. Dialysis was initiated 3 weeks after graft transplantation. Follow-up took place at 3 months, 6 months, 1 year, 2 years and 3 years. OUTCOME MEASURES The end points were allograft rejection rate, access blood flow (as assessed by Doppler ultrasound), primary and secondary patency rates, and complications. RESULTS During the period October 1996 to May 2006, 68 allografts were transplanted into 43 patients (mean age 59.5 years; 34.9% female); 31 patients received ABO-mismatched grafts. The procedures comprised 43 first transplantations, 16 second transplantations, 6 third transplantations and 3 fourth transplantations. There was no precipitation between alloantigens isolated from the formaldehyde-fixed allografts and antisera on an agarose gel, indicating a lack of alloantigenicity (in contrast to the results obtained with alloantigens from unfixed allografts). No clinical signs of hyperacute or acute graft rejection were observed, and there was no histological evidence of lymphocyte infiltration on tissue samples obtained from failed grafts. At 1 month after transplantation, mean access blood flow was 696ml/min (range 410-1,280 ml/min). Rates of primary patency (i.e. without intervention) were 90% at 3 months, 85% at 6 months, 74% at 1 year, 53% at 2 years and 42% at 3 years; corresponding rates of secondary patency (i.e. until complete failure) were 95%, 93%, 90%, 73% and 62%, respectively. Complications mainly comprised thrombosis (25 cases), hematoma (3 cases) and pseudoaneurysms (2 cases). The costs of a formaldehyde-fixed arterial allograft and a PTFE graft in China were calculated as US$250 and $1,250, respectively. CONCLUSION Formaldehyde-fixed arterial allografts show promise as an alternative to PTFE grafts for hemodialysis access in patients with poor vascular health. [ABSTRACT FROM AUTHOR]

Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis. Background. Vascular access dysfunction is the most important cause of morbidity and hospitalization in the hemodialysis population in the United States at a cost of well over one billion dollars per annum. Venous neointimal hyperplasia characterized by stenosis and subsequent thrombosis, is the major cause of polytetrafluoroethylene (PTFE) dialysis graft failure. Despite the magnitude of the problem, there are currently no effective therapies for the prevention or treatment of venous neointimal hyperplasia in PTFE dialysis grafts. We believe that this is partly due to the lack of a validated large animal model of arteriovenous stenosis that could be used to test out novel interventions. Methods. Seven-centimeter PTFE loop grafts were placed between the femoral artery and vein of domestic pigs. The grafts were removed at 2, 4, 7, 14 and 28 days after surgery and subjected to a detailed histological and immunohistochemical examination. Results. Significant neointimal hyperplasia and venous stenosis developed by 28 days at the graft-vein anastomosis. There was minimal neointimal hyperplasia at the graft-artery anastomosis. Venous neointimal hyperplasia (VNH) was characterized by (a ) the presence of smooth muscle cells/myofibroblasts; (b ) angiogenesis within both the neointima and adventitia; and (c ) the presence of an active macrophage cell layer lining the PTFE graft material. These results are very similar to the human lesion previously described by us in dialysis patients. Conclusions. We have developed and validated a pig model of venous neointimal hyperplasia that is very similar to the human lesion. We believe that this is an ideal model in which to test out novel interventions for the prevention and treatment of clinical hemodialysis vascular access dysfunction. [ABSTRACT FROM AUTHOR]

Purpose: Hemodialysis vascular access dysfunction is an enormous clinical problem that causes great morbidity and costs well over one billion dollars per annum. The vast majority of hemodialysis vascular access dysfunction occurs as a result of venous stenosis and thrombosis at the graft-vein anastomosis. At a cellular level, this venous stenosis is the result of venous neointimal hyperplasia (VNH). There are, unfortunately, no effective therapies for VNH. The purpose of this study was to assess the role of external radiation therapy in preventing VNH and venous stenosis.Methods and Materials: Seven-centimeter polytetrafluoroethylene loop grafts were placed bilaterally between the femoral artery and vein of 12 Yorkshire Cross pigs. One side was treated with a single 16-Gy dose of external beam radiation with a linear accelerator, while the contralateral side served as an internal control. Swine were killed after 28 days, and the grafts were carefully dissected out and removed. Neointimal hyperplasia and luminal stenosis were then assessed morphometrically at the graft-vessel anastomoses.Results: External beam radiation therapy significantly reduced the amount of luminal stenosis at the graft-vein anastomosis, with minimal local and systemic toxicity.Conclusions: External beam radiation therapy could be a useful and clinically relevant local treatment for venous stenosis in polytetrafluoroethylene dialysis grafts. [Copyright &y& Elsevier]