Timmy Lee

Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis.

Hemodialysis vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of this vascular access dysfunction is venous stenosis as a result of venous neointimal hyperplasia within the perianastomotic region (arteriovenous fistula) or at the graft-vein anastomosis (polytetrafluoroethylene, or PTFE, grafts). There have been few effective treatments to date for venous neointimal hyperplasia, in part, because of the poor understanding of the pathogenesis of venous neointimal hyperplasia. Therefore, this article will (1) describe the pathology of hemodialysis access stenosis in arteriovenous fistulas and grafts, (2) review and describe both current and novel concepts in the pathogenesis of neointimal hyperplasia formation, (3) discuss current and future novel therapies for treating venous neointimal hyperplasia, and (4) suggest future research areas in the field of hemodialysis vascular access dysfunction.

Severe venous neointimal hyperplasia prior to dialysis access surgery

BACKGROUND Venous neointimal hyperplasia is the most common cause of arteriovenous (AV) fistula and graft dysfunction following dialysis access surgery. However, the pathogenetic impact of pre-existing venous neointimal hyperplasia at the time of AV access creation on final clinical success is currently unknown in the setting of advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. The aim of this study was to perform a detailed histological, morphometric, and immunohistochemical analysis of vein specimens in advanced CKD and ESRD patients collected at the time of new vascular access placement. METHODS Vein samples from 12 patients were collected at the time of AV access creation near the site of AV anastomosis. Histological, immunohistochemistry and morphometric studies were performed on these vein samples. RESULTS Examination of the tissue specimens obtained at the time of surgery showed neointimal hyperplasia in 10 of 12 specimens, ranging from minimal to very severe. The majority of cells within the neointima were myofibroblasts with a minority of contractile smooth muscle cells present. CONCLUSION Our work represents a detailed description of the morphometric and cellular phenotypic lesions present in the veins of CKD and ESRD patients, prior to dialysis access placement. These studies (i) suggest the future possibility of a new predictive marker (pre-existing venous neointimal hyperplasia) for AV dialysis access dysfunction and (ii) open the door for the future development of novel local therapies for optimization of the venous substrate on which the dialysis access is created.

Decreased Cumulative Access Survival in Arteriovenous Fistulas Requiring Interventions to Promote Maturation

BACKGROUND AND OBJECTIVES New arteriovenous fistulas (AVF) are frequently unsuitable for hemodialysis because of AVF nonmaturation. Aggressive endovascular or surgical interventions are often undertaken to salvage nonmaturing AVFs. The effect of early interventions to promote AVF maturation on subsequent long-term AVF outcomes is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We evaluated 173 hemodialysis patients from two academic centers who received a new AVF. Of these, 96 (56%) required no further intervention, 54 (31%) required one intervention, and 23 (13%) required two or more interventions to achieve suitability for dialysis. We calculated AVF survival and frequency of postmaturation interventions in each group. RESULTS Cumulative AVF survival (access cannulation to permanent failure) in patients with two or more versus one versus zero interventions before maturation was 68% versus 78% versus 92% at 1 year, 57% versus 71% versus 85% at 2 years, and 42% versus 57% versus 75% at 3 years. Using Cox regression analysis with interventions before maturation, age, sex, race, diabetes, peripheral vascular disease, access site, and obesity in the model, intervention before maturation (two or more) was the only factor associated with cumulative AVF survival. The number of interventions required to maintain patency after maturation was 3.51 ± 2.20 versus 1.37 ± 0.31 versus 0.76 ± 0.10 per year in patients with two or more versus one versus zero interventions before maturation. CONCLUSIONS Compared with AVF that mature without interventions, AVF that require interventions have decreased cumulative survival and require more interventions to maintain their patency for hemodialysis.

Comparison of survival of upper arm arteriovenous fistulas and grafts after failed forearm fistula

Although arteriovenous fistulas are considered superior to grafts, it is unknown whether that is true in the subset of patients with a previous failed fistula. For investigation of this question, a prospective vascular access database was queried retrospectively to compare the outcomes of 59 fistulas and 51 grafts that were placed in the upper arm after primary failure of an initial forearm fistula. Primary access failure was higher for subsequent fistulas than for subsequent grafts (44 versus 20%; P = 0.006). Fistulas required more interventions than grafts before their successful use (0.42 versus 0.16 per patient; P = 0.04). The time to catheter-free dialysis was longer for fistulas than for grafts (131 versus 34 d; P < 0.0001) and was associated with more episodes of bacteremia before permanent access use (1.3 versus 0.4 per patient; P = 0.003). Cumulative survival (from placement to permanent failure) was higher for fistulas than for grafts when primary failures were excluded (hazard ratio 0.51; 95% confidence interval 0.27 to 0.94; P = 0.03), but similar when primary failures were included (hazard ratio 0.99; 95% confidence interval 0.61 to 1.62; P = 0.97). Fistulas required fewer interventions to maintain long-term patency for dialysis after maturation (0.73 versus 2.38 per year; P < 0.001). In conclusion, as compared with grafts, subsequent upper arm fistulas are associated with a higher primary failure rate, more interventions to achieve maturation, longer catheter dependence, and more frequent catheter-related bacteremia. However, once the access is usable for dialysis, fistulas have superior cumulative patency than do grafts and require fewer interventions to maintain patency.

Standardized Definitions for Hemodialysis Vascular Access

Vascular access dysfunction is one of the leading causes of morbidity and mortality among end‐stage renal disease patients. Vascular access dysfunction exists in all three types of available accesses: arteriovenous fistulas, arteriovenous grafts, and tunneled catheters. To improve clinical research and outcomes in hemodialysis (HD) access dysfunction, the development of a multidisciplinary network of collaborative investigators with various areas of expertise, and common standards for terminology and classification in all vascular access types, is required. The North American Vascular Access Consortium (NAVAC) is a newly formed multidisciplinary and multicenter network of experts in the area of HD vascular access, who include nephrologists and interventional nephrologists from the United States and Canada with: (1) a primary clinical and research focus in HD vascular access dysfunction, (2) national and internationally recognized experts in vascular access, and (3) a history of productivity measured by peer‐reviewed publications and funding among members of this consortium. The consortium’s mission is to improve the quality and efficiency in vascular access research, and impact the research in the area of HD vascular access by conducting observational studies and randomized controlled trials. The purpose of the consortium’s initial manuscript is to provide working and standard vascular access definitions relating to (1) epidemiology, (2) vascular access function, (3) vascular access patency, and (4) complications in vascular accesses relating to each of the vascular access types.

Who should be referred for a fistula? A survey of nephrologists

BACKGROUND There is marked variation in the use of the arteriovenous fistula (AVF) across programmes, regions and countries not explained by differences in patient demographics or comorbidities. The lack of clear criteria of who should or should not get a fistula may contribute to this, as well as barriers to creating AVFs. METHODS We conducted a survey of Canadian and American nephrologists to assess the patient variables considered to determine the timing and type of access requested. Perceived barriers and absolute contraindications to access were also collected. RESULTS An immediate referral for a fistula was more highly preferred when patients are <65 years old, have minimal comorbidities or have no history of failed accesses. In older patients, and in those with increased comorbidities or a previously failed fistula, US nephrologists selected arteriovenous grafts as an alternative to the fistula, while Canadian nephrologists selected primarily catheters. Referral for vascular mapping was more common in the USA than in Canada. Gender did not influence the timing or the type of access. Perceived barriers to establishing a mature fistula included patient refusal for creation (77%) or cannulation (58%), delay in decision regarding dialysis modality (71%), wait time for surgical creation (55%) and high failure-to-mature rate (52%). We found that 27% of Canadian and 43% of American nephrologists indicated no absolute contraindications for permanent vascular access. CONCLUSIONS This study demonstrated marked variability in timing and criteria used to select patients for referral for a vascular access between nephrologists practicing within Canada and the USA. Establishing minimal eligibility criteria for fistulae is an important area of future research.

Optimal Hemodialysis Vascular Access in the Elderly Patient

The optimal vascular access for elderly patients remains a challenge due to the difficulty balancing the benefits and risks in a population with increased comorbidity and decreased survival. Age is commonly associated with failure to mature in fistula and decreased rates of primary and secondary patency in both fistula and grafts. In the elderly, at 1 and 2 years, primary patency rates range from 43% to 74% and from 29% to 67%, respectively. Secondary patency rates at 1 and 2 years range from 56% to 82% and 44% to 67%, respectively. Cumulative fistula survival is no better than grafts survival when primary failures are included. Several observational studies consistently demonstrate a lower adjusted mortality among those using a fistula compared with a catheter; however, catheter use in the elderly is increasing in most countries with the exception of Japan. Both guidelines and quality initiatives do not acknowledge the trade‐offs involved in managing the elderly patients with multiple chronic conditions and limited life expectancy or the value that patients place on achieving these outcomes. The framework for choice of vascular access presented in this article considers: (1) likelihood of disease progression before death, (2) patient life expectancy, (3) risks and benefits by vascular access type, and (4) patient preference. Future studies evaluating the timing and type of vascular access with careful assessments of complications, functionality, cost benefit, and patients’ preference will provide relevant information to individualize and optimize care to improve morbidity, mortality, and quality of life in the elderly patient.

Vascular stenosis: biology and interventions.

Purpose of reviewThe aim of this review will be to summarize recent concepts pertaining to the pathophysiology of dialysis access stenosis and to then use this information to highlight novel interventions (both diagnostic and therapeutic) for dialysis access dysfunction. The studies covered in this review will include experimental and observational studies in addition to clinical trials. Recent findingsAn important biological focus of this review will be an emphasis on the role of the adventitia and progenitor cells in the pathogenesis of dialysis access dysfunction. The main interventional focus will be on access surveillance, local drug delivery and other novel therapeutic interventions. An important underlying theme throughout this review will be an emphasis on arteriovenous fistulae and on the many advantages of local therapeutic interventions in the specific clinical setting of dialysis access dysfunction. SummaryVascular access dysfunction remains a significant cause of morbidity and mortality for hemodialysis patients. We believe that a better understanding of the biological mechanisms of vascular access stenosis will help guide the development of novel therapies to prevent and treat dialysis access stenosis.

Novel Paradigms for Dialysis Vascular Access: Downstream Vascular Biology–Is There a Final Common Pathway?

Vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of vascular access dysfunction is venous stenosis from neointimal hyperplasia within the perianastomotic region of an arteriovenous fistula and at the graft-vein anastomosis of an arteriovenous graft. There have been few, if any, effective treatments for vascular access dysfunction because of the limited understanding of the pathophysiology of venous neointimal hyperplasia formation. This review will (1) describe the histopathologic features of hemodialysis access stenosis; (2) discuss novel concepts in the pathogenesis of neointimal hyperplasia development, focusing on downstream vascular biology; (3) highlight future novel therapies for treating downstream biology; and (4) discuss future research areas to improve our understanding of downstream biology and neointimal hyperplasia development.

Preexisting Venous Calcification Prior to Dialysis Vascular Access Surgery

Vascular calcification is present in arterial vessels used for dialysis vascular access creation prior to surgical creation. Calcification in the veins used to create a new vascular access has not previously been documented. The objective of this study was to describe the prevalence of venous calcification in samples collected at the time of vascular access creation. Sixty‐seven vein samples were studied. A von Kossa stain was performed to quantify calcification. A semi‐quantitative scoring system from 0 to 4+ was used to quantify the percentage positive area for calcification as a fraction of total area (0: 0; 1+: 1–10%; 2+: 11–25%; 3+: 26–50%; 4+: >50% positive). Twenty‐two of 67 (33%) samples showed evidence of venous calcification. Histologic examination showed varying degrees of calcification within each cell layer. Among the subset of patients with calcification, 4/22 (18%), 19/22 (86%), 22/22 (100%), and 7/22 (32%) had calcification present within the endothelium, intima, media, and adventitia, respectively. The mean semi‐quantitative scores of the 22 samples with calcification were 0.18 ± 0.08, 1.2 ± 0.14, 1.6 ± 0.13, and 0.36 ± 0.12 for the endothelium, intima, media, and adventitia, respectively. Our results demonstrate that vascular calcification is present within veins used to create new dialysis vascular access, and located predominately within the neointimal and medial layers.