4.2.5 Endothelial loaded gel foam wrap (Vascugel)

Vascugel is an endothelial-cell-loaded wrap comprising a gel foam with allogeneic aortic endothelial cells [1, 53, 121]. Vascugel mediates its effects through the local delivery of "functional" endothelial cells at the anastomosis to promote outward vascular remodeling and prevent neointimal hyperplasia [1]. Preclinical studies involving porcine models of AVF and AVG have reported that local application of Vascugel resulted in a reduction in thrombus formation and vessel wall inflammation, an increase in luminal diameter and outward remodeling accompanied by reductions in MMP-2 expression, neovascularization and adventitial fibrosis [119, 120]. A phase II trial by Conte et al. [121] suggested that the use of Vascugel was a safe approach for local response to injury control at anastomotic sites, although it did not significantly affect primary and assisted patency rates in treated AVF and AVG compared with placebo (Table 1). A retrospective analysis of this trial showed an improved primary patency when Vascugel was used in AVGs of diabetic patients (p = 0.05), although the results of such a post hoc analysis should be interpreted with caution [53]. In summary, Vascugel has been identified as a safe intervention, though its clinical benefit on vascular access function has not been consistently demonstrated in human trials. Adequately powered RCTs investigating its clinical application are still needed.

### 4.2.6 Antiproliferative agents: COLL-R (drug-eluted combination product of collagen membrane and sirolimus)

Sirolimus (rapamycin) is an antiproliferative agent with immunosuppressive, anti-inflammatory and antiproliferative effects [139, 140], that has been shown to reduce vascular smooth muscle cell proliferation [13] and neointimal hyperplasia in vascular access [122]. When delivered locally, sirolimus reduces neointimal hyperplasia in coronary re-stenosis [1, 141–143]. COLL-R is a drug-eluted combination product of sirolimus and a collagen membrane, which can be implanted around the adventitial surface either at the arteriovenous anastomosis of the AVF or at the graftvein anastomosis of the AVG [1, 13, 122]. Sirolimus is then eluted from the COLL-R, inhibiting neointimal proliferation at the anastomosis [122], translating clinically to a potential improvement in vascular access maturation and patency [13]. A single-arm phase II study by Paulson et al. [122] containing a cohort of 12 hemodialysis patients undergoing AVG formation with intraoperative COLL-R placement demonstrated primary unassisted patency rates of 75% at 12 months and 38% at 24 months and a thrombosis rate of 0.37 episodes per patient year (Table 1) [122]. In a sub-group of 5 patients, whole blood sirolimus levels reached a mean peak of 4.8 ng/mL at 6 h and were less than 1 ng/mL at 1 week. Results from a phase III RCT evaluating AVF suitability for dialysis at 6 months with and without a perivascular Sirolimus-Eluting Collagen Implant are currently awaited (NCT02513303).

#### 4.2.7 Paclitaxel-coated balloon angioplasty

Drug-eluting balloons can deliver antiproliferative agents (such as paclitaxel) at angioplasty sites and thereby reduce neointimal hyperplasia and restenosis following endothelial injury caused by the angioplasty [1, 144]. Paclitaxel-coated balloon (PCB) angioplasty has been successfully used to treat coronary stenosis [145] and

peripheral vascular disease [146]. In 40 patients with stenotic AVFs and AVGs, PCB angioplasty resulted in better target lesion and circuit primary patency rates at 6 months compared to high pressure balloon (HPB) angioplasty (70% vs 25% respectively, p < 0.001) [124] . Lai et al. [147] also reported improved AVF patency rate at 6 months in 10 patients (70% vs 0%, p < 0.01) although this was no longer statistically significant at 12 months (20% vs 0%, P > 0.05). A subsequent single center RCT by Kitou et al. [123] randomized 40 patients to receive PCB angioplasty or HPB angioplasty for dysfunctional AVFs, with a 12-month follow-up (Table 1). Primary endpoints included device success, anatomic success, clinical success and target lesion revascularization-free survival with secondary endpoints of dialysis circuit primary patency and procedure related complications [123]. Use of PCB angioplasty in dysfunctional AVFs resulted in superior target lesion revascularization-free survival (PCB 308 days; HPB 161 days; HR 0.478; 95% CI 0.236–0.966, p = 0.03) and dialysis access circuit primary patency (PCB 270 days; HPB 161 days; HR 0.479; 95% CI 0.237–0.968; p = 0.04) in comparison to HPB angioplasty, though, additional HPB post dilatation was required in 65% of cases. Current trial results support the use of PCB angioplasty to prevent re-stenosis in AVF. However, higher costs compared to conventional angioplasty and the lack of larger RCTs currently prevent its routine use in clinical practice.

6. Conclusion and future direction

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

Conflict of interest

Author details

Rebecca Hudson<sup>1</sup>

Australia

105

comes and should be evaluated with innovative trial designs.

The authors have no conflict of interest to declare.

, David Johnson1,2,3\* and Andrea Viecelli1,2

1 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Centre for Kidney Disease Research, University of Queensland, Brisbane,

\*Address all correspondence to: david.johnson2@health.qld.gov.au

3 Translational Research Institute, Brisbane, Australia

provided the original work is properly cited.

The medical community's understanding of the pathology and pathogenesis of vascular access dysfunction has improved dramatically in recent times and enabled the development of novel targeted treatment approaches. The combination of interventions focusing on upstream events (i.e. optimization of hemodynamics and reduction in vascular injury through surgical/endovascular techniques) and downstream pathways (antiproliferative and anti-inflammatory therapies) may be a promising treatment approach to be assessed in future trials. Emphasis of a multipronged approach including optimization of process of care, education, surgical skills and surveillance combined with targeted therapies may yield the best out-

### 5. Process of care and individualization

Systemic and local therapies to improve arteriovenous access outcomes have been limited, as outlined above. A multipronged approach including optimization of process of care may be more powerful to increase the use of AVFs or AVGs, as opposed to CVCs, than a single therapeutic intervention. An integrated approach to arteriovenous access care which included nephrologists, vascular surgeons, radiologists, access coordinators, and scheduled access procedures with tracked outcomes was demonstrated by Allon et al. [148] to reduce complications associated with surgical access procedures. These benefits included a 60% decreased rate of AVG thrombosis, improved graft secondary patency procedures, and an increase in the AVF creation rate from 33 to 69%. Arora et al. [149] found that patients who were referred to a nephrologist at least 4 months prior to dialysis initiation were 10 times more likely to have a successful functioning access at the first dialysis session, with 40% in the early referral group initiating dialysis with permanent vascular access (80% AVFs, 20% AVGs) vs 4% in the late referral group. This was supported by Roubicek at el [150] who found that 53% of patients referred early for arteriovenous access creation had functional AVFs vs 12% who were referred late. Having a vascular access coordinator can improve the number of AVFs created and decrease vascular access-related hospitalizations and infections [151]. Other strategies, including vein preservation policies, patient education regarding vein protection and access care, preoperative vein mapping and timely access creation have been found to increase fistula prevalence, decrease primary vascular access failure and increase cumulative patency [152–154]. The literature suggest that superior arteriovenous access success is achieved when the AVF is created by a skilled vascular surgeon, [45–49], with the emphasis being placed on the number of AVFs created over the total years of training [48, 50]. In the post-operative setting, timely assessment of arteriovenous access at 4 weeks is recommended to ensure access function is adequate, and to enable early surgical or endovascular intervention to prevent or treat primary access failure. Finally, arteriovenous access cannulation by appropriately trained staff has been shown to prolong AVF survival, while also minimizing the risk of infection.
