Current Status of Synthetic and Biological Grafts for Hemodialysis

Patients with chronic kidney disease (CKD) stage 4 or 5 have the option of kidney transplantation, hemodialysis (HD), peritoneal dialysis (PD), or conservative management.1 National Kidney and Urologic Disease Information Clearinghouse reported that in 2007, there were 368, 544 U.S. residents with ESRD who were receiving dialysis, of whom 341, 264 were undergoing HD.2 Quality of life and long-term survival of patients with CKD who are on HD depends on the successful placement of vascular access, as autogenous arteriovenous access, prosthetic arteriovenous access, or tunneled central venous catheter. DOQI guidelines are emphatic that autogenous arteriovenous access placement should be considered first, as it provides the optimal vascular access, followed by prosthetic grafts if autogenous arteriovenous access placement is not possible. There is a great deal of controversy regarding the choice of synthetic or biological material, as the guidelines suggest that it should be based on surgeon's experience and preference. The evidence to support the superiority of tapered versus uniform tubes, thickversus thinwalled characteristics, elastic versus non-elastic arterial, stretch vs. standard PTFE, externally supported vs. unsupported grafts, is still evolving. An ideal vascular graft would have the following characteristics: 1) appropriate size to match host vessels, 2) mechanical strength, 3) low thrombogenicity/ complete endothelialization, 4) rapid/ complete healing, 5) ease of handling, 6) resistance to infection, 7) structural durability in face of repeated needle puncture, 8) low incidence of hyperplastic intimal changes and 9) low cost.3 In this chapter, we will review the development of vascular grafts over the years and discuss the advantages of one over the other.


Introduction
Patients with chronic kidney disease (CKD) stage 4 or 5 have the option of kidney transplantation, hemodialysis (HD), peritoneal dialysis (PD), or conservative management. 1 National Kidney and Urologic Disease Information Clearinghouse reported that in 2007, there were 368, 544 U.S. residents with ESRD who were receiving dialysis, of whom 341, 264 were undergoing HD. 2 Quality of life and long-term survival of patients with CKD who are on HD depends on the successful placement of vascular access, as autogenous arteriovenous access, prosthetic arteriovenous access, or tunneled central venous catheter. DOQI guidelines are emphatic that autogenous arteriovenous access placement should be considered first, as it provides the optimal vascular access, followed by prosthetic grafts if autogenous arteriovenous access placement is not possible. There is a great deal of controversy regarding the choice of synthetic or biological material, as the guidelines suggest that it should be based on surgeon's experience and preference. The evidence to support the superiority of tapered versus uniform tubes, thick-versus thin-walled characteristics, elastic versus non-elastic arterial, stretch vs. standard PTFE, externally supported vs. unsupported grafts, is still evolving. An ideal vascular graft would have the following characteristics: 1) appropriate size to match host vessels, 2) mechanical strength, 3) low thrombogenicity/ complete endothelialization, 4) rapid/ complete healing, 5) ease of handling, 6) resistance to infection, 7) structural durability in face of repeated needle puncture, 8) low incidence of hyperplastic intimal changes and 9) low cost. 3 In this chapter, we will review the development of vascular grafts over the years and discuss the advantages of one over the other.

Prosthetic grafts for hemodialysis
Although the first synthetic graft used for HD access in the United States was made of Dacron dating back to the early 1970s, unfavorable results and the availability of better prosthetic materials like expanded PTFE (ePTFE) forced its abandonment. In 1976, Dr. Baker presented the first results of ePTFE grafts in 72 HD patients. Since then ePTFE remains the graft of choice for vascular access. 4 ePTFE is considered the material of choice due to the fact that it is readily accessible, ease of implantation, good medium term patency, and relatively low complication rates compared to other synthetic and biological materials. 5 The medical community has made strenuous efforts to increase the use of autogenous arterıovenous access, prevalence has increased from 22% in 1995 to 57.7% in 2011. However, the use of synthetic grafts still remains significant (18.4% prevalence in 2011). 6,7 2.1 Indications for use of prosthetic grafts Autogenous arteriovenous access are clearly superior in terms of long term patency to grafts, but not feasible in many patients undergoing HD 8 . The indications for prosthetic grafts include: lack of suitable vessels particularly in elderly and diabetic patients, need for immediate cannulation and in children who cannot tolerate multiple painful venipunctures. 5

Complications associated with prosthetic grafts
Graft failures are typically caused by stenosis (leading cause of graft failure) due to thrombosis and neointimal hyperplasia at site of anastamosis, as well as graft infection (contributes to 10-15% of graft failure). 9,10 Other less common complications of prosthetic accesses include; steal syndrome, seromas, aneurysm formation, central vein stenosis and bleeding. 11 Thrombosis seems to occur soon after implantation due to technical problem, with a clot typically forming at the surface of the graft when it is first exposed to blood. The clot is formed initially of platelet aggregates, and then fibrin and thrombin is laid down via activation of the coagulation cascade. Platelet activity is generally most intense during the first 24 hours and subsides to a very low level after 1 week. 9 Neointimal hyperplasia in prosthetic conduits can be attributed to upstream and downstream events. The upstream factors include; hemodynamic stress at the graft-vein anastamosis, compliance mismatch between the graft material and vein (more studies required to establish this factor), arterial injury at the time of graft placement, intrinsic properties of the synthetic graft itself (shown to attract macrophages which then secrete specific cytokines bFGF, PDGF, and VEGF), graft injury from dialysis needles, as well as the presence of uremia (causing endothelial dysfunction even prior to synthetic graft implant). [12][13][14] The downhill events are essentially a consequence of the upstream events. Pro-inflammatory cells release cytokines promoting the migration of smooth muscle cells and myofibroblasts from the adventitia media into the intimal layer, where they proliferate and cause lesions of neointimal hyperplasia. 13 These stenotic lesions are usually treated by percutaneous angioplasty (PTA) or open patch angioplasty, which unfortunately, predisposes the patient to restenotic lesions due to endothelial and smooth muscle cell injury. 15 Infection is the second most common complication of synthetic grafts and can lead to further complications such subacute bacterial endocarditis, epidural or brain abscess. 11 These complications can lead to graft failure in up to 35% of patients. 16 Graft infections have an incidence rate as high as 2%, and are 4 times as prevalent in synthetic grafts when compared to autogenous veins. 9 Common causative organisms are Staphylococcus aureus (26.32% of  Table 1. Clinical trials of prosthetic grafts for hemodialysis. www.intechopen.com infections cultured), methacillin resistant Staphylococcus aureus (21.05%), followed by Pseudomonas aeruginosa (5.26%). 11 The largest number of infections occur when patients are going under routine dialysis (more than 50% of patients) and as a complication of chronic cannulation, rather than postoperative complications. 11 Reducing Staphylococcus aureus carrier state in patients undergoing HD and improving antiseptic technique may reduce the rate of infections in grafts.

Characteristics of PTFE grafts
While PTFE is available in various configurations and is produced by various manufacturers, very few have proven to be more beneficial in improving patency in randomized clinical trials for long-term. 1

Effect of wall thickness
In order to examine the effect of wall thickness on patency, Lenz et al. 17 investigated both standard wall and thin wall configuration of PTFE. Although the incidence of complications and mortality did not statistically differ amongst the 2 groups, standard ePTFE had better patency rates. Studies comparing 2 manufacturers of ePTFE grafts: Gore-Tex® (W.L. Gore and Associates, Flagstaff, AZ) and Impra® (C. R. Bard Inc., Murray Hill, NJ) did not find any difference in the performance of 6-mm standard ePTFE grafts. 18 19

Effect of stretch characteristics
In an attempt to reduce kinking of the graft in areas of angulation and to improve intraoperative handling, the graft was modified to stretch (Gore-Tex® Stretch). Tordoir et al. reported a cumulative primary patency rate of 59% in the stretch ePTFE group compared to 29% in standard ePTFE group at 1 year (p < 0.01). In addition, there were significantly fewer thrombotic events for the stretch ePTFE grafts as opposed to the standard ePTFE grafts (40%vs. 12%, p<0.001). 20 Early cannulation of stretch ePTFE grafts was not found to increase peri-operative morbidity rates or decrease 12-month cumulative primary patency rates. 21 In contrast, another study comparing the patency of early cannulation with late cannulation in Gore-Tex® stretch grafts showed that graft patency after thrombosis formation was significantly higher in the late cannulation group (p=0.0002). 22

Effect of ringed reinforcement
Ring reinforced grafts were created to reduce kinking at the apex of loop grafts and decrease incidence of thrombosis associated with external compression. In a retrospective study in which 632 reinforced and non-reinforced PTFE grafts were compared for patency and complications, it was found that non-reinforced grafts had higher primary and secondary patency rates. 23

Effect of cuff or hood on venous ourflow
One of the few modifications that improved patency rates in PTFE vascular grafts was placing a cuff or hood on the venous outflow. The main objective of placing a cuffed PTFE graft is to enlarge the outflow, and reduce mechanical sheer stress in order to reduce thrombotic occlusion caused by neointimal hyperplasia. 1 In a computer simulated model, Venaflo® II (C. R. Bard Inc., Murray Hill, NJ), a flared-end ePTFE graft to simulate a vein  cuff, showed measurable improvements in reducing wall shear stress gradient, wall shear stress angle gradient, and radial pressure gradient. 25 Sorom et al. 26 found that Venaflo® II was associated with increased blood flow rates during HD and improved graft patency compared with ePTFE graft. Similarly, in a smaller study it was found that a flared-end ePTFE graft provided stable blood flow and satisfactory graft patency during 2 years of follow-up, even in high risk patients with a prior history of vascular access thrombosis. 27 However, a European study did not show improvement in patency rate despite a reduction in thrombotic occlusion and stenosis. 24

Effect of coating PTFE
Another technique meant to improve PTFE graft has been coating the PTFE vascular grafts with carbon or heparin to prevent early graft failure and improve overall patency rates. 28 In a canine model, Tsuchida et al. showed that the graft platelet accumulation index (GPAI) was significantly (p<0.05) lower in the carbon lined PTFE group when compared to the control PTFE group. 29 They concluded that carbon lining decreases platelet accumulation on PTFE grafts. Propaten®, ePTFE with bioactive heparin covalently bound to it (W.L. Gore and Associates) has also been shown to be effective in improving graft patency. It is the only vascular graft of its kind approved for HD access on the market. Davidson et al. 30 found 20% improved primary graft patency of about 80% at one year when comparing Propaten® to standard ePTFE. In order to diminish the risk of neointimal hyperplasia. Cagiannos et al. 31 studied the effects of coating an ePTFE graft with rapamycin in a porcine model. They showed that the rapamycin coated grafts significantly (P <0.0001) lowered cross sectional narrowing in the outflow graft when compared to non-coated grafts; as well as no evidence of medial necrosis or aneurysmal degeneration. After a four week observation period, coated grafts showed features of diminished neointimal hyperplasia compared to untreated ePTFE grafts. Researchers have also analyzed the effect of a bioabsorbable vascular wrap mesh containing paclitaxel on neointimal hyperplasia in a sheep model. Paclitaxel coated mesh significantly reduced neointimal hyperplasia and neointimal capillary density without toxicity to adjacent vessels. 32 2.3.6 Self-sealing grafts K/ DOQI recommends that PTFE grafts should not be routinely used until at least 2 weeks after placement and not until swelling has subsided so that palpation of the course of the graft can be performed. This time is needed for tissue-to-graft incorporation, reducing peri graft hematoma. 1 Due to this complication, newer self-sealing grafts have been designed that can be cannulated sooner. 11 Vectra® vascular grafts (C. R. Bard Inc., Murray Hill, NJ) made of a proprietary blend of segmented polyetherurethaneurea and a siloxane containing a surface-modifying additive (SMA), were designed to provide early cannulation, reducing the need for temporary central venous catheters to provide access until the graft matures. In a study of 76 patients, in which Vectra® grafts were compared to transposed brachio-basilic vein (TBB) autogenous access, Kakkos et al. 33 found that aggressive graft surveillance and endovascular treatment methods resulted in equivalent long-term secondary patency rates. The advantage of earlier use of Vectra® graft must be balanced against the need for more frequent secondary interventions and the risk of graft infection. In a single center study, Jefic www.intechopen.com et al. obtained 81% (108 of 133 grafts) cannulation rate within 4 days of Polyurethane (PU) [Thoratec® Vascular Access Graft] graft placement in which none of the recipients required a temporary catheter. A shorter mean bleeding time after withdrawal of dialysis needle was also acquired in the PU graft group (4.0 minutes vs. 9.2 minutes in ePTFE group). 34 Similarly, Glickman et al. showed that PU grafts had achieved better hemostasis at cannulation sites compared to ePTFE sites when the two were compared at 5 minutes or less after dialysis (P<0.0001). Also, they showed that 53.9% of all PU grafts were cannulated before 9 days vs. none of the ePTFE grafts (P<0.001). 35 In the HIV-positive ESRD patient population, reduction of temporary catheter use and prevention of infection is critical. A study of 30 consecutive HIV positive patients receiving Vectra® graft implantation showed a lower infection rate (10% vs. 45%) than published reports of infection in PTFE grafts. It was concluded that the unique self-sealing property of the Vectra® grafts reduced the development of perigraft hematoma and may have accounted for decreased infection. 36

Biological conduits for hemodialysis
Biological graft materials tend to have less intimal hyperplasia at the venous anastamosis, reduced tendency to thrombose, and a lower risk of infection when compared to PTFE. 11 Butler et al. compared bovine heterographs to PTFE and found that the synthetic graft had significantly fewer late thromboses, increased resistance to infection, easier to repair and had comparable longevity. 37 Anderson et al. found that bovine heterographs required twice as many revisions per dialysis month to maintain patency. 38 SynerGraft® 100 (SG100 [CryoLife Inc., Atlanta, GA]) is a modified bovine ureter graft with some similarities to synthetic graft (similar internal diameter and strong tissue matrix). This graft has been processed to remove xenograft cells while maintaining a collagen matrix that is not chemically cross-linked by aldehydes allowing re-population by autologous cells. Matsuura et al. reported a primary patency rate of 72.6% and 58.6% for SG 100 vs. 57.4% and 54.7% for the ePTFE grafts at 6 months and 12 months, respectively. SG 100 graft showed fibroblast cell migration and proliferation with incorporation into the surrounding subcutaneous tissue after 10 weeks, and procollagen synthesis demonstrated at 24 weeks; while the ePTFE graft had no evidence of cellular ingrowth. 39 In a study of 23 patients receiving SG 100 grafts, Darby et al. found that the bovine ureter graft was a stable vascular access conduit, providing a suitable graft alternative when autologous vein was not available. Their study showed 29% primary, 45% primary assisted, and 81% secondary patency rates at 1 year, with only a 5% infection rate. 40 On the other hand, Chemla et al. found that both grafts were adequate conduits for HD, the anticipated advantages for SG 100 were not seen in either patency or stability. 41

Future developments in prosthetic and biological conduits for hemodialysis
The use of pharmacological agents may hold the promise of long-term graft patency. Treatment with 200 mg of dipyridamole and 25 mg of aspirin twice daily resulted in significant improvement of patency rates while adverse effects in both the treatment and placebo groups remained the same. 45 Other agents, such as fish oil and anticoagulants have also been tried with limited success (table 4).    In an approach of reducing neointimal hyperplasia by decreasing mechanical sheer stress, a new double channel (Bi-Flow) graft was designed. These grafts showed laminar flow and lower levels of turbulence, leading to lower risk of stenosis. 46

Conclusions
Prosthetic grafts should be reserved for situations where autogenous vein is not available to perform an access. The most commonly used prosthetic graft is e-PTFE based. Newer advances in medication bonding to decrease thrombosis and formation of intimal hyperplasia may be promising. In addition, various graft characteristics such as flared-end and stretch may provide better patency. Biologic grafts are being tested; however, at this point data are lacking to show superiority over prosthetic grafts. This area is a fertile ground for randomized clinical trials in the search for a man made or biologic graft that would equal autogenous vein in patency and complication rates.

Definitions
Primary Patency: Interval of time from access placement to any intervention necessary tomaintain patency of access. Assisted Primary P a t e n c y : I n t e r v a l of t i m e f r om a c c e s s placement to time of intervention necessary to maintain the functionality of the access. Secondary Patency: Interval of time from access placement to access abandonment including intervening surgical or endovascular manipulations

Disclaimer
The views expressed in this article are those of the authors and do not necessarily reflect the official policy of the Department of Army, the Department of Defense, or the US government.