VIEWS, VISIONS AND VISTAS IN DIALYSIS

Future Directions for Vascular Access for Hemodialysis Prabir Roy-Chaudhury* and Lindsay Kruska† *Dialysis Vascular Access Research Group, Division of Nephrology, University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, Ohio, and †Division of Nephrology, University of North Carolina, Chapel Hill, North Carolina

ABSTRACT 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.

Currently, there are approximately 400,000 chronic hemodialysis patients in the United States, all of whom require a means of vascular access (1). Hemodialysis vascular access remains a major source of morbidity for patients, as well as a major cost to create and maintain with an estimated annual cost of $1 billion (2). This so called “Achilles heel” of dialysis has become an area of great interest over the past several decades. There have been exciting advances in understanding the biology of vascular access that have led to potential therapeutic interventions, development of new devices and biocompatible vascular grafts, research into the role of genetics in vascular access outcomes, and a new focus on individualization of care in the Fistula First era. The aim of this paper was to describe these advances and describe future directions for the field of dialysis vascular access.

1-year cumulative survival of 70%. This 1-year survival is likely an overestimate due to the exclusion of primary AVF failures in many studies (3). More contemporary data again demonstrate a disappointingly high primary failure rate of 40–60%. In particular, the NIH Dialysis Access Consortium AVF study documented that only 40% of AVFS were usable at between 4 and 5 months postsurgery (4,5). Arteriovenous grafts (AVG), most commonly made of polytetrafluoroethylene, are not plagued by the maturation problems observed in fistulas, but often develop aggressive venous stenosis, most commonly at the graft-vein anastomosis leading to dysfunction and failure (6). Their primary patency rates are astonishingly low with rates reported as low as 23% at 1 year (7). They also often require intensive procedural upkeep (repeated angioplasty and stent or stent graft placement) to maintain patency with all of the attendant morbidity and cost (4). In addition, the results of these interventional procedures at the graft-vein anastomosis on overall dialysis access patency are minimal, especially in the longer term. Thus, while placing a stent graft at the time of angioplasty increases the primary patency of the target lesion from 23% to 46% at 6 months, 2-year dialysis access circuit primary patency remains dismal at 9.5% as compared to 4.5% for angioplasty alone. Surely we can do better. . . Tunneled dialysis catheters (TDC) are generally easy to insert and immediately useable, but have high rates of infection, thrombosis, and malfunction which limit use. Unfortunately, 80% of incident hemodialysis patients start with a tunneled dialysis catheter (1). We believe that this is a “process of care” problem rather than a “biology or technology” problem; but one which impacts hugely on patient quality of life, survival, and cost.

The Problem Although it is widely accepted that arteriovenous fistulas (AVF) are the preferred access for hemodialysis, their utility is plagued by failure to mature thus prolonging need for catheter use with its associated morbidity, particularly risk of infection. Studies from 1977 to 2002 show a mean primary failure rate of AVF of approximately 25% with Address correspondence to: Prabir Roy-Chaudhury MD, PhD, Division of Nephrology, University of Cincinnati, MSB G-251, 231, Albert Sabin Way, Cincinnati OH 452670585, Tel.: +513-558-4006, Fax: +513-558-4309, or e-mail: [email protected]. Seminars in Dialysis—Vol 28, No 2 (March–April) 2015 pp. 107–113 DOI: 10.1111/sdi.12329 © 2014 Wiley Periodicals, Inc. 107

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The Biology of Vascular Access Dysfunction: Over the past decade, considerable advances have been made in understanding the vascular biology and pathobiology of dialysis vascular access. This knowledge is of paramount importance as it has the potential to identify therapeutic targets that could improve the outcomes of both primary vascular access (AVF/AVG/TDC) placement and the interventions that are performed to address the low primary patency rate, e.g., angioplasty, bare metal stents, and stent grafts. Predialysis Vascular pathology has been demonstrated to precede surgical access creation or intervention in CKD patients. Studies have demonstrated that in many patients venous neointimal hyperplasia is present prior to access creation (Fig. 1). Immunohistochemical evaluation showed a majority of myofibroblasts and a small population of contractile smooth muscle cells in these lesions (8). It has been postulated that uremia, inflammation, oxidative stress, and hypertension all may contribute to these lesions. While there has been much speculation (and opinion) that patients with preexisting neointimal hyperplasia will be at greater risk of AVF maturation failure, a recent study documented that patients with more advanced neointimal hyperplasia were not at risk of developing more stenosis postsurgery (9). AVF and AVG Pathology The pathological lesion in nonmaturing AVF is neointimal hyperplasia, most commonly in the juxta anastomotic segment of the fistula. These lesions are comprised of the same cellular phenotypes (10) as are present in the presurgical lesions. AVG dysfunction is most commonly due to stenosis in the

Media

Neointima

graft-vein anastomosis (6). At a histological level, the lesion of neointimal hyperplasia in AVGs is similar to the stenotic lesion that occurs in AVFs, with the exception that the neointimal hyperplasia in direct contact with PTFE graft material tends to have more extracellular matrix components as compared to that not in direct contact with PTFE graft material (11). An important characteristic of neointimal hyperplasia in PTFE grafts is a layer of macrophages and macrophage giant cells that line the surface of the graft. These cells are likely to be the source of important inflammatory mediators such as chemokines and cytokines that could drive the lesion of neointimal hyperplasia (see below); they could also potentially be a target for future therapeutic intervention. An additional characteristic of both AVF and AVG stenosis at a histological level is the presence of adventitial and neointimal microvessel formation. The potential role of these microvessels in driving or blocking neointimal hyperplasia is unknown at the present time as is the potential to use them for therapeutic targeting (Fig. 2). In addition to the neointimal hyperplasia characterized by presence of myofibroblasts and development of a neointima, grafts develop neovascularization and macrophages in the advential layer and periadventitial region which can lead to dysfunction (12). AVF and AVG Pathogenesis At a very broad vascular biology level, the final amount of vascular stenosis be it the coronaries, peripherals, or vascular access, is always a function of the combined impact of neointimal hyperplasia and the type of vascular remodeling: positive or outward which results in a larger lumen size and so tends to be good for successful AVF or AVG function, and negative or inward which tends to be bad for successful AVF or AVG function. As depicted diagrammatically in the upper panel of Fig. 3, the presence of a very significant amount of vessel wall

% Stenosis

46.6 ± 9.3

I/M Area Ratio

0.24 ± 0.07

Average IM Thickness

0.34 ± 0.12

Maximal IM Thickness

1.16 ± 0.30

Fig. 1. Preexisting neointimal hyperplasia: Note the significant amount of preexisting neointimal hyperplasia in a venous segment sample taken at the time of creation of the vascular access (adapted from Lee et al. (8)).

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A

* SMA x 200

*

B

C

vWF x 200

PGM-1 x 400

Fig. 2. Pathology of dialysis vascular access stenosis: (A) the stenotic lesion in a patient with dialysis vascular access dysfunction. (B) Documents prominent microvessel formation within the lesion of neointimal hyperplasia in the setting of dialysis access dysfunction, while (C) shows a prominent macrophage giant cell on the luminal side of a PTFE graft (B and C have been adapted from Roy-Chaudhury et al. (12)).

Original lumen size

Significant Neointimal Hyperplasia + Expansive Remodeling

Final lumen size

200%

100%

Patent Access Minimal Neointimal Hyperplasia + Negative Remodeling

100%

Stenotic Access

25%

Fig. 3. Vascular remodeling and neointimal hyperplasia in dialysis vascular access stenosis: Note that it is always the combination of neointimal hyperplasia (vessel wall thickening) and the type of vascular remodeling (outward or inward) that determines the final lumen size.

thickening or neointimal hyperplasia does not result in vascular stenosis, because it occurs in combination with outward or positive remodeling. On the other hand, even a small amount of neointimal hyperplasia or vessel wall thickening could result in a significant amount of vascular stenosis if it occurs in combination with negative or inward remodeling as described in the lower panel in Fig. 3. At a more specific dialysis vascular access level, however, it is critically important to identify the specific pathways that are responsible for upstream events (could be both good and bad) as also the downstream vascular response to these events (again could be both good and bad). The upstream events include hemodynamic shear stress alterations (could be both good or bad), surgical injury from vessel handling and sutures, direct cannulation injury, and for AVGs, injury from the inflammatory response engendered by PTFE (this latter group is likely all bad). An additional upstream event that could be considered to be a downstream event as well, that we believe is very important is the presence of uremia, inflammation, oxidative stress, and the endothelial dysfunction that is often associated with it. These factors are likely to play a major role in modulating the downstream response to upstream events. Downstream events, on the other hand, involve the specific mechanisms associated with vascular remodeling (outward or inward) and neointimal hyperplasia such as cytokines and chemokines. Indeed, we have often speculated that, at the end of

the day, it is perhaps the interaction between upstream stressors and the downstream response to these stressors which ultimately determines whether or not an AVF or an AVG is successful. Upstream Events The key upstream events are hemodynamic shear stress, surgical injury, cannulation, endothelial and smooth muscle cell injury as a result of endovascular interventions performed to treat the initial stenosis and the inflammatory response engendered by both PTFE graft material and the baseline uremic state. The effect of flow patterns, in particular, in the setting of AVFs has become an important area of interest. In laminar flow patterns, wall shear stress induces quiescence of endothelial cells and of the adjacent smooth muscle cells by potentially increasing production of several vasoactive compounds including nitric oxide, as also promoting endothelial cell migration at sites of injury (13). Using complex computational fluid dynamic models, alterations in wall shear stress have been shown to localize to areas of stenosis. Both reductions and oscillations in wall shear stress, despite high flow, appear to have negative effects. (14). Further, CFD studies demonstrate that alteration in the anastomotic angle from 90 degrees to 30 degrees can attenuate this stress and potentially decrease the juxta-anastomotic propensity for stenosis (15). Preliminary data from patient imaging studies show that the CFD data hold true in vivo (16). Downstream Events The response to the above upstream events modulates pathways that determine the magnitude of both outward versus inward remodeling and the amount of neointimal hyperplasia (6,12,17,18). Pathways Responsible Inward Remodeling

for

Outward

and

The key mechanistic pathway for this is likely to be the amount of nitric oxide produced by endothelial cells which would then result in dilatation or the lack thereof. Another mediator in this process could be the matrix metalloproteinases which are known to destroy the internal and external elastic lining in

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the arterial setting, thus allowing for a dilatation of the vessel. The exact contribution of this pathway in the setting of venous anatomy and physiology remains understudied at this time. Pathways Responsible for Neointimal Hyperplasia The initial upstream injury events result in the activation, proliferation, and migration of fibroblasts, myofibroblasts, and smooth muscle cells from the media and perhaps, the adventitia into the intimal region resulting in neointimal hyperplasia. Important pathways that are thought to contribute to this process are inflammation, oxidative stress, and endothelial dysfunction. Heme oxygenase-1 (HO-1) is an enzyme that catalyzes heme degradation. It is up-regulated in the setting of vascular injury with a protective antioxidant effect. Interestingly, AVFs created in heme oxygenase knockout mice have more neointimal hyperplasia as compared to wild-type animals (19). It has also been demonstrated that patients with less HO-1 production due to genetic polymorphisms (long GT repeats) have worse AVF patency (20). HO-1 also appears to play a role in the expression of proinflammatory mediators such as monocyte chemotactic protein 1 (MCP1) and matrix metalloproteinases (MMPs) (21). MCP-1 is a chemokine that has numerous roles in vascular pathology including endothelial cell activation and migration, smooth muscle cell proliferation, monocyte recruitment, and induction of procoagulant mediators (22–24). Experimental vein graft studies have shown increased MCP-1 correlates with increased neointimal hyperplasia (25). Matrix metalloproteinases have varying roles including degradation of perivascular collagen and elastin-promoting vasodilation, but also promotion of proliferation of smooth muscle cells and inflammatory cells which are crucial in the development of neointimal hyperplasia (26,27). The absence of HO1 appears to inhibit the positive effects of MMPs in promoting vascular dilation (21). Epigenetics Epigenetics is the study of alterations in gene expression leading to a particular phenotype and is a fairly new area of interest in the vascular access world. The mechanisms of epigenetic differences include alterations in DNA methylation, histone modification, and microRNAs. Defining these differences can potentially shed light on some vascular access pathologies and lead to earlier markers of vascular access dysfunction (28). For example, eNOS is an important endothelial cell product which is underexpressed in dysfunctional vessels. The expression of eNOS appears to be under the regulation of the methylation status of the eNOS promoter with hypomethylated promoters expressing normal amounts of vascular smooth muscle cell eNOS (29).

Novel Therapeutic Interventions The current approach to maintenance of vascular access is mainly through balloon angioplasty. Unfortunately, repeated angioplasty itself can lead to decreased survival of dialysis vascular access (30,31). It is therefore critically important to apply our current understanding of the pathology and pathogenesis of dialysis vascular access dysfunction as described above to develop novel therapies in this area. In particular, we believe that targeting some of the pathways described above (outward versus inward remodeling, neointimal hyperplasia, inflammation, oxidative stress, and endothelial dysfunction) as opposed to the “traditional” targets of thrombosis and stenosis will result in effective therapies for dialysis vascular access dysfunction. The following paragraphs will describe a number of such therapies. PRT-201 PRT-201 is a recombinant human type I pancreatic elastase that cleaves amino acid sequences in elastin (32,33). Elastin is a protein which gives blood vessels elasticity and controls vessel diameter (34). Elastin must be applied locally during surgery given that antiproteases in blood inactivate it if given systemically (35). It has been shown to have beneficial effects on blood vessel diameter and blood flow in animal models (36,37). An initial study on the use of PRT-201 in AVF suggested an improved primary patency (38). A recently published Phase II randomized control study comparing PRT-201 against placebo demonstrated improved intraoperative blood flow and a trend toward improved secondary patency in the treated group (39). A large randomized study of PRT-201 is currently underway in the United States. Drug-Eluting Balloons Drug-eluting balloons as a means of local delivery of an antiproliferative agent at the site of angioplasty are being explored. A preliminary study of paclitaxel-eluting balloon demonstrated improved AV access primary patency at 6 months; 70% as compared to 25% in the control group treated with standard angioplasty balloon dilation (40). Numerous devices are being developed and are at various stages of testing. At the current time, however, these balloons do not have approval for use in the United States. Endothelial Cell Implants Endothelial cell injury is an important mediator of vascular access pathology. Gel foam wraps loaded with endothelial cells have been developed for perivascular placement around the arteriovenous or graft-vein anastomosis. The biological rationale for this product is that these endothelial cells will

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produce a number of “good” mediators which will then block the endothelial dysfunction that is present in uremic patients. Despite initial positive results (41), this product is no longer being developed due to business reasons. Surgical Techniques Recognition that alterations in wall shear stress can result in areas of stenosis suggests that alterations in surgical technique, which change the anatomical configuration of the dialysis access, could be used to minimize this injury. Bharat et al. reported less juxta anastomotic stenosis and primary fistula failure in radiocephalic AVFs created using a piggybacking straight onlay technique (pSLOT) compared to two other surgical methods (42). Similarly, the Optiflow Vascular Anastomotic is a device that fixes the anastomotic angle of an AVF at 60 degrees and thus can standardize surgical technique. In addition, the Optiflow’s prosthetic material may shield the peri-anastomotic region and prevent stenosis. In pig studies, the device was found to be safe and possibly effective in preventing luminal stenosis (43). A human pilot study in 10 patients demonstrated safety and technical feasibility and a larger study is underway currently (44). Far Infrared Therapy Far infrared radiation is invisible electromagnetic energy with wavelengths ranging 5.6–1000 lm. It has been used as thermal therapy with some success in improving vascular endothelial function in peripheral arteries, postulated to be due to increased eNOS function (45). Far infrared therapy (FIT) has also been demonstrated to stimulate the expression of heme oxygenase 1 (45). A preliminary clinical study of its use in dialysis access showed increased blood flow and unassisted patency (46). A recent clinical trial also showed a significant increase in clinical maturation at 12 months from 60% in untreated to 82% in those treated with FIT (47).

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coronary artery bypass. Its utility in hemodialysis access is obvious. Over the past several decades, numerous approaches have been attempted with some prospects for clinical use. Irradiated xenogenic implants are attractive due to their availability, though they have not been widely used. Several products are available commercially, which include ProCol, a bovine mesenteric vein graft, and Omniflow I and II, a bovine collagen matrix epithelialized in sheep. The Omniflow grafts have shown primary patency rates of up to 80% at 1 year (49). Important limitations of xenogenic implants are limited mechanical strength, a tendency to develop aneurysms (50), and increased cost over traditional grafts. More recently, the Humacyte corporation (Humacyte, Inc, Morrisville, NC, USA) has developed a tissue-engineered vascular graft (TEVG) produced in vitro by growing allogeneic smooth muscle cells from human donors on a biodegradable scaffold, which are then decellularized (51). Data from an initial out of US study (in Poland) were presented at the 2013 AHA meeting documenting an unassisted primary patency of 70% at 6 months as compared to an expected 50% for PTFE grafts. The potential absence of aneurysm formation and infection could be the greatest benefits of this technology over and above a future documented improvement in primary patency. Stem cell technology is also advancing the field of TEVG with numerous cell types being utilized currently including bone marrow mononuclear cells, mesenchymal stem cells from various sources, pericytes, and endothelial precursor cells. These are an attractive option given their ability to differentiate into multiple cell types and for vessels that mimic native vessels. All originate from adult stem cells that can be harvested from a patient’s own tissues (52). A complicating factor is the delay between cellular harvesting and the creation of the final product as also the quality or lack of quality of cells derived from uremic patients (unless these are stored at birth). Other Innovations

Innovative Graft Materials Traditional PTFE graft material requires approximately 2–3 weeks of maturation prior to use to allow incorporation of the graft material into the surrounding tissue. Polyurethane graft options exist that allow cannulation within 24 hours, providing an option for catheter avoidance (48). More recently, the Acuseal graft which could have the potential for early cannulation due to a silicone elastomer sandwiched between two PTFE layers has been approved in the United States. Biological Grafts and Tissue-Engineered Blood Vessels Interest in small caliber bioengineered vessels has been long-standing with its original application in

In some patients, no options exist for permanent vascular access and they are relegated to chronic dialysis with a catheter. A new option for catheter placement in patients with central venous stenosis is being developed which uses an “inside out” technique to allow safe and effective placement of tunneled catheters in the upper circulation and thus avoidance of chronic femoral catheters (53). Process of Care and Individualization Although the biologic, molecular, and genetic areas of research are exciting, one cannot overlook the importance of process of care in vascular access. Timely referral to nephrology is the first step in the process and primary care providers must be

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educated about the role of nephrology in patient care. A multidisciplinary approach to vascular care has been demonstrated to dramatically decreased AVG thrombosis (by 60%) as well as increased incident AVF from 33% to 69% (54). In addition, the presence of a vascular access coordinator has been shown to improve prevalent access and decrease access related hospitalizations and infections (55). Kaiser Permanente of Southern California has recently published their experience with dialysis vascular access. Using a collaborative team model as well as a predialysis care monitoring program, incident AVF use for dialysis initiation has increased from 31% in 1998 to 79% in 2012 with a corresponding decrease in catheters and AVG (56). This suggests that the use of a comprehensive care team can improve vascular access outcomes without any medical or procedural interventions and could perhaps allow for the most bang for our buck. In summary, we believe that these are exciting times for dialysis vascular access. We are beginning to better understand the pathology and pathogenesis of dialysis vascular access dysfunction and are seeing the first generation of products that target these pathways. Perhaps, more importantly, we are also beginning to appreciate the importance of process of care issues within the vascular access space. It is likely that a combination of these two advances will truly allow us to practice “smart medicine” and so provide better vascular access care for our patients.

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Acknowledgments Dr. Roy-Chaudhury is supported by NIH 5U01DK82218, NIH 5R01DK088777, a VA Merit Review 5I01BX002390, NIH 5R21EB016737-02, NIH 5R21E B016737, NIH, 5R41DK101206, NIH 5R41DK100156, and an industry grant from WL Gore.

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