|Year : 2019 | Volume
| Issue : 2 | Page : 33-41
Molecular targets for improving arteriovenous fistula maturation and patency
Jolanta Gorecka1, Arash Fereydooni1, Luis Gonzalez1, Shin Rong Lee1, Shirley Liu1, Shun Ono1, Jianbiao Xu1, Jia Liu2, Ryosuke Taniguchi1, Yutaka Matsubara1, Xixiang Gao3, Mingjie Gao4, John T Langford1, Bogdan Yatsula1, Alan Dardik5
1 Department of Surgery and the Vascular Biology and Therapeutics Program, Yale School of Medicine, Yale University, New Haven, USA
2 Department of Surgery and the Vascular Biology and Therapeutics Program, Yale School of Medicine, Yale University, New Haven, USA; Department of Vascular Surgery, The Third Xiangya Hospital; Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
3 Department of Surgery and the Vascular Biology and Therapeutics Program, Yale School of Medicine, Yale University, New Haven, USA; Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
4 Department of Surgery and the Vascular Biology and Therapeutics Program, Yale School of Medicine, Yale University, New Haven, USA; Department of Vascular Ultrasonography, Xuanwu Hospital, Capital Medical University, Beijing, China
5 Department of Surgery and the Vascular Biology and Therapeutics Program, Yale School of Medicine, Yale University; Department of Surgery and of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven; Department of Surgery, VA Connecticut Healthcare System, West Haven, USA
|Date of Submission||03-Jan-2019|
|Date of Decision||01-May-2019|
|Date of Acceptance||03-May-2019|
|Date of Web Publication||9-Oct-2019|
Prof. Alan Dardik
Yale University School of Medicine, Department of Surgery and of Cellular and Molecular Physiology, 10 Amistad Street, Room 437, PO Box 208089, New Haven, CT 06520-8089
Source of Support: None, Conflict of Interest: None
The increasing prevalence of chronic and end-stage renal disease creates an increased need for reliable vascular access; although arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, 60% fail to mature and only 50% remain patent at 1 year. Fistulae mature by diameter expansion and wall thickening; this outward remodeling of the venous wall in the fistula environment relies on a delicate balance of extracellular matrix remodeling, inflammation, growth factor secretion, and cell adhesion molecule upregulation in the venous wall. AVF failure occurs via two distinct mechanisms with early failure secondary to lack of outward remodeling, that is, insufficient diameter expansion or wall thickening, whereas late failure occurs with excessive wall thickening due to neointimal hyperplasia and insufficient diameter expansion in a previously functional fistula. In recent years, the molecular basis of AVF maturation and failure are becoming understood to develop potential therapeutic targets to aid maturation and prevent access loss. Erythropoietin-producing hepatocellular (Eph) carcinoma receptors, along with their ligands and ephrins, determine vascular identity and are critical for vascular remodeling in the embryo. Manipulation of Eph receptor signaling in adults, as well as downstream pathways, is a potential treatment strategy to improve the rates of AVF maturation and patency. This review examines our current understanding of molecular changes occurring following fistula creation, factors predictive of fistula success, and potential areas of intervention to decrease AVF failure.
Keywords: Arteriovenous fistula, chronic kidney disease, fistula failure, hemodialysis, maturation
|How to cite this article:|
Gorecka J, Fereydooni A, Gonzalez L, Lee SR, Liu S, Ono S, Xu J, Liu J, Taniguchi R, Matsubara Y, Gao X, Gao M, Langford JT, Yatsula B, Dardik A. Molecular targets for improving arteriovenous fistula maturation and patency. Vasc Invest Ther 2019;2:33-41
|How to cite this URL:|
Gorecka J, Fereydooni A, Gonzalez L, Lee SR, Liu S, Ono S, Xu J, Liu J, Taniguchi R, Matsubara Y, Gao X, Gao M, Langford JT, Yatsula B, Dardik A. Molecular targets for improving arteriovenous fistula maturation and patency. Vasc Invest Ther [serial online] 2019 [cited 2020 Feb 20];2:33-41. Available from: http://www.vitonline.org/text.asp?2019/2/2/33/268675
| Introduction|| |
The prevalence of end-stage renal disease is rising worldwide, with a disproportionately larger increase in developing countries. This presents a growing need for renal replacement therapies, which include peritoneal dialysis, renal transplantation, and hemodialysis. The majority of patients in the United States use hemodialysis as the primary modality of renal replacement therapy, requiring reliable permanent vascular access., The three main types of hemodialysis vascular access include temporary dialysis catheters, arteriovenous grafts, and arteriovenous fistulae (AVF). AVF are the preferred access secondary to improved patency rates and fewer complications, such as infections and need for reintervention to maintain access patency.,,
AVF types are classified as simple direct, vein transposition, or vein translocation. Simple direct fistulae use arteries and veins in their native positions. Examples include the distal radial artery-to-cephalic vein fistula (Brescia-Cimino), radial artery-to-median antecubital vein, brachial artery-to-cephalic vein, and femoral artery-to-saphenous vein. Vein transposition fistulae transfer a segment of the vein to a more optimal position for fistula cannulation, although the downstream portion is left intact. These fistulae can be constructed in one-stage or two-stage approaches. Examples include the brachial-basilic transposition, radial-basilic transposition, and femoral-saphenous transposition. Vein translocation fistulae involve moving a vein to a different anatomic location, requiring a venovenous anastomosis and venoarterial anastomosis. The most common venous conduits used for translocation are the saphenous vein and the femoral vein.,
The 2008 Society for Vascular Surgery practice guidelines recommend placing accesses in upper extremities before lower extremity and body wall sites. Fistulae should be placed as distally in the upper extremity as possible, with the order of preference being direct fistulae, vein transposition, and vein translocation. The National Kidney Foundation guidelines also confirm this order of preference, favoring distal to proximal AVF. Further, fistulae can be created using end-to-side or side-to-side techniques; although there has been conflicting evidence regarding the superiority of one technique over another, a recent review suggests that there is a similar maturation rate between these configurations. Finally, side-to-side techniques are more likely to be associated with arterial steal syndrome.
| Mechanisms of Fistula Maturation and Failure|| |
Following AVF creation, the vein is exposed to very high (supra-arterial) magnitudes of turbulent shear stress in a low pressure environment, leading to “maturation” of both the arterial inflow and venous outflow segments; vessel remodeling is necessary to sustain the high flow rates required for a successful dialysis session. Adaptation of the vein to the increased magnitude of turbulent shear stress requires diameter expansion and wall thickening. This outward remodeling of the fistula relies on a delicate balance of extracellular matrix (ECM) remodeling, inflammation, growth factor secretion, and cell adhesion molecule upregulation in all three layers of the venous wall.,,, In contrast to AVF, arteriovenous grafts are exposed to arterial magnitudes of laminar shear stress in a high (arterial) pressure environment; although prosthetic grafts cannot adapt, by definition, vein grafts in similar configurations adapt mainly via wall thickening, with less dilation. Percutaneous arteriovenous fistulae (pAVF), such as those created using the new endovascular access systems, are exposed to a slightly different fistula environment than surgically created AVF; pAVF are exposed to very high magnitude laminar shear stress in a low pressure environment; early studies of pAVF demonstrate poor maturation rates despite balloon angioplasty at the time of fistula creation, suggesting that high pressure and/or turbulent shear stress may be necessary in a fistula to achieve adequate maturation [Table 1].,,
|Table 1: Flow hemodynamics characterizing several dialysis access modalities|
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During fistula maturation, the ECM of the venous limb shows multiple changes as an adaptive response to the “arterialized” fistula environment. These changes can be categorized as 3 temporal phases; an early phase (breakdown), a transition phase (reorganize), and a late phase (rebuild). The early phase is characterized by an increased ratio of matrix metalloproteinase (MMP) to tissue inhibitor of metalloproteinase expression, which results in degradation of collagen and elastin that likely facilitates cell migration during the transition and late phases. Reorganization of the venous architecture and rebuilding of the ECM with larger noncollagenous and glycoproteins such as fibronectin occur after the breakdown phase to complete fistula maturation.
While ECM degradation is regulated by MMP, its deposition is modulated by transforming growth factor-β (TGF-β). Diverse cell types in the venous wall, such as endothelial cells, smooth muscle cells (SMC), and inflammatory cells, produce TGF-β, and its expression is upregulated during both early and late phases of AVF maturation. TGF-β activation promotes SMC proliferation and activation of fibroblast transition to a myofibroblast phenotype; thus, TGF-β overexpression contributes to stenosis of the venous limb of AVF., In humans, differences in TGF-β1 polymorphisms correlate with AVF patency, whereby higher TGF-β1 production leads to decreased patency. Thus, manipulation of the TGF-β pathway may be a potential therapeutic target to improve AVF maturation and/or patency.
While local inflammation of the vessel wall is necessary for successful fistula maturation, elevated systemic inflammatory markers predict fistula failure., Locally, macrophages and T-cells play an important role in AVF maturation, with maturation being promoted by M2-type macrophages and a lack of T-cell activity resulting in failure of AVF maturation. Furthermore, the presence of CD4 + T-cells in mature AVF coincides with the presence of macrophages, and the absence of mature T-cells results in reduced macrophage infiltration., Systemic inflammation correlates inversely with AVF maturation, and higher levels of C-relative protein increase the risk of AVF failure. Interestingly, prednisolone, a drug with anti-inflammatory properties, enhances venous outward remodeling.
Successful AVF maturation relies on venous wall thickening and diameter expansion to support flow rates required for successful hemodialysis. AVF failure occurs via two distinct mechanisms: early fistula failure occurs secondary to lack of diameter expansion and wall thickening, whereas late failure occurs as a result of neointimal hyperplasia (NIH) and impaired outward remodeling, leading to excessive wall thickening in a previously functional conduit [Figure 1]. Unfortunately, primary maturation and patency rates of AVF remain low. Up to 60% of AVF fail to mature by 5 months after creation, and published reports consistently show primary patency rates of 60% at 1 year and 51% at 2 years, with secondary patency rates of 71% at 1 year and 64% at 2 years.,, Factors such as diabetes, peripheral vascular disease, congestive heart failure, and older age are poor prognostic factors for successful AVF function. Furthermore, studies have demonstrated prolonged maturation time, decreased patency, and increased early thrombosis of AVF in female patients, differences not accounted for by smaller vein size in women.,,
|Figure 1: Schematic representation of baseline venous wall and structural changes following fistula creation in a functional fistula, as well as one that fails to mature (early failure) or fails later (late failure) secondary to neointimal hyperplasia and impaired outward remodeling|
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| Predicting Arteriovenous Fistulae Maturation and Patency|| |
Noninvasive techniques, such as duplex ultrasound, are the principal tools in assessing the venous system pre- and post-operatively. While physical examination may reveal potentially suitable veins, duplex ultrasound mapping is the mainstay of preoperative venous assessment. As with arterial assessment, ultrasound gives important morphology and orientation, such as vein diameter, patency, continuity, distensibility, location, and depth. Adequate detection of useful veins is an important obstacle that can be overcome with ultrasound, as physical examination is typically associated with detection rates of suitable veins of <50%, whereas use of ultrasound increases the rate of finding of suitable veins in over 75% of patients. Detection of central venous thrombosis and/or stenosis is also a valuable use of ultrasound in the preoperative assessment.
Vein diameter is the single most important predictor of successful AVF construction, barring any evidence of thrombosis. Landmark data demonstrated increased number of AVF created, with a decrease in arteriovenous graft and catheter use, when preoperative duplex ultrasound was used for venous assessment. In addition, a 92% early maturation rate and >80% 1-year patency rate were reported when the vein diameter was between 2.5 and 3.0 mm on preoperative assessment. Another study reported higher maturation rates with increasing vein diameter, including an 82% maturation rate in veins 3.11–3.70 mm in diameter. Should a vein of adequate size not be available, more proximal access is recommended.
Autogenous AVF should be mature and accessible for cannulation by 3 months postoperatively. A palpable thrill, a bruit, and visible bulging of the AVF are typically found on physical examination. A mature AVF generally has three components. First, the AVF must have a diameter that is large enough to permit safe cannulation with the dialysis needles without infiltration; 6 mm diameter is conventional, with 6 inches of outflow length. Second, the cannulation sites must be superficial enough to repeatedly recognize the landmarks for accurate and safe cannulation; 6 mm from the skin surface is the common location. Third and most importantly, the access flow rate should be at least 600 ml/min by 6 weeks after creation. These principles (6 mm diameter, 6 mm from the skin, 600 ml/min flow, 6 weeks, and 6 inches of outflow) form the “Rule of the 6's” commonly espoused for access surgery in the United States [Table 2]. However, these clinical criteria differ in various regions of the world. For example, in Europe, China, and Japan, hemodialysis is typically performed with lower flow rates and longer dialysis sessions. The Dialysis Outcomes and Practice Patterns Study, a large, international, prospective cohort study, showed an association between longer duration hemodialysis sessions and lower mortality, a synergistic mortality-reducing effect with higher dialysis dose and longer treatment time, as well as an association of higher risk of mortality and complications with faster ultrafiltration rates. As of 2012, many European countries maintained mean prescribed blood flow rates between 300 and 350 mL/min, with China using flow rates between 200 and 300 mL/min, and Japan using the lowest rates, near a mean of 200 mL/min. It remains unclear, however, if AVF flow at these lower rates, before initiation of hemodialysis, should be used to assess successful AVF maturation, as there is a higher risk of thrombosis and failure at lower access flow rates.
|Table 2: “Rule of 6's” guidelines to determine adequacy of fistula maturation for dialysis access|
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There has been renewed interest in going beyond static anatomic descriptors, such as vessel diameter and depth, toward the development of metrics that capture vessel dynamics to predict which AVF are most likely to mature. Several investigators have examined mechanical properties including vessel distensibility, compliance (inverse of elasticity), and stiffness (e.g. Young's modulus) of candidate veins and arteries for fistula creation. A study measuring the distensibility of forearm veins using strain-gauge plethysmography in 17 patients before AVF creation found that venous distensibility, and not arterial/venous luminal diameters, was predictive of AVF success. Using venography before and after cuff-induced venous occlusion, another study showed that radiocephalic fistula success increased 7.4 fold when veins were more distensible (dilate >0.35 mm after occlusion). In addition, increasing stiffness (Young's modulus) of an excised circumferential venous segment during AVF creation correlated with AVF failure. The relationship between arterial stiffness and AVF outcomes using preoperative measurements of pulse-wave velocity (PWV ∝ √stiffness) in patients undergoing AVF creation has also been examined; however, there was no correlation between systemic arterial stiffness and AVF failure.,
How do the mechanical properties of the vein change after fistula creation? Does the mature fistula gain a more elastic (lower compliance) arterial phenotype or enhance its venous compliance? Reports investigating the mechanical properties of remodeled vein grafts in patients who underwent peripheral bypass showed that vein grafts become stiffer (less compliant), presumably due to enhanced collagen deposition during vein graft wall thickening., Although the venous wall also thickens and exhibits collagen deposition during AVF remodeling, it is not currently known whether AVF similarly stiffen or not, as the degree of outward remodeling and the molecular signatures of venous remodeling are different for AVF compared to vein grafts.,
| Molecular Identities In Arteriovenous Fistulae|| |
Erythropoietin-producing hepatocellular (Eph) carcinoma receptors are the largest subgroup of the receptor tyrosine kinase family. Together with ephrins, their ligands, Eph receptors play an essential role in vascular development and determine arterial versus venous identities in the embryo., Eph receptors and ephrins are both divided into subtypes A and B based on mutual affinities and on sequence conservation. In humans, the five Eph-B receptors (Eph-B1-4 and 6) are stimulated by ephrin-B transmembrane ligands, while the nine Eph-A receptors (Eph-A1-8 and 10) are activated by ephrin-A glycosylphosphatidylinositol-linked ligands. Most Ephs interact with multiple ephrin ligands, whereas Eph-B4 binds exclusively to Ephrin-B2. Eph-B4-Ephrin-B2 interaction is vital to neural development, malignant tumor progression, and vascular remodeling particularly during fistula maturation.,,,,,,
Ephrin-Eph signaling on adjacent cells can be activated in clusters and propagate in a bi-directional fashion. In addition to typical forward signaling from the ligand Ephrin-B2 to the receptor Eph-B4, reverse signaling from Ephrin-B2 into the same cell can also be activated.,,, This bi-directional signaling is particularly important during vascular development and establishment of both arterial and venous identities. Ephrin-B2 determines arterial identity while Eph-B4 is a crucial determinant of venous identity. Moreover, Ephrin-B2 and Eph-B4 continue to be expressed in adult arterial and venous endothelium, respectively. The reciprocal effect between Ephrin-B2 and Eph-B4 may mediate spatial positional signals through distinct propulsion and repulsion during angiogenesis and vessel assembly.,, Furthermore, Eph-B4 senses changes in mechanical forces, such as those present during remodeling as a result of hypertension and after AVF creation.
Eph receptor activation leads to downstream signaling via the PI3K-Akt pathway, resulting in cell migration and proliferation, functions that are critical for venous remodeling., Eph-B4 also modulates adaptation and AVF maturation with distinct patterns of altered vessel identity.,, During successful AVF maturation, the venous limb gains expression of ephrin-B2 and has increased Eph-B4 expression, relative to control veins, suggesting acquisition of dual arterial-venous identity in the AVF. Although the source of ephrin-B2 signaling during AVF maturation remains unknown, ephrin-B2 is thought to be membrane bound to be functional; circulating endothelial progenitor cells may be a source. In animal studies, treatment of a fistula with Ephrin-B2/Fc, a specific bivalent ligand to Eph-B4, resulted in less thickening and outward remodeling, decreased NIH, and improved fistula patency. Furthermore, loss of Eph-B4 activity in heterozygous mice leads to increased AVF venous wall thickening, compared to controls, suggesting that Eph-B4 regulates wall thickening during AVF maturation.,
| Strategies to Improve Fistula Maturation and Patency|| |
Various therapies have been studied to treat access failure and improve maturation and long-term patency. Drugs used to decrease inflammation and cellular recruitment, as well as gene therapy aimed to decrease SMC proliferation have been evaluated to decrease NIH, unfortunately with little clinical success.,,,,, Alteration of fistula geometry to decrease disturbed flow and improve fistula hemodynamics, including novel surgical techniques such as radial artery deviation and reimplantation (RADAR), has shown some success in Europe., Trials evaluating external devices such as VasQ™ (Laminate Medical Technologies), which provide optimal fistula angles, are ongoing. A controversial technique for promoting AVF maturation is balloon-assisted maturation. Balloon-assisted maturation is performed by repeated, long-segment angioplasty from the perianastomotic venous segment along the venous outflow, dilating the vein in staged sessions. This procedure, thought to cause more rapid outward remodeling of the venous limb and allowing for quicker maturation, has been relatively successful in several centers.,,
Several molecular pathways may be potential mechanisms to regulate AVF patency in future clinical trials. During AVF maturation, the venous limb shows increased expression of Eph-B4 receptor and Ephrin-B2 ligand, consistent with gain of dual arterial-venous identity. Activation of Eph-B4 with Ephrin-B2/Fc leads to reduced venous wall thickening, reduced outward remodeling and ultimately improves AVF patency rates in animal studies. Mutagenesis studies of the Eph-B4 receptor identified tyrosine 774 as a critical phosphorylation site for Eph-B4 signaling, and expression of mutant Eph-B4 receptors with a nonfunctional tyrosine 774 resulted in reduced Eph-B4 activity during AVF maturation, promoting venous wall thickening and outward remodeling. Thus, stimulating phosphorylation of Eph-B4 tyrosine 774 may be a novel strategy to promote AVF patency.
In vivo, Eph-B4 activation attenuates Akt1 phosphorylation leading to reduced venous wall thickening, reduced outward remodeling, and improved long-term patency. This was corroborated with studies using constitutively active-Akt1 that showed increased venous wall thickening and dominant negative-Akt1 studies that showed reduced outward remodeling. Therefore, Eph-B4 can regulate venous remodeling via an Akt1-mediated mechanism. Rapamycin, an immunosuppressive agent and inhibitor of SMC proliferation and migration, functions by regulating Akt pathway signaling and thus may enhance adaptive remodeling; accordingly, rapamycin is currently being investigated in preclinical and clinical trials.,, We propose that rapamycin may improve AVF patency by reducing Akt1-mTORC1 signaling during AVF maturation.
Elastin in the vessel wall provides elastic recoil; diminished elastin results in enhanced outward remodeling and attenuation of NIH, suggesting that elastin degradation may improve AVF maturation., Although randomized, double-blinded, placebo-controlled trials have reported mixed results, the largest and most recent trial shows elastase improves unassisted maturation and primary patency at low doses, without associated safety concerns., In addition, elastase application during arteriovenous graft placement increased intraoperative outflow venous diameter and blood flow, with a trend toward increased secondary patency and a decrease in procedures necessary to maintain primary patency. Paclitaxel, a chemotherapeutic and anti-mitotic agent, during drug-coated balloon angioplasty inhibits NIH and has shown encouraging 6-month patency rates.,, Unfortunately, increased infection rates are a major concern for paclitaxel use in AVF. In addition, the use of paclitaxel is currently less frequent with the recent reports of associated mortality.
Caveolin-1 (Cav-1) is a major scaffolding protein that regulates vascular remodeling and angiogenesis by inhibiting endothelial nitric oxide synthase (eNOS)., AVF maturation is associated with increased Cav-1 expression and caveolae formation in the venous endothelium., Knockout of Cav-1 in mice leads to increased eNOS phosphorylation, increased venous wall thickness, and increased outward remodeling, relative to wild type (WT) mice. In addition, Eph-B4-mediated AVF remodeling is abolished in Cav-1 KO mice treated with Ephrin-B2/Fc. These findings suggest that Cav-1 acts downstream of Eph-B4, and the Eph-B4-Cav-1 axis regulates adaptive remodeling during AVF maturation, and thus, manipulation of Cav-1 signaling may be another potential strategy to improve AVF patency. eNOS is critical for vascular health and venous wall adaptation, although its effect on AVF maturation is not fully understood. Recent animal studies have shown that overexpression of eNOS following fistula creation results in larger lumen area and decreased shear stress, compared to WT animals. In addition, disruption of nitric oxide signaling in a rat chronic kidney disease model resulted in lower flow rates, smaller fistula diameters, and increased oxidative stress following fistula creation. A schematic representation depicting the cellular receptors and signaling pathways involved in venous remodeling is shown in [Figure 2].
|Figure 2: Schematic representation of cells, receptors, and downstream signaling pathways involved in adaptive venous remodeling following fistula creation|
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| Conclusion|| |
Although AVF are the preferred access type for hemodialysis, AVF maturation and patency rates remain low. Successful fistula maturation relies on venous dilation and wall thickening in the fistula environment that is associated with acquisition of dual arterial-venous identity. Fistula failure can occur early, secondary to lack of maturation, or late, as a result of excessive NIH and wall thickening. Although venous diameter and distensibility predict AVF success, preoperative identification of an ideal vein remains elusive.
Multiple strategies to improve AVF maturation and patency have been studied with varying degrees of success. Optimization of fistula hemodynamics via alteration of surgical techniques, such as RADAR, shows promising results with decreased NIH. Improvement of fistula nonmaturation has been attempted mainly with assistive therapies including angioplasty, stenting, and elastase therapy, with limited success. Manipulation of Eph-B4/ephrin-B2 signaling and their downstream signaling pathways, including Akt1, may enhance venous adaptive remodeling and warrant additional future studies.
Financial support and sponsorship
This work was supported by the Association of VA Surgeons Resident Research Award [J.G.], the National Institutes of Health R01-HL128406 and R01-HL144476 [A.D.], as well as with the resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, CT.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]