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Novel Approaches to Arteriovenous Access Creation, Maturation, Suitability, and Durability for Dialysis

2020; Elsevier BV; Volume: 5; Issue: 6 Linguagem: Inglês

10.1016/j.ekir.2020.02.1024

2468-0249

Maria V. DeVita, San Kyaw Khine, Hristo Shivarov,

Acute Kidney Injury Research

Since the arteriovenous fistula (AVF) was first conceived over 50 years ago, the goal to create a vascular conduit with predictable and reproducible maturation and durability continues to elude caregivers. Recently, however, advances in the understanding of vascular biology and new technologies now provides us with some optimism; we are moving toward a viable solution. A quickly maturing, sustainable, and durable arteriovenous access may soon be attainable. This review will discuss these advances. There are novel approaches to AVF creation and devices to enhance maturation, advances in arteriovenous graft material(s), and devices to safely prolong the use of tunneled dialysis catheters. Although hemodialysis (HD) access remains a complex problem, these innovations may lead the way to optimizing the care and the quality of life of those patients who have no choice but to proceed with HD. Since the arteriovenous fistula (AVF) was first conceived over 50 years ago, the goal to create a vascular conduit with predictable and reproducible maturation and durability continues to elude caregivers. Recently, however, advances in the understanding of vascular biology and new technologies now provides us with some optimism; we are moving toward a viable solution. A quickly maturing, sustainable, and durable arteriovenous access may soon be attainable. This review will discuss these advances. There are novel approaches to AVF creation and devices to enhance maturation, advances in arteriovenous graft material(s), and devices to safely prolong the use of tunneled dialysis catheters. Although hemodialysis (HD) access remains a complex problem, these innovations may lead the way to optimizing the care and the quality of life of those patients who have no choice but to proceed with HD. The creation and maturation of the ideal AVF remains elusive. The goal to simply create a conduit for vascular access for HD, with predictable and reproducible maturation, and with durability continues to be difficult to obtain despite many attempts to address this problem. The reasons for this elusiveness are myriad. First, we, as clinicians, still cannot precisely determine who will progress to end-stage renal disease (ESRD) or, if there is progression, when dialysis will need to be initiated (e.g., onset of uremic symptoms). As a result, we lack evidence and guidance as to when optimally to create an AVF. The Fistula First, Catheter Last Initiative1Lacson E. Lazarus J.M. Himmelfarb J. Ikizler T.A. Hakim R.M. Balancing fistula first with catheters last.Am J Kidney Dis. 2007; 50: 379-395Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar recommends creation of an AVF at least 6 months before the anticipated start of HD. However, the gap between unnecessary creation of AVF and initiation of HD with a catheter is large. O'Hare et al.2O'Hare A.M. Batten A. Burrows N.R. et al.Trajectories of kidney function decline in the 2 years before initiation of long-term dialysis.Am J Kidney Dis. 2012; 59: 513-522Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar reported that there are multiple trajectories of progression, so that as many as 10% to 17% of patients will not ever have their AV access used because they have not reached ESRD. At the other end of the spectrum, approximately 80% of patients on new-start HD still initiate HD with a catheter. Based on the United States Renal Data System (USRDS) 2018 Annual Report, at the time of initiation of HD, 62.5% of patients start treatments with a catheter only. Those with catheters and maturing fistula or grafts (AVG) are 16.1 % and 1.6 %, respectively. Sole AV fistula and graft use is a mere 16.7 % and 3.0 %, respectively. In many patients on HD, the AV fistula remains the most common vascular access (64.5%), followed by patients with catheters (18.9 %) or AVG (16.6 %).3USRDS 2018 Annual Data Report. Volume 2: End-Stage Renal Disease-Vascular Access. 2018; ch 3. https://www.usrds.org/2018/view/v1_03.aspx.Google Scholar Furthermore, the Dialysis Access Consortium (DAC) trial showed that as many as 60% of AVFs were not suitable for dialysis at 6 months and that these nonmaturing AVFs need up to 3 supplemental procedures to achieve suitability for dialysis.4Dember L.M. Beck G.J. Allon M. et al.Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.JAMA. 2008; 299: 2164-2171Crossref PubMed Scopus (596) Google Scholar The dysfunction is usually as a result of initial failure to mature or, after maturation, the development of venous stenosis (and/or thrombosis). Indeed, many AVFs created require interventions to facilitate maturation.5Harms J.C. Rangarajan S. Young C.J. Barker-Finkel J. Allon M. Outcomes of arteriovenous fistulas and grafts with or without intervention before successful use.J Vasc Surg. 2016; 64: 155-162Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar This problem is in contrast to the relative ease of initiation of peritoneal dialysis (PD). For PD, when a patient becomes mildly uremic, PD catheter placement is scheduled. The surgical site generally heals within a few weeks, and PD training can start unencumbered. Dialysis starts predictably and with durability of access (although not every catheter works perfectly). Likewise, an AVG can be placed and used within a predictable time frame. However, AVGs are not durable; they have very high rates of stenosis, thrombosis, and infection. Finally, a tunneled HD catheter is also predictable but not safe or durable over time. In addition to being unable to determine the timing of initiation of dialysis precisely, we have a poor understanding of the vascular biology and changes to the vasculature that transpire once an AV access is created. To improve outcomes, we need to develop therapies or techniques to secure the primary maturation of AVF or avoid stenosis, thrombosis, and infection in AVG and avoid infections and clots in catheters.6Nath K.A. Allon M. Challenges in developing new therapies for vascular access dysfunction.Clin J Am Soc Nephrol. 2017; 12: 2053-2055Crossref PubMed Scopus (7) Google Scholar To this end, recent focus has been on the vascular biology of arteriovenous accesses. By evaluating vasopathic or vasoprotective molecules, novel approaches are being explored. These approaches address the problem of inward remodeling: a reduction of luminal diameter due to neointimal hyperplasia or address insufficient outward remodeling, increasing luminal diameter by vasodilation, and/or structural enlargement. This latter process mitigates against inward remodeling by maintaining adequate luminal diameter in the face of neointimal hyperplasia.7Roy-Chaudhury P. Sukhatme V.P. Cheung A.K. Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint.J Am Soc Nephrol. 2006; 17: 1117-1127Crossref Scopus (428) Google Scholar,8Shiu Y.T. Rotmans J.I. Geelhoed W.J. Pike D.B. Lee T. Arteriovenous conduits for hemodialysis: how to better modulate the pathophysiological vascular response to optimize vascular access durability.Am J Physiol Renal Physiol. 2019; 316: F794-F806Crossref PubMed Scopus (22) Google Scholar At present, most of our attention is placed on addressing maturation failure weeks to months after the creation of the AVF. The newer novel approaches are applied at the time of the creation of the AVF. To better understand these approaches, it is important to have some knowledge of the cellular and molecular aspects of arteriovenous access dysfunction. Typically, failure of an AVF to mature is a characteristic juxta-anastomotic stenosis from either venous constriction or venous neointimal hyperplasia (NIH).7Roy-Chaudhury P. Sukhatme V.P. Cheung A.K. Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint.J Am Soc Nephrol. 2006; 17: 1117-1127Crossref Scopus (428) Google Scholar Briefly, this latter pathology is thought to be the result of endothelial and smooth-muscle injury from shear stress, turbulent flow, and/or tissue injury at time of surgery. This injury then triggers activation of myofibroblasts and fibroblasts within the endothelial wall, also generating expression of cytokines and other mediators, such products as endothelin, platelet-derived growth factor (PDGF), vascular endothelial growth factor, and transforming growth factor beta (TGF-β). Subsequently, venous neointimal hyperplasia results from the migration of smooth muscle cells and myofibroblasts from the media to the intima. In addition, there is ongoing proliferation, inflammation, and oxidative stress. Furthermore, there may also be adventitial angiogenesis and proliferation of macrophages that line the perivascular region.6Nath K.A. Allon M. Challenges in developing new therapies for vascular access dysfunction.Clin J Am Soc Nephrol. 2017; 12: 2053-2055Crossref PubMed Scopus (7) Google Scholar NIH has long been thought to be the culpable process in failure of AVF maturation. However, recent studies call this singular event into question.9Tabbara M. Duque J.C. Martinez L. et al.Pre-existing and postoperative intimal hyperplasia and arteriovenous fistula outcomes.Am J Kidney Dis. 2016; 68: 455-464Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar,10Allon M. Robbin M.L. Young C.J. et al.Preoperative venous intimal hyperplasia, postoperative arteriovenous fistula stenosis, and clinical fistula outcomes.Clin J Am Soc Nephrol. 2013; 8: 1750-1755Crossref PubMed Scopus (46) Google Scholar What is known is that an imbalance between NIH, inward remodeling (too much), and vasodilation, outward remodeling (inadequate), leads to access failure. The mechanisms within the milieu of the perivascular anastomotic region still need to be fully elucidated. Another demonstrated feature in failure of AVF is related to poor artery or vein selection (too small, too deep). As the science of AV access creation has evolved, it is now clearly recognized that the vessels used to create an access have to be of proper size and quality. Standard vessel criteria for creation of access that have now been generally accepted are a vein diameter for AVF of 0.25 cm and for an AVG 0.4 cm with an artery diameter of 0.2 cm.11Robbin M.L. Gallichio M.H. Deierhoi M.H. Young C.J. Weber T.M. Allon M. US vascular mapping before hemodialysis access placement.Radiology. 2013; 217: 83-88Crossref Scopus (214) Google Scholar The vessels must also be superficial enough to enable easy palpation and cannulation. Presurgical vessel mapping is now mandatory. A recent concern is that the surgical procedure itself can cause vascular injury, thereby contributing to failure of AVF maturation. This is thought to be the result of stretching and manipulation of the vein when handled during surgery. In addition to cellular factors, there is hemodynamic stress at anastomotic sites, producing turbulent flow.12Lee T. Roy-Chaudhury P. Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis.Adv Chronic Kidney Dis. 2009; 16: 329-338Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar Finally, an important factor contributing to access stenosis is endothelial and smooth-muscle cell injury from angioplasty.13Chang C.J. Ko P.J. Hsu L.A. et al.Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis.Am J Kidney Dis. 2004; 43: 74-84Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar The first description of an AVF for chronic intermitted HD was the Brescia-Cimino radiocephalic fistula, reported in 1966.14Brescia M.J. Cimino J.E. Appel K. Hurwich B.J. Chronic hemodialysis using venipuncture and a surgically created arteriovenous fistula.N Engl J Med. 2010; 10: 193-199Google Scholar This simple procedure of connecting one's own artery to a draining vein, thereby internalizing the AV access, was revolutionary. Typical anatomic sites used today are the radiocephalic, brachiocephalic, and basilic vein transposition. Previous conduits had external components that were susceptible to infections and thromboses and were not durable. Unfortunately, over the past 50 years there have not been any major breakthroughs to resolve the problems associated with AV access: failure to mature, infection, stenosis, and thrombosis. This problem remains a tremendous gap toward optimizing the care and quality of life for those patients on HD. For a prosthetic AV graft, venous stenosis develops. The subsequent reduced flow facilitates formation of a thrombosis at the graft-vein anastomosis or in the proximal vein. An artery-graft stenosis may also occur and precipitate thrombosis. Venous stenosis in the AVG is usually the result of neointimal hyperplasia7Roy-Chaudhury P. Sukhatme V.P. Cheung A.K. Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint.J Am Soc Nephrol. 2006; 17: 1117-1127Crossref Scopus (428) Google Scholar (in contrast to AVF, in which this is less clear). This review will discuss novel therapies to improve creation of AV access, maturation, and suitability for dialysis. First, there are new devices to create AVF from an endovascular approach. Then, of interest, are 2 devices to help optimize the configuration of the vascular anastomosis. There are several explorations into therapies being tested that aim to enhance primary maturation by addressing changes to the vasculature at the time of AVF creation. Another area includes those therapies that address failure of maturation and development of stenoses and/or thromboses. In addition, there will be a discussion on various modifications to AVGs. Finally, there are 3 new devices/therapies to limit infection and clotting of central venous catheters (CVCs). There are 2 new FDA approved devices to create an AVF via an endovascular approach: the everlinQ endoAVF system (TVA Medical, Becton Dickenson and Company, Franklin Lakes, NJ) and the Ellipsys Vascular System (Avenu Medical, San Juan Capistrano, CA) (Table 1).Table 1Endovascular devicesDeviceDesignEntryAnastomotic techniqueNotesEllipsys Vascular Access System (Avenu Medical, San Juan Capistrano, CA)Single-catheter venous access systemUltrasound-guidedRetrograde venous access obtainedContact between deep communicating vein and proximal radial arteryJaws of device puncture vein and artery walls, side to sideTissue fusion to cut and weld an elliptical anastomosis between the artery and veinTissue fusion requires heat and pressure to be applied at the same timeUsually requires another procedure to promote arterial flow through the anastomosis or to outflow traitseverlinQ endoAVF system (TVA Medical, Becton Dickenson and Company, Franklin Lakes, NJ)Two catheters, 1 arterial, 1 venous; magnets establish alignment between closely approximated deep vessels in forearmUltrasound and angiographic guidanceBrachial vein and artery approach–contrast use guide movement to ulnar artery and veinSide-to-side by radiofrequency energy generated from venous catheter and ceramic backstop in arterial catheter. Slit by tissue vaporizationUsually requires embolization of brachial vein (used for access) to help augment flow into superficial veins Open table in a new tab The everlinQ endoAVF system employs 2 catheters, each with a series of magnets. The creation of the AVF consists of cannulation of both the brachial vein and the brachial artery. These magnetic catheters are then advanced into the ulnar vein and artery, respectively. The magnets embedded within the catheters are attracted and align. Once in position, a radiofrequency pulse generated from an electrode is deployed and creates the anastomosis between these ulnar vessels. The device was evaluated in the Novel Endovascular Access Trial (NEAT).15Lok C. Rajan D.K. Clement J. et al.Endovascular proximal forearm arteriovenous Fistula fistula for hemodialysis access: results of the prospective, multicenter Novel Endovascular Access Trial (NEAT).Am J Kidney Dis. 2017; 70: 486-497Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar A single-arm, multicenter study, it evaluated the safety and efficacy of creating AVF using this percutaneous/endovascular system. The efficacy end points of the study were. AVF physiologically suitable for dialysis, defined as brachial artery flow > 500 ml/min, vein diameter > 4 mm, and functional usability of the endoAVF. Fifty-nine patients were included in the final analysis. Of these, 87% of the patients had a physiologically suitable AVF; however, functional usability as determined by dialysis nurses was 64%. In addition, only 52% were functional without any interventions; the remainder needed secondary interventions to assist maturation. There are now 6F and 4F introducers for cannulation of the brachial artery and vein, and radial or ulnar systems, respectively. Of note, coiling of the brachial vein seems critical to the success of creation of the AVF and has its own set of consequences. The Ellipsys Vascular Access System (Avenu Medical, Inc., San Juan Capistrano, CA) involves a thermal resistance anastomosis device (TRAD).16Hull J.E. Elizondo-Riojas G. Bishop W. Voneida-Reyna Y.L. Thermal resistance anastomosis device for the percutaneous creation of arteriovenous fistulae for hemodialysis.J Vasc Interv Radiol. 2017; 28: 380-387Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Here, a single catheter is used to create a percutaneous fistula under ultrasound guidance. After cannulation of a deep communicating vein, the catheter is advanced in a retrograde fashion. A closely aligned portion of the proximal radial artery is selected for access. The jaws of the device puncture through the closely approximated walls of both vessels. The catheter then generates thermal energy to fuse the artery and vein, creating an elliptical anastomosis. The efficacy and safety of TRAD was also recently evaluated.16Hull J.E. Elizondo-Riojas G. Bishop W. Voneida-Reyna Y.L. Thermal resistance anastomosis device for the percutaneous creation of arteriovenous fistulae for hemodialysis.J Vasc Interv Radiol. 2017; 28: 380-387Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Twenty-six patients underwent creation of AVF, with a success rate of 88% (23 of 26 patients). At 6 weeks, 87 % of the AVF were patent, and 80% were used for HD at 3 months. However, the need for additional procedures—such as balloon dilation, vein embolization, vein ligation, venous transposition, and valvulotomy—were common, being required in 87% of AVFs. No major complications related to the device were documented. Neither of these 2 products has been tested against more traditional means of AVF creation. It is also important to note that these percutaneously created fistulae are low flow, and successful use will need to be accompanied with education about the AVF and proper cannulation. A recent review describes these 2 techniques in greater detail.17Jones R.G. Morgan R.A. A review of the current status of percutaneous endovascular arteriovenous fistula creation for haemodialysis access.Cardiovasc Intervent Radiol. 2019; 42: 1-9Crossref PubMed Scopus (22) Google Scholar Two devices that aim to enhance the success of traditional surgical AVF creation and maturation are being tested. These devices seek to optimize the geometrical configuration of the fistula, thereby minimizing turbulence, promoting laminar flow, and attenuating NIH. The VasQ (Laminate Medical Technologies, Tel Aviv, Israel) is an external conduit support system for vascular access, which is placed at the time of creation of AVF (Figure 1).18Vascularnews. Laminate receives IDE approval from FDA to initiate study of the VasQ device.https://vascularnews.com/laminate-receives-ide-approval-fda-initiate-study-vasq-device/Date accessed: January 6, 2020Google Scholar The device externally surrounds and supports the index vein and artery near and around the anastomosis, acting as a scaffolding to preserve the ideal angle of anastomosis. It is purported to reduce turbulent flow and prevent neointimal hyperplasia.19Hye R.J. Peden E.K. O'Connor T.P. et al.Human type i pancreatic elastase treatment of arteriovenous fistulas in patients with chronic kidney disease.J Vasc Surg. 2014; 60: 454-461Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar A small clinical trial with 20 patients was performed to test the product. All the patients were implanted with VasQ at the time of creation of AVF. The end points were venous flow, primary patency, and unassisted maturation rates of the AVF. The patency rates were 95%, 79%, and 79% at 1, 3, and 6 months, respectively; maturation rates were 80%, 79%, and 74%, respectively. At the 6-month follow-up, 14 of 15 patients who required HD were able to have their AVFs cannulated. A larger study examining the efficacy of VasQ is actively recruiting a target of 80 patients (NCT03246984) undergoing creation of a new brachiocephalic (50 patients) or radiocephalic (30 patients) AVF. The follow-up period to assess the patency and freedom from any intervention to maintain or reestablish patency will be 12 months and is expected to be completed in mid-2020.20Chemla E. Velazquez C.C. D'Abate F. Ramachandran V. Maytham G. Arteriovenous fistula construction with the VasQTM external support device: a pilot study.J Vasc Access. 2016; 17: 243-248Crossref PubMed Scopus (30) Google Scholar In contrast to the external VasQ device, the Optiflow device (Bioconnect Systems, Fort Washington, PA) is an implantable anastomotic connector, also used to standardize the creation of AVF at a set angle (Figure 2).21Yevzlin A.S. Valliant A.M. Interventional nephrology: novel devices that will one day change our practice.Clin J Am Soc Nephrol. 2013; 8: 1244-1251Crossref PubMed Scopus (3) Google Scholar This nonthrombogenic silicone-polyurethane connector is inserted during the surgery to sit within the anastomosis of the AVF to maintain a set luminal size to optimize flow. The placement and configuration allow for consistency in both the size and the angle of the arterial anastomosis. The concept is that, by using this device, the geometry and flow path at the anastomosis is predetermined and predictable, thereby attenuating the likelihood of inflow stenosis, turbulent flow, and perhaps NIH. The OPEN (Optiflow PatEncy and MaturatioN) study, published in 2014, showed promising results in 41 subjects undergoing creation of a new AVF, permitting progression to a phase 3 trial.22Nikam M. Chemla E.S. Evans J. et al.Prospective controlled pilot study of arteriovenous fistula placement using the novel Optiflow device.J Vasc Surg. 2015; 61: 1020-1025Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,23Chemla E. Tavakoli A. Nikam M. et al.Arteriovenous fistula creation using the OptiflowTM vascular anastomotic connector: the OPEN (Optiflow PatEncy and MaturatioN) study.J Vasc Access. 2014; 15: 38-44Crossref PubMed Scopus (15) Google Scholar There are no new data on this product available at this time. There have been multiple trials investigating products to reduce neointimal hyperplasia, enhance dilation of blood vessels used for AVF, or interfere with the blood clotting processes, including—but not limited to—use of clodipogrel, statins, fish oil, aspirin, and coumadin. Most have been unsuccessful.4Dember L.M. Beck G.J. Allon M. et al.Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.JAMA. 2008; 299: 2164-2171Crossref PubMed Scopus (596) Google Scholar,24Viecelli A.K. Pascoe E. Polkinghorne K.R. et al.The Omega-3 fatty acids (Fish Oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) study: the updated final trial protocol and rationale of post-initiation trial modifications.BMC Nephrol. 2015; 16: 89Crossref PubMed Scopus (14) Google Scholar,25Chan K.E. Lazarus J.M. Thadhani R. Hakim R.M. Anticoagulant and antiplatelet usage associates with mortality among hemodialysis patients.J Am Soc Nephrol. 2009; 20: 872-881Crossref PubMed Scopus (149) Google Scholar New products all seek to enhance maturation rates by applying or adding the product at the time of creation of AVF and aim to reduce tissue inflammation and NIH. These can be considered a priori interventions. In contrast, the standard approach today is postcreation, maturation-failure interventions: procedures employed at a time after AVF creation/use (Table 2).26Sadaghianloo N. Declemy S. Jean-Baptiste E. et al.Radial artery deviation and reimplantation inhibits venous juxta-anastomotic stenosis and increases primary patency of radial-cephalic fistulas for hemodialysis.J Vasc Surg. 2016; 64: 698-706Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholarTable 2Local drug delivery products at time of AVF creationProductStatusTrial name(s)SponsorSirolimusCompleted recruitment July 2019, ongoing 6- and 12-mo dataTrial to Evaluate the Sirolimus-Eluting Collagen Implant on AV Fistula Outcomes (ACCESS), NCT 02513303Vascular TherapiesHuman Acellular Vessel (HAV, Humacyte, Inc, Durham, NC)Ongoing phase-3 trialNCT 03181245HumacyteVonapanitaseCompleted phase-3 randomized controlled trial, spring 2019PATENCY-1PATENCY-2NCT 01305824NCT 02110901ProteonVascugelTo date no phase-3 trialNCT01806545ShirePaclitaxel-eluting MeshTerminated 2011 for imbalance in graft infection between groupsNCT 00448708AngiotechAVF, arteriovenous fistula. Open table in a new tab AVF, arteriovenous fistula. As described previously, creation of the AVF is associated with hemodynamic changes and vascular injury that can cause cells in the middle and outer vessel wall layers to secrete extracellular material and proliferate. These events can result in intimal hyperplasia, stenosis, and thrombosis of the AVF. The novel therapies all address this vascular biology, some with limited success. The sirolimus-eluting collagen membrane (SeCM) is an investigational product developed for the intraoperative local perivascular delivery of sirolimus. The product, a sirolimus-impregnated collagen wrap, is applied circumferentially at and around the site of the vascular anastomosis, just after successful creation of the AVF. Sirolimus has clinically proven antiproliferative properties when used in coronary artery percutaneous coronary intervention.27Moses J.W. Leon M.B. Popma J.J. et al.Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.N Engl J Med. 2003; 349: 1315-1323Crossref PubMed Scopus (4052) Google Scholar Initial data using the product in AVG were promising.28Paulson W.D. Kipshidze N. Kipiani K. et al.Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R).Nephrol Dial Transplant. 2012; 27: 1219-1224Crossref PubMed Scopus (50) Google Scholar The utility in enhancing maturation of AVF is now under investigation in a randomized, multicenter single-blind controlled study evaluating arteriovenous outcomes with and without perivascular simolimus-eluting collagen implant (SeCl) in subjects on HD (Trial to Evaluate the Sirolimus-Eluting Collagen Implant on AV Fistula Outcomes [ACCESS]), NCT 0251330). Patient recruitment was completed in July 2019. Six- and 12-month data are expected in the beginning of 2020. Vonapanitase (PRT-201) is a recombinant human chymotrypsin-like elastase that can cleave peptide bonds in the protein elastin found in vessel walls. Applying vonapanitase during AVF surgery, immediately following successful creation of the AVF, is thought to augment maturation of the fistula patency and prevent formation of critical stenosis and thrombosis. The enzyme is rapidly absorbed into the outermost layer of the vessel wall, acting to enhance outward remodeling by fragmenting elastin fibers. This hypothesis was tested in PATENCY 1 (NCT02110901) a double-blind placebo-controlled study. The primary end point was primary patency, defined as the time from creation of the fistula until thrombosis or a procedure to restore or maintain the patency. The secondary end point was secondary patency, the time from creation of the fistula until abandonment. In the study, 349 patients who were on HD, or approaching it, were enrolled. Immediately after successful surgical creation of an AVF, the study-drug solution was applied topically to the artery and vein at the anastomosis for 10 minutes. The data showed no significant improvement of primary patency but did show an increased rate of secondary patency.29Bleyer A.J. Scavo V.A. Wilson S.E. et al.A randomized trial of vonapanitase (PATENCY-1) to promote radiocephalic fistula patency and use for hemodialysis.J Vasc Surg. 2019; 69: 507-515Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar A follow-up trial, PATENCY-2, was a multicenter randomized, double-blind placebo-controlled trial that enrolled 603 patients with chronic kidney disease (CKD). It followed a similar protocol as PATENCY-1; the active drug solution was applied at time of radiocephalic AVF creation. In April 2019, the sponsor company, Proteon Therapeutics (Waltham, MA), reported that the study did not achieve significance; at 12 months, 69.7% of vonapanitase-treated AVF were in use, compared with 65.1% in the control group (P= 0.328). Secondary patency demonstrated by Kaplan-Meier curves was also not significant between groups (78% vs. 76% respectively, P = 0.932). The next step in investigating the use of this product for enhancing AVF maturation has not yet been determined. Vascugel (NCT 01806545) (Pervasis Therapeutics, Inc., Cambridge, MA) is a unique