A departure from the “extreme mantra” of Fistula First unlocks the door to a new, dynamic vision that could swing the pendulum back to increased arteriovenous graft (AVG) use. But, this hinges on shared decision-making with patients and sight lines being firmly set on “long-term strategy for a patient’s entire dialysis journey”. It will also involve conversations around options that include arteriovenous fistula (AVF), early-cannulation AVG (ecAVG) and tunnelled central venous catheter (TCVC). Then, availability, applicability—including timing and anatomy—and how each device handles and performs, will determine the choice of which one to use, say experts, who also highlight the plethora of innovations vascular access grafts have undergone.
Matteo Tozzi (University of Insubria, Varese, Italy) captures an entire field of thinking when he says AVGs are often seen as a “necessary evil”—their implantation and value accepted as collateral for avoiding TCVC placement (the latter devices are generally perceived as the real offender and last resort of access options and maintenance, as their use is entwined with increased central venous stenosis, infection and higher all-cause mortality).
Tozzi believes that the most recent Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines from 2019 breathe fresh life into expanding the scope of AVG placement. But, he contends, this relies on distinguishing patients into two categories—those predicted to have adequate native fistula maturation for dialysis and those in whom this is unlikely. In the second group, early-cannulation prosthetic grafts offer the possibility of rapid haemodialysis initiation followed by a switch to a native fistula, he opines. Those who have a long history of several failed access procedures, and older, frail patients, are also suitable candidates for graft placement.
Considered AVG implantation gains groundswell of support
Tozzi’s view is that, while Fistula First was a fantastic initiative, it also inadvertently resulted in many patients relying on long-term CVC for dialysis when their “first” native access did not mature, and was therefore unutilised. The latest KDOQI revision focuses on attainment of the “right access, in the right patient, at the right time, for the right reasons”, which resolves that policy wobble, he says. The change also signalled a shift from choosing between an AVF and AVG to a more dynamic vision in which, depending on the patient, an ecAVG could be a solid first path to dialysis, after which an AVF is created and matured to enable a subsequent switch.
The core of this argument rests on research from David Kingsmore (University of Glasgow, Glasgow, UK), who insists that “the preconceptions surrounding graft use are not based on evidence” and that they are “inappropriately discredited”. He explains how grafts can be used in novel ways, not to compete with AVFs, but to reduce the use of CVCs. “The biggest misperception is the comparative outcomes of AVGs versus the alternatives that clearly demonstrate AVGs are a worthwhile consideration in patients without an obvious good target for an AVF that leads to potentially unnecessary TCVC use,” Kingsmore adds.
He is convinced that current clinical practice should consider AVG use best suited to “anywhere an AVF will not be available for dialysis—whether it is dysfunction of an existing AVF, failed AVF procedures, or urgent starts”. Kingsmore continues: “Most importantly, their use benefits younger, female patients with diabetes in whom the short- and longer-term consequences of TCVC tend to be: infection, repeated procedures, central vein stenosis and the knowledge that, even if transplanted, 50% will require additional dialysis in 10-to-15 years.”
Interjecting on graft advances he would welcome, he adds: “The main innovation we need is for new technology to guide the need for intervention for venous stenosis. We currently have good grafts and good treatments for the main complication, venous stenosis, but there are interesting developments in remote, self-reporting, intelligent stents that would negate the need for surveillance”.
Shared decision-making involving patients is key
Some physicians believe that procedure-driven incentivising is the real malignant force. Karen Stevenson (University of Glasgow, Glasgow, UK) emphasises that the rightful place for any device, including “maligned” grafts, is best brought to light when their use is aligned to the needs of the patient. So, determining where grafts might be a good fit for patients—rather than being driven by a fixed access type—is the guiding principle.
Tozzi concurs that access creation is a bespoke and tailored procedure. “Today, this procedure is very heterogeneous. The patient population is extremely diverse and there is often only one type of right or correct access. Creation needs to be tailored to the patient, and the patient and proceduralist need to go together to achieve the goal of vascular access,” he says.
“Dialysis access decision-making has changed significantly with the development of ecAVGs,” Stevenson states. “They offer options to patients at decision points in their care that can alter their vascular access journey, such as with urgent haemodialysis start or to manage an AVF complication where previously the only option on offer was TCVC. The challenge is how to implement in practice if providers are working in silos.”
Patients’ views on grafts form a fundamental basis on which graft use might be accelerated, if appropriate, notes Stevenson. “In deriving the Vascular Access Quality of Life measure (VASQoL; a validated 11-item vascular access-specific quality of life measure), patients described hugely variable vascular access journeys,” she says. “Consistent themes were that, whilst their vascular access function, appearance and feel were very important, key findings were that creating and maintaining an access that did not interfere with activities they really needed to still be able to do (work/caring) and that they wanted to take part in (hobbies/interests) had a great impact on kidney failure patients’ quality of life. Specifically, patients wanted to be included in decisions about the care of their access—which confirmed the importance of shared decision-making.”
Stevenson sets out her vision clearly, adding: “In the past, dialysis access research has been procedure- or intervention-based. I hope, in 2022, that we can shift our focus and research to an approach that is more patient-centred, and involves shared decision-making and long-term strategy for a patient’s entire dialysis access journey. We need to shift away from consultations that are single procedure-based and involve patients in the decisions about creation and long-term maintenance of their vascular access. That requires conversations that include fistula, TCVC and ecAVG options.”
Overcoming the pitfalls of arteriovenous grafts
Still, before widespread AVG use is accepted, the chinks in their reputation for longevity and infection rates need to be faced down. Right on cue, InnAVasc’s founder and director of Clinical Operations Shawn Gage reminds readers that it is always “important to recall that the standard AVGs still used for the majority of arteriovenous access were never specifically engineered to be stuck with a dialysis needle”. He also notes: “They were developed to be peripheral arterial replacements, so it is surprising that we have gotten away with using them for haemodialysis for as long as we have. They were disadvantaged from the beginning.
“Grafts certainly serve a very important purpose in the access lifecycle for most patients with end-stage kidney disease [ESKD]. I think there are now decades of experience to showcase how grafts perform in comparison to AVFs and catheters. In general, this is defined as somewhere in the middle in terms of patency, longevity and infection. In some patients, grafts are the only mode of vascular access that can function reliably. But, we can do better for our patients.”
Responding to the question: “Does the evidence back the claims that these devices are more prone to infection and thrombosis?”, Gage says: “If one excludes fistulas that fail to mature, I think it is reasonable, in general, to accept (based on decades of data) that autologous AVFs tend to have a lower incidence of infection and thrombosis than AVGs. This is mostly a biological issue. AVGs do not favourably incorporate into the surrounding tissue, but rather scar. This does not lend itself toward enjoying the rich microvascular environment that is native to autologous access.
“Therefore, AVGs are less efficient at eradicating unwanted bacteria that may have been introduced via dialysis needle or from within the blood stream. Furthermore, AVGs do not develop an endothelium and can often exhibit more extreme flow dynamics at the venous juxta-anastomotic zone, which heavily influences neointimal hyperplasia of the venous outflow, both of which contribute to the increased thrombogenicity of AVGs.”
In addition to grafts dedicated for haemodialysis, including the development of ecAVGs, there are several new lines of innovation that have transformed both the standard prosthetic AVG and biological grafts. Chief among them, Tozzi notes, are new biological and biosynthetic grafts, such as the Axess graft (Xeltis)—an endogenous tissue regeneration graft—or a graft crafted from silk cocoons in which the fibrin has very good biological properties.
Novel devices offer promise in vascular access
Xeltis recently announced initiation of a clinical trial evaluating its Axess graft, which it claims is the first ever restorative synthetic graft. “Axess grafts enable early puncturing shortly after implanting. Over time, they turn into living blood vessels as their porous microstructure is colonised by the patient’s own tissue,” according to a company press release shortly following the announcement. Several patients requiring dialysis have already been successfully implanted as part of the European first-in-human trial.
Elaborating on this futuristic implant—a graft built from biosynthetic polymer—which after some months is completely regenerated with live tissue from patients, Tozzi notes that in time this graft transforms into a tube lined by the patient’s own cells, owing to the fact it is based on endogenous tissue restoration technology.
Innovative steps are being taken on the other side of the Atlantic too—with US-based clinical-stage biotechnology firm Humacyte developing its own solution to some of the most pressing challenges faced by AVGs. More specifically, it is attempting to tackle a prevailing problem associated with graft materials like polytetrafluoroethylene (PTFE) by proposing a biological alternative.
The company is currently working on a universally implantable bioengineered human tissue—a human acellular vessel (HAV)—at commercial scale. These HAVs are created by culturing human vascular smooth muscle cells on a biodegradable polymer matrix within bioreactors that provide pulsatile mechanical strain. The final, completed vessel comprises human vascular extracellular matrix constituents and has the mechanical strength of the original vessel, without cellular components that might stimulate immunologic recognition in the host.
Late last year, five-year data from a phase 2 clinical trial of 29 patients who received Humacyte’s HAV for arteriovenous access in haemodialysis were presented at the American Society of Nephrology (ASN) Kidney Week (2–7 November 2021, virtual). These data suggested long-term durability and functional haemodialysis access in patients with ESKD who dialyse three times per week, with the study’s authors also reporting no HAV conduit infections during follow-up.
Freedom from needless needlestick injuries
The InnAVasc Graft (IG) is designed to reduce the risk of complications and bleeding from repeated dialysis for both in-centre and home haemodialysis, allow for immediate use post-implant, and promote easy location of a safe stick zone target. The company states that the IG has been designed specifically to address three key issues: back and side wall injury (via protective backplates), excessive bleeding (using self-sealing materials specifically engineered for needle sticks) and lack of cannulation confidence (with easy-to-identify raised target stick zones).
In January this year, InnAVasc announced receipt of US Food and Drug Administration (FDA) permission to commence the third phase of enrolment for a pivotal clinical study assessing safety and effectiveness with IG, which is designed to be used immediately post-implant.
Declaring his interest, Gage—who has been working on this device with the view to protecting patients from all-too-frequent cannulation-related injuries—says: “I think there are huge potential advances on the AVG front with the IG and also from an overall renal care perspective.” Gage predicts a “swinging of the pendulum” back towards grafts over the next decade. “From significant AVF and AVG data, we realise that not all AVFs are good and that AVGs have a solid value in the arteriovenous access lifecycle,” he continues.
“It is no secret that, when fistulas work, they can work really well, but both modes of vascular access play a critical role for our patients. We are in the process of transitioning from the extreme mantra of Fistula First to a more reasonable practice of ‘the right access, for the right patient, at the right time, and for the right reasons’. If we continue to review all relevant factors with our patients as outlined in the ESKD Life-Plan [a concept introduced by the National Kidney Foundation as part of its 2019 KDOQI guideline update] as we go forward, that will likely include better planning for AVFs, decreased use of catheters, and increased use of AVGs.”
Many of these graft innovations are set to feature at the Charing Cross symposium (CX 2022; 26–28 April, London, UK, in-person and virtual).