ReDVA

Overcoming problems around vascular access Patients suffering from kidney failure depend on peritoneal or haemodialysis to purify their blood, yet the failure of renal dialysis vascular access is a significant and serious problem. The ReDVA project is a joint industry-academia research programme that aims to overcome the scientific and technical barriers associated with the failure of vascular access, as Dr Shona Matthew explains

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All haemodialysis patients need some

Multi-disciplinary

form of vascular access. An arteriovenous fistula (AVF) is the preferred choice, as it reduces the risk of subsequent complications and serious infections in comparison to the other options; arteriovenous grafts and central venous catheters. AVF’s are created by surgically joining an artery to a vein so that the fast flowing blood from the artery is fed directly into the vein, causing the vein to dilate and the vein walls to thicken over a period of weeks or months. This process is known as maturation. A mature fistula provides the high flow rates required to ensure that the patient receives adequate dialysis clearance within a standard 3-4 hour dialysis session and is robust enough to withstand repeated cannulations.

“Because of the high failure rates and limited number of suitable sites on the body, surgeons prefer to create the first AVF in the wrist. This is not always possible as the patient’s vessels may be too small; so two potential fistulae sites are lost straight away,” says Dr Shona Matthew of the ReDVA project. “It is not uncommon for all suitable AVF sites in the body to be ‘used up’ and once that happens there’s very little else that can be done.”

Repeated AVF failure impacts on patient morbidity and mortality. It also costs healthcare services a large amount of money each year as patients require an immediate and often temporary form of vascular access, and further surgery to create a new AVF. The ReDVA project was formed to investigate the problems associated with renal dialysis vascular access, bringing together partners from industry and academia with the shared goal of improving clinical understanding in this challenging area.

The multi-disciplinary nature of the project means that the problems around haemodialysis vascular access are being approached from several different angles.

A lot of attention was initially devoted to analysing the existing guidelines for vascular access. “In the first year of the project, partners worked together on literature reviews, looking at existing guidelines for vascular access across the world. Several members of the ReDVA team worked with European Renal Best Practice, to update their guidelines, and one of our fellows had a Cochrane systematic review title accepted,” says Dr Matthew.

Single slice image through a patient’s arm acquired using MRI scanner.

Imaging ReDVA clinicians, physicists and engineers looked at pre-operative AVF vein mapping. “Before a patient goes for surgery, the surgeon will use ultrasound (US) to ‘map’ the patient’s vein and artery to ensure that they are suitable, as recommended in all the current guidelines,” explains Dr

Matthew. Very few centres offer more than one post-operative US scan to check on the maturation process, preferring a more ‘hands on’ assessment until a problem arises. However, Dr Matthew says that her NHS colleagues apply a highly pro-active imaging approach. “In Dundee we have a system where we use US to scan our patient’s vessels before their surgery and then again at regular intervals after surgery.”

This allows problems to be picked up and hopefully resolved before they affect the maturation process, or the patient’s dialysis treatment. “We are trying to encourage other centres to be more proactive with US imaging and so we developed optimised imaging protocols, which we shared with other centres,” says Dr Matthew.

Researchers from the University of Dundee, the University of Limerick and Vascular Flow Technologies also looked at Magnetic Resonance Imaging (MRI) as a tool for pre-surgical vein mapping and post-surgical surveillance, as they believe that MRI may offer additional information, which cannot be obtained with US. For example, many renal patients require a central venous catheter (CVC) at some point, perhaps as a form of temporary vascular access or as a conduit for administering drugs and fluid during surgery. Central vein stenosis is a common complication of using a CVC and needs to be considered when planning further AVF surgery, as it can lead to post operative complications. “This type of stenosis cannot be detected using US, but can be imaged with MRI, ” says Dr Matthew.

However, MRI is not routinely used as it’s quite expensive, not easy to access

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and the contrast agents used in MRI are contraindicated for patients with poor renal function, as some agents have been linked to a disease called nephrogenic systemic fibrosis (NSF) in this cohort.

ReDVA researchers worked to develop an MRI protocol that allowed them to acquire detailed 3D images of the patient’s vessels without the use of a contrast agent. Seven patients listed for AVF formation were scanned with MRI, both before surgery and at various time points after, allowing researchers to track the geometric changes in their vessels during maturation. The main limitation of using non-contrast imaging was the length of time that the patient had to spend in the scanner so that researchers could obtain the images they required.

Data analysis Knowing that a contrast agent would dramatically speed up this type of image acquisition, ReDVA researchers used the power of big data to investigate the safety of the macrocyclic Gadolinium based

A 3D model of a patient’s fistula, created using patient images.

3D model of a patient fistula.

Computational Fluid Dynamics contrast agents used in-centre. “We looked at data from over 24,000 contrast enhanced MRI scans, acquired in our hospitals between Jan 2004 and Dec 2016. We identified, linked and analysed the data of all patients, including those considered ‘at risk’, such as patients with poor renal function - many of whom had undergone numerous contrast-enhanced MRI scans. Our detailed analysis failed to find significant differences in the very low rates of adverse events between patients with normal renal function and those with poor renal function,” stresses Dr Matthew.

The imaging element of the project also holds implications for the computational dimension of the project. When a fistula is formed, blood flow changes from a natural spiral laminar flow, into a disturbed flow. “Suddenly you’ve got this high-pressure, high-velocity arterial blood flow in a vein,” explains Dr Matthew.

This unnatural flow affects wall sheer stress - where once you had levels that were moderately uniform and uni-directional, the wall shear stress is now disturbed and oscillating. The reason why this matters is that cells on and within the arterial wall respond to this by releasing chemical messengers that can cause blockage or failure

Image of an interventional procedure being carried out on the Thiel Cadaver model.

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At a glance Full Project Title DEVELOPMENT OF HEMODYNAMIC SOLUTIONS IN RENAL DIALYSIS VENOUS ACCESS FAILURE (ReDVA) Project Objectives The ReDVA project proposes to perform a joint industry-academia research programme to overcome the scientific and technical barriers to the understanding, development and adoption of technologies to combat the significant clinical problem of the failure of renal dialysis venous access.

Project Funding Funded by the European Commission.

EU contribution: T2 635 228 Project Partners Univerisity of Dundee (Professor Houston), Queen Elizabeth Hospital Birmingham (Mr Nick Inston), Guerbet, Paris (Dr Eric Lancelot), Vascular Flow Technologies, Dundee (Craig Dunlop), University of Limerick (Professor Michael Walsh).

Contact Details Chief Investigator, Professor Graeme Houston University of Dundee Dundee DD1 4HN T: +44 1382 632 651 E: j.g.houston@dundee.ac.uk W: www.redva.eu

Mr Nick Inston FRCS PhD. (Left) Professor Graeme Houston (Right)

of the fistula. The specific circumstances that cause failure are not known at present but it is something which researchers in the project aim to shed light on. “Our colleagues have been looking at blood flow patterns in realistic fistulas obtained from the MRI images using computational models,” says Dr Matthew. “This involves looking at what we call intimal hyperplasia on the vessel wall where the muscle cells in the vein wall multiply at an accelerated rate. It can cause lesions, narrow the vessel, block it, or narrow and block a graft.”

The human body is highly complex, so it takes a multi-disciplinary team of physicists, sonographers, radiographers, engineers, and interventionists to figure out what’s happening, even in a relatively small part of it.

Image Guided Therapy Research Facility Recently in Dundee, ReDVA’s Chief Investigator, Professor J Graeme Houston, in collaboration with ReDVA partners, led the development of a unique resource, The Image Guided Therapy Research Facility, bringing together three key resources. State-ofthe-art imaging facilities, including 128 interventional CT, C-Arm X-ray and 1.5 T MRI coupled with the multidisciplinary network of ReDVA clinicians, anatomists, engineers and scientists to provide the basis for the development of Thiel embalmed human cadavers as a model for both teaching and the testing of preclinical devices, including those

We’re looking at the problems associated with arteriovenous fistulae, and we’re trying to improve understanding of factors that impact on AVF patency rates. Researchers from a number of disciplines are involved in the project, so we can look at the problems from a number of perspectives Due to the development of stenosis, some of the ReDVA patients required post-operative interventions within months of their AVF surgery, to prevent their fistula failing. The data collected during their interventions was collated and analysed alongside that of many other patients who had undergone similar interventions, allowing the long-term success rates of interventional techniques to be compared.

intended as an alternative form of vascular access. Thiel embalmed human cadavers retain many of the living properties of the human body, including a patent vascular system, so flow can be introduced into the bodies, simulating anatomically accurate models. This model, developed as part of the ReDVA project, is attracting a significant amount of interest from clinicians and industry.

Efstratios Kokkalis attending an interventional training day at Ninewells Hospital.

Mr Nick Inston FRCS PhD. Consultant Surgeon at Queen Elizabeth Hospital, University Hospitals Birmingham. As part of the ReDVA study was one of the leads for the European Renal Best Practice Guidelines group on Vascular access, presented at the Vascular Access Society and acted as supervisor for two ReDVA fellows.

Professor Graeme Houston is currently Co-Director of the Clinical Research Imaging Facility, at the University of Dundee and NHS Tayside collaboration, delivering clinical imaging for both research and NHS services. He has published 250 papers and holds over 30 patents comprising 12 patent families, 11 design patents.

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