Title: Should we ligate haemodialysis fistulas in patients once they have been transplanted successfully? A feasibility study
Funder: Department of Health and Social Care

Abstract: Background Arteriovenous fistula (AVF) are the best means of providing haemodialysis, and compared to dialysis via a central venous catheter, are associated with fewer complications and reduced sepsis-related mortality. However, the low resistance, high-outflow state that is generated by AVF formation results in ventricular hypertrophy from greater cardiac workload. Increasing evidence suggests this may increase cardiovascular morbidity and mortality. Research question Should patients who are dialysing via an AVF have it disconnected after kidney transplantation? Aims and Objectives Our ultimate objective is to perform a multicentre randomised controlled trial (RCT) that tests our main hypothesis: In stable renal transplant patients, fistula disconnection improves cardiorespiratory fitness, thereby increasing patients activity levels and improving quality of life. Our immediate objectives relating to the current application are: To conduct a feasibility study that mirrors the proposed RCT, but that uses pre-defined cut-offs with regards patient recruitment and retention rates to justify progression to the RCT. To integrate qualitative assessment of the patient and clinician trial experience in order to gauge acceptability of the proposed trial design and processes. To assess patient compliance with wearing an accelerometer (activity sensor). Methods Forty consenting adult kidney transplant recipients who are at least one year from transplant with good transplant function (eGFR > 45 mL/min/1.73m2) and with a patent AVF will undergo formal cardiopulmonary exercise testing (CPET), with quantification of their maximal oxygen consumption (peak VO2). Baseline activity levels and other quality of life (QoL) domains will be assessed using the Short Form-36 questionnaire, and by wearing a wrist accelerometer for a week. Fistula blood flow will be measured by doppler ultrasound. Participants will then be randomised to surgical disconnection of their fistula or to continued conservative management (standard care). CPET, accelerometry, and QoL assessment will then be repeated six months later. To identify issues that may compromise the main RCT, participants and clinicians views and trial experience will be assessed qualitatively, through semi-structured interviews. Analysis Progression to the main RCT will be determined by whether pre-defined rates of: patient participation; adherence to randomisation; study completion are met during the feasibility study. The main RCT will be powered to detect a clinically-relevant increase in the primary endpoint (peak VO2) following AVF disconnection of 2 mL/Kg/min. Secondary endpoints will include QoL assessment and activity levels (accelerometer data). Design of the RCT protocol will be guided by the qualitative analysis to optimise patient participation and retention. Timelines for delivery We aim to address definitively our research question within six years: the feasibility study will run for two years; the main RCT for a further three, with a year allocated between for further trial funding application. Anticipated Impact and Dissemination Approximately 8000 kidney transplant patients in the UK still have a working AVF; in addition, approximately 30% of the 3200 recipients transplanted annually will have an AVF at transplant. The main RCT will address definitively the cardiorespiratory improvements gained from AVF ligation, and will enable these patients to make an informed decision on whether to have their AVF disconnected.

Lay abstract: Kidney transplantation is the best form of treatment for most patients with kidney failure, and there are currently around 41,000 people in the UK with a working kidney transplant. Although outcomes from transplantation are very good, people with a working transplant do not live as long as the general population, with a fifth of transplant patients dying from heart disease. If we could prevent some of these heart-related deaths, outcomes for transplantation would be even better. Before they receive a transplant, patients often require a period of haemodialysis , whereby the blood is cleansed by regularly attaching the patient to an artificial kidney machine. For this, patients often have an operation to create an arteriovenous fistula , which involves joining a vein in the arm directly onto a nearby artery. Once created, the fistula vein expands and the blood flow through the vein increases markedly. While this is ideal for providing access for haemodialysis, the increased blood flow means that the heart has to work harder, and studies have shown that the heart becomes bigger and its muscle thicker. Although not proven, it seems likely that these changes to the heart may contribute to the extra deaths from heart disease that occur in kidney transplant recipients. This is important, because we estimate that about one quarter of people with a kidney transplant still have a working fistula, and there is currently no clear guidance on how to manage fistulas following kidney transplantation. Our study will examine whether an operation to disconnect the fistula vein from the artery improves heart function in kidney transplant patients. As preliminary work for a much larger study, we will recruit forty consenting patients with good, stable kidney transplant function, and who still have a working fistula. All patients will have a special test that measures the very limit to which they can exercise; this shows how well their heart is functioning. The patients will be randomly assigned to either have their fistula left alone or to have it disconnected, and the exercise test will be repeated six months later. Patients will also wear a wrist monitor that records their activity levels before and after fistula disconnection, and we will assess if patients feel their quality of life has changed following their operation. An important part of this preliminary study will be trying to understand how patients feel about their involvement, and identifying any issues that prevent their participation, as well as any aspects of the trial that could be improved. We will use the findings from this preliminary study to fine-tune the design of our larger study, so that, ultimately, we can make clear recommendations to transplant patients about having their fistula disconnected.

Research activity codes: 6.4 SURGERY
Health categories: RENAL AND UROGENITAL