Title: The High-volume Haemodiafiltration vs High-flux Haemodialysis Registry Trial (H4RT)
Funder: Department of Health and Social Care

Abstract: Design: A non-blinded randomised controlled trial comparing the clinical and cost-effectiveness of two dialysis methods – high-volume HDF and high-flux HD. Randomisation: 1:1, stratified by site, age and residual renal function. The primary analysis will be intent to treat using proportional hazards regression adjusting for variables used to stratify the randomisation. Setting: Secondary care renal units. Target population: Adult patients on in-centre, maintenance HD for ESKD Exclusion criteria: Lack of capacity to consent; Clinician predicted life expectancy less than 3 months; On maintenance HD less than 4 weeks; Living kidney donor transplant or home dialysis scheduled within 3 months; Treatment with HDF for more than 3 months prior to recruitment to the trial or prior intolerance of HDF; Not suitable for high-volume HDF for other clinical reasons. Health technology assessed: Intervention= High-volume HDF (aiming for 21+L of substitution fluid per session adjusted to body surface area (1)) Comparator= High-flux HD aiming for a small solute clearance comparable to the high-volume HDF Difference between current and planned care In HD and HDF toxins are removed by diffusion, but in HDF there is also (i) convection to remove 21+L of toxin-containing fluid and (ii) substitution/ replacement of that volume with 21+L of sterile fluid. For the patient, the treatment appears very similar with the same frequency and duration. Measurement of costs and outcomes The primary outcome will be a composite of non-cancer mortality or hospital admission with a cardiovascular event or infection within 3 years. Secondary outcomes with include all-cause mortality, cardiovascular and infection related morbidity and mortality, health-related quality of life (QoL), cost-effectiveness and environmental impact. Basleine data will be collected by research personnel, but all follow up data will be collected continuously by the Registry from renal electronic health records, linkage to health care databases and patient questionnaires. Sample size The trial is powered to be able to detect a clinically meaningful 25% reduction in the composite primary end-point (HR 0.75) based on 65% of participants experiencing this end-point over a median of 3 years follow up. To optimise recruitment and avoid excluding eligible patients because they are already participating /want to participate in other trials, an additional adjustment has been made that assumes up to half of patients in both groups will take part in another trial. Adjustment has also been made anticipating cross-over between arms (15% from HD to HDF & 5% from HDF to HD). The number of events required to detect this difference with 90% power and a two-sided 5% significance level is 801, which requires 1348 participants in total. To allow for 10% loss to follow-up, we require 1527 participants and will recruit 1550. (See Section 6.7 in the detailed project description for details.) Project timetables and recruitment rate Following set-up in months 1-6, recruitment will begin in 20 sites over 18 months (months 7-24), i.e. 78 patients per site. Participation is estimated at 30% of eligible patients initially, increasing to 40% after 4 months with Quintet Recruitment Intervention (2). Participants will be followed through the UK Renal Registry to month 56 (minimum 2 years 8 months, median 3 years) with analysis and write up in months 57-60.

Lay abstract: Aim of the research To see whether removing and replacing 21 or more litres of fluid from the blood at the time of a standard dialysis treatment reduces death or hospitalisation from cardiac events or infections in people with kidney failure. Effects on quality of life, admission to hospital, symptoms, infection rates and costs will also be examined. Background to the research Most people with kidney failure need blood cleaning treatment (haemodialysis) 4 hours 3 times a week up at a hospital/ clinic. This is for the rest of their life unless they are fit to receive a kidney transplant. Survival and quality of life on haemodialysis are poor. The addition of filtration (the removal and replacement of fluid) to regular haemodialysis (which allows toxins to leave the blood with minimal fluid removal/ replacement) is known as haemodiafiltration. This does not noticeably change the dialysis procedure as far as the patient is concerned – it is still 4 hours 3 times a week – it just requires changes in equipment and nurse practice. It does however require a greater volume of high quality water. By removing toxins more effectively, haemodiafiltration may improve survival, especially if high volumes are used (i.e. more than 21L of water removed and replaced per session). On the downside, such volumes of filtration could remove essential proteins or introduce toxins or infections from the water supply. We therefore need to establish if haemodiafiltration results in benefits to patients, is safe and justifies any additional financial and environmental (e.g. water) costs. Design and methods used This study will randomly allocate patients already on dialysis in one of 20 centres in the UK to either continue on haemodialysis or switch to haemodiafiltration. A research nurse will collect the initial clinical information. All follow-up will be carried out using data already routinely collected by the UK Renal Registry or by linking with other heath care databases. Quality of life information will also be collected by the Registry using paper and electronic forms using methods it has developed for routine collection. Recruiting to this trial may be difficult if clinicians, nurses, and patients have strong preferences. These views may be based on clinical judgement or anecdotal experience. Interviews will be carried out and conversations studied in the preparatory and recruitment stages of the study. Potential or actual barriers to recruitment will be identified and strategies to optimise recruitment developed. This may include pre-emptive design of study materials, training and delivery of feedback while recruitment is underway. Patient and public involvement The topic for this registry trial has been discussed and selected by patients on the Registry’s Patient Council and a local kidney patient association. Both groups involve about 15-20 dialysis and former dialysis (transplant) patients. While quality of life is important, the current lack of scientific evidence that quality of life improved with haemodiafiltration was thought to be a risk to the success of the trial. Patients therefore wanted the study to focus on survival and life-threatening hospital admissions, but also look at quality of life, safety and environmental impact. Dissemination Findings from the research will be made public through patient newsletters, social media and patient meetings. They will also be written up in research journals and presented at conferences.

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