Title: Randomised Evaluation of Sodium Dialysate Levels on Vascular Events_x000D_ (RESOLVE).
Funder: Department of Health and Social Care

Abstract: Each year, 8000 people in the UK suffer kidney failure and start dialysis. Dialysis sustains life, but at enormous cost, both in terms of health care spending but more importantly in terms of poor quality of life and drastically shortened life expectancy. The most common form of dialysis, haemodialysis, cleans the blood and removes excess water, but must be performed three times a week. It is a difficult treatment, with many patients continuing to suffer from excess fluid build-up, swelling, shortness of breath and fatigue. In addition, build-up of salt (sodium) may contribute to the high rates of heart attacks, strokes, and heart failure that affect people receiving long-term dialysis._x000D_ _x000D_ The Randomised Evaluation of Sodium dialysate Levels on Vascular Events (RESOLVE) study aims to improve the lives of people on haemodialysis with a simple change in dialysis machine settings. At most dialysis centres, the dialysate sodium (the amount of salt in the fluid that washes the blood) is set at between 135mmol/l and 142mmol/l and all people treated at that centre receive the same level. Small studies suggest that sodium levels closer to the lower end of this range (closer to 135mmol/l) may increase the removal of excess salt from the body and reduce fluid build-up. However, these same studies also suggest that levels closer to the upper end of the range (142mmol/l) may make the dialysis procedure more stable and lower the chance of blood pressure dropping during the dialysis session, improving the tolerability of dialysis and potentially avoiding ‘stunning’ effects on the heart. Reduced fluid build-up and avoiding stunning are both thought to reduce the risks of heart disease and strokes in people receiving haemodialysis therapy. Both higher and lower levels may thus be beneficial – but what level should a dialysis centre choose? The RESOLVE study will determine if a lower or higher dialysate sodium setting is preferable in terms of improving heart health and life expectancy. _x000D_ _x000D_ The RESOLVE study will randomly allocate 100 dialysis units across the UK to a default dialysate sodium of either 137mmol/l or a dialysate sodium of 140mmol/l for approximately 3 years. Using information from the NHS and the UK Renal Registry, the number of people at each centre suffering a heart attack, stroke, heart failure, hospitalisation and death will be tracked. The results of the study will determine if the higher or lower dialysate sodium is superior._x000D_ _x000D_ The RESOLVE study is a simple, innovative and collaborative quality assurance study drawing on information already collected in everyday practice. It places no burden on people receiving dialysis as no extra procedures are required beyond considering participation. As a randomised study, it will provide reliable evidence and allow hospitals to ascertain which of these two standard practices is best. Patients will benefit as the best practice will be adopted everywhere. The RESOLVE study is currently active at 149 dialysis units in 5 countries with over 15,000 participants, and with another 165 units preparing to participate. We seek funding to give UK dialysis patients the opportunity to become involved. The UK contribution will be crucial to the overall success of the RESOLVE study. At the end of the project, putting the lessons learned into practice will be free and immediate, with benefits for tens of thousands of people in the UK and millions receiving dialysis around the world.

Lay abstract: Research question_x000D_ Does a lower unit default dialysate sodium of 137mmol/L, compared to 140mmol/L, result in fewer cardiovascular events or improve survival in haemodialysis recipients? _x000D_ _x000D_ Background_x000D_ People with chronic kidney failure receiving haemodialysis suffer high rates of death and cardiovascular events. Sodium retention, hypertension and fluid overload are important mediators of morbidity and mortality in this population. Most haemodialysis units use a default (or standard) dialysate sodium concentration ranging from 135 to 142mmol/L. A lower dialysate sodium concentration improves sodium removal, but at the cost of increased intradialytic haemodynamic instability. Few randomized studies have investigated this question, and none were powered for clinically relevant outcomes such as cardiovascular events, hospitalization or mortality._x000D_ _x000D_ Aims and objectives_x000D_ To compare the risk of a composite of acute myocardial infarction (AMI), stroke, or all-cause mortality in adult maintenance haemodialysis patients dialyzing at units with a lower default dialysate sodium of 137mmol/L, compared to those with a higher default dialysate sodium of 140mmol/L, in a pragmatic cluster randomized trial._x000D_ _x000D_ Methods_x000D_ One hundred dialysis units, managed by 35 trial sites, in the UK will be randomized to use a default dialysate sodium of 137mmol/L or to use 140mmol/L. Follow up and outcomes on all patients dialyzing at these units, or joining during the study period, will be ascertained from administrative (NHS digital) and registry (UK Renal Registry) data. The study will form part of a global cluster randomized study, enrolling a total of 414 units (globally), and an estimated 50,000 participants. The study duration will be defined by reaching 26,910 primary events, providing 90% power to detect a 10% difference in risk of the primary outcome. Patients at each unit will be offered the opportunity to opt-out of use of their data for this study. All other care will follow usual unit policies and procedures, and clinicians responsible for the participating patients will be able to vary individual participant dialysate sodium if a clinical indication arises._x000D_ _x000D_ Timelines for delivery_x000D_ Ethical approval and randomisation of 80% of units by end 2022, remainder of units randomised by end 2023, follow up complete end 2024, publication of primary analysis in 2025, UK-specific substudies to follow in 2025-6._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ As a change in default dialysate sodium is simple to implement and essentially free, this study will have immediate impact. The impact will be global and local. Furthermore, the health economic and secondary analyses of healthcare utilization among UK dialysis patients will provide a unique insight into this burdensome and costly treatment.

Research activity codes: 6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS
Health categories: RENAL AND UROGENITAL