What is already known about this topic and why is it important?

Historically, ‘adequate’ dialysis treatment has been equated with targets for small solute clearance, which has led to ever-increasing dialysis dose to achieve this, but with little attention paid to the alternative approach, this being the optimisation of residual kidney function for as long as possible after commencing treatment. Following the HEMO study, which did not show that further increasing the dialysis dose had a significant impact on survival, the emphasis has switched to volume management. There is a growing body of evidence that poorly regulated volume status, especially when determined from Bioimpedance (BI) devices showing excess fluid in the extracellular space, often coupled with a loss in muscle mass, is associated with poor survival. Equally, there is evidence that strategies employed to increase fluid removal by increasing the dialysis ultrafiltration rate also increase the risk of intra-dialytic hypotension or cardiac stunning, and are also associated with increased mortality. Furthermore, volume depletion is an important risk factor for loss of residual renal function. This dilemma has led to the concept that BI could be used to set target post-dialysis weights that lead to normalisation of fluid status. The maintenance of residual kidney function in patients commencing dialysis is associated with considerable advantages, not least improved patient survival. The CANUSA study found that each 250ml of urine per day increased 2-year survival by 36% in peritoneal dialysis and in the NECOSAD study complete anuria in HD patients increased the relative risk of death 17-fold compared to those with some preserved kidney function. Other benefits include improved wellbeing, better quality of life and less need to remove high fluid volumes during dialysis sessions with its above mentioned risks of intra-dialytic hypotension, cardiac stunning and potentially increased mortality. It is therefore surprising how few clinical trials have focused on interventions to maintain residual kidney function as a key benefit to HD patients – the exception being ultrapure dialysate, which is now standard care. Worse than this, a frequently applied fluid-management strategy is to reduce the post-dialysis target weight until minimal or no anti-hypertensive drugs are required, as evidence that adequate control of volume status has been achieved. Our recent survey of fluid management practice patterns in UK units, indicates that this is still being pursued in the majority of units, despite the risk it poses to residual kidney function by setting in place a continuing vicious cycle of volume depletion, excessive thirst and high inter-dialytic fluid gains. The introduction of BI technology provides clinicians with an opportunity to break this cycle while avoiding the risk of excessive over-hydration. The anticipated benefit to patients would be a change in clinical practice in which a more balanced approach to the bidirectional risks of hyper- and hypovolaemia is taken that is associated with improved wellbeing, fewer dialysis-related symptoms, possibly less dialysis in those commencing treatment in an incremental fashion, and potentially better survival.

The concern that this proposed research will address is that BI technology is being adopted indiscriminately in many units around the world without clear evidence of benefit and a potential risk of harm. Specifically, there is a paucity of studies that show how BI might be used to benefit the patient beyond surrogates such as blood pressure and left ventricular mass, and there is evidence from at least one trial that using BI aggressively in this context, i.e. aiming to achieve volume depletion post dialysis, results in a more rapid loss of residual kidney function. It is also of note that dialysis regimes employing increased treatment times, such as those investigated by the Frequent HD Trials Network, found that prolonged nocturnal treatments that are more likely to lead to volume depletion resulted in accelerated the loss of residual kidney function. The relative preservation of residual kidney function in peritoneal dialysis patients, who unlike HD patients are not rendered hypovolaemic after each dialysis session, is likely in part to explain the better early survival observed in patients on this modality. If this adjusted survival disadvantage for HD patients – 10-20% during the first 2 years of treatment – could be closed by better preserving residual kidney function, many lives would be extended. There is therefore a pressing need to undertake studies that focus on surrogates with clear patient benefit, such as residual kidney function, that also ensure that the risks of excessive volume depletion are avoided.

How will you carry out your study?

As a prospective, multicentre randomised controlled trial to determine if incorporation of bioimpedance into the setting of the post dialytic weight reduces loss of residual kidney function in incident centre-based HD patients, with the potential to improve clinical outcomes, in particular dialysis related symptoms, hospitalisation and survival. The BISTRO trial has opened for recruitment in April 2017 and closed recruitment in September 2019. It is now in its follow-up stage.

How will you decide which patients are included in your study?

Via inclusion and exclusion criteria, as below:

Inclusion criteria

- Adults aged >18 years, within 3 months commencing centre-based maintenance haemodialysis as an outpatient (Day 0) due to advanced kidney disease CKD stage 5, planned or unplanned, via arterio-venous fistula, graft or central venous catheter (i.e. with or without permanent vascular access) to informed consent date (end of 3 month period).

- Commencing dialysis on any regimen, including having incremental dialysis initiation. All of the following circumstances are permissible:

• Failing kidney transplant patients with no planned transplant surgery date booked
• Permanent transfer from peritoneal dialysis to haemodialysis
• Patients presenting with acute kidney injury that failed to recover – i.e.1st session of haemodialysis as outpatients will be day 0
• Patients on active transplant list with no planned transplant surgery date

- Residual kidney function: For patients who have not yet but are about to start dialysis treatment they should have a daily urine volume > 500ml/day OR a measured mean urea and creatinine clearance ≥3ml/min/1.73m2 determined from a 24 hour collection; for patients already on dialysis they should have a urine volume >500ml during the short inter-dialytic period OR a measured mean urea and creatinine clearance ≥3ml/min/1.73m2, determined from the same timed inter-dialytic urine collections and an average of the post- and pre-dialysis plasma urea and creatinine concentrations.

- Subjects with limb amputations who fit the above criteria

Exclusion criteria

- Unable or unwilling to give informed consent

- Unable to comply with trial procedures, e.g. collection of urine output

- Likely survival prognosis or planned modality transfer < 6 months - Subjects with limb amputations when the foot is not accessible AND it is not possible to take hand to hand measurements

How many patients do you anticipate including?

The trial has recruited a total of 439 participants. It is now in its follow up stage.

For how long will you follow up these patients?

From a minimum of 12 to a maximum of 24 months.

What value will UKRR data add to the project?

The UKRR individual (pseudonymised) level data will be linked to current trial data and to a HES data download. This will information will be part of Health Economics cost benefit analysis, provide greater granularity of dialysis sessions, (e.g. fluid removal, BP), and long-term legacy effects beyond completion of the trial.

What new information will your study generate and how will this benefit patients?

Of 54,000 people in the UK treated with kidney replacement therapies, 24,000 receive centre-based haemodialysis (HD) at an annual tariff of £24,000 excluding additional costs such as travel, drugs, access procedures and inpatient episodes. In this high-cost setting bio-impedance (BI) has the potential to enhance the productivity of HD care by helping clinicians make appropriate and safe treatment decisions as defined by principles underpinning the Department of Health’s QIPP Policy. Preservation of residual kidney function is associated with superior outcomes for HD patients across a number of domains and BISTRO is the first substantial trial to investigate this, including the possibility that BI helps preservation on urine output. BI also has potential to address several of the NHS Outcomes Framework domains, including prevention of premature death, improving outcomes by addressing a number of NICE chronic kidney disease standards such as cardiovascular risk, blood pressure and avoidance of acute illness episodes and enhancing the quality of life for people on dialysis (i.e. long-term condition), and contributing through improved engagement and activation to a more positive patient experience.