Evaluation of the Effect of Cooled Haemodialysis on Cognitive Function in Patients Suffering With End-stage KD

Study Overview
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Brief Summary
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The Investigators aim to perform a feasibility study that will inform the development of a definitive, fully powered, randomised, controlled clinical trial in the future. The main hypothesis that would be tested in this future trial is that patients treated with regular conventional haemodialysis will have a lesser decline in cognitive function and a better quality of life over one year by using cooler dialysis fluid at 35°C, versus a standard dialysis fluid temperature of 36.5°C. This also should reflect in improvements in their abilities for activities of daily living and therefore, reduce carers' burden. If successful the treatment could be universally applied at no extra cost.

Detailed Description
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Patients with End-Stage Kidney Disease (ESKD) need haemodialysis to remove excess toxins and fluid from the body and maintain life. They also must restrict their fluid intake, take a median of 19 medications and follow a special diet1. In the UK, 26 000 patients receive haemodialysis at a hospital three times a week for around 4 hours at a yearly cost of £636 million. The numbers needing haemodialysis are rising by 7% per year due to an increase in ageing, diabetes, obesity and hypertension. The best form of treatment for kidney failure is kidney transplantation, but there is a shortage of organ donors with older people being least likely to receive a kidney transplant. The average age of dialysis patients in the UK is 65 with 4-year survival expectancy less than 40% - which is worse than for most cancers. The three most common causes of death are cardiovascular disease, infections and cancer with the greatest mortality in the first three months of starting dialysis. Haemodialysis is a huge burden for patients and their family or carers. Most endure unpleasant dialysis-related symptoms and reduced quality-of-life with high rates of depression, cognitive impairment, hospital admissions and social isolation. Unsurprisingly, dialysis patients value quality-of-life more than life expectancy. Several medications currently used at considerable cost to improve survival and quality-of-life have shown no benefit. High rates of cognitive impairment in dialysis patients are poorly understood Increasing severity of Chronic Kidney Disease (CKD) is associated with a graded increase in prevalence of cognitive impairment and decrease in brain perfusion independent of vascular risk factors. Diagnostic methods vary but recent reviews summarise at least moderate cognitive impairment in 30-70% of dialysis patients. Cognitive impairment in haemodialysis patients is independently associated with higher rates of depression and mortality. To date, no interventions are proven to slow cognitive decline and this poorly understood association was recently reviewed. Co-segregation of atherosclerotic risk factors, cannot entirely account for excess risk. There are multiple factors CKD and haemodialysis specific factors including oxidative stress, malnutrition and inflammation. Haemodialysis allows accumulation of several neurotoxins that reduce brain perfusion and blood-brain barrier integrity. Intradialytic hypotension is implicated in excessive cognitive impairment Haemodialysis involves cycles of removing varying volumes of fluid, electrolytes and toxins that accumulate between treatments. Hypotension partially results from fluid removal rates exceeding plasma refill rates. Ubiquitous left ventricular hypertrophy and aortic stiffness further lower the threshold for haemodialysis to inflict recurrent multi-organ ischemia-reperfusion injury. Haemodialysis might cause worsening of cognitive impairment by inducing haemodynamic instability, fluid shifts, cerebral ischaemia or cerebral oedema. Intradialytic hypotension is common affecting 30-40% of treatments and is consistently associated with at least a 30% increase in mortality and reduced quality-of-life. These dynamic changes in Blood Pressure (BP) and perfusion might be associated with altered cognition but the data are sparse and conflicting, possibly reflecting differences in study design; such as different methods and timings for cognitive assessments. Several small studies show cognitive function is best immediately before haemodialysis, worse during haemodialysis and improves the day after with a possible link to sudden fluid removal . Our own experience, using the Montreal Cognitive Assessment in 100 haemodialysis patients also showed cognitive decline during haemodialysis. A recent retrospective study of 121,000 patients report that peritoneal dialysis is associated with a 26% lesser-adjusted risk of newly diagnosed dementia compared to haemodialysis. One plausible mechanism of that benefit is that peritoneal dialysis does not cause sudden reductions in blood pressure. Absence of intradialytic hypotension is emerging as a novel treatment goal 30. One possible way to prevent hypotension is to increase treatment time or frequency to allow more gentle fluid removal. A clinical trial of 245 patients showed 6 times weekly haemodialysis improved physical health scores whilst reducing intradialytic hypotension, fluid gains and left ventricular mass. A preliminary repeated measures study of 12 patients showed extended overnight haemodialysis was associated with improved cognitive function scores. These data are encouraging but come at the expense of increased treatment complications, cost and are currently unfeasible in most UK centres and worldwide. The use of cooler dialysate (34-35°C) to prevent intradialytic hypotension was first described in 1981. However, this therapy remains greatly underused because of perceptions about thermal symptoms. Cooler dialysate doesn't necessarily lower core-temperature and it is thought to prevent intradialytic hypotension by preventing a rise in core temperature and subsequent systemic vasodilation. A recent systematic review of cooler dialysate analyzed 26 trials in 484 patients. Compared with standard temperature dialysis, cooler dialysis reduced the rate of intradialytic hypotension by 70% (95% CI, 49-89%). Confidence in the estimates was limited by small sample sizes, attrition and a lack of appropriate blinding with no trial reporting long-term outcomes. A recent RfPB grant funded pilot clinical trial in 38 patients, showed lower temperature of dialysis fluid prevented the progression of ischemic brain white matter changes after one year which appeared to be linked to hemodynamic stability. The same trial also reported cooler dialysis fluid improved cardiac structure and function . The effects of cooler dialysate on cognitive impairment, quality-of-life and illness burden have not been robustly tested or are not known. How well tolerated cooler dialysis fluid is also not well reported. A recent editorial called for larger trials using this cheap and universally applicable intervention that focused on these patient important outcomes. The current low usage of cooler dialysate in the UK affords an opportunity to definitively test this simple modification to haemodialysis as a potential intervention to prevent cognitive dysfunction and quality-of-life. There are several uncertainties around study design of a definitive trial of cooler dialysate and cognitive impairment, hence the need to formally assess these in a feasibility study.

Official Title
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Evaluation of the Effect of Cooled Haemodialysis on Cognitive Function in Patients Suffering With End-stage Kidney Disease: Feasibility Study

Conditions
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Cognitive Impairment

Intervention / Treatment
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* Procedure: Lower Temperature Group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is aged >18 years. Receiving haemodialysis three (3) times per week for ESKD, for at least 3 months Having proven mental capacity to understand the study and give informed consent Exclusion Criteria: Established diagnosis of dementia in a memory clinic or specialised service. Receiving Acetylcholine Esterase Inhibitors Receiving antipsychotic or antidepressants unless stable on treatment for at least 6 weeks Current participation in a study of an investigational medicinal product Inter-current infection An operation date for a living donor kidney transplant within the period of the trial Patients expected to survive less than 1 year according to the treating nephrologist Patients prone to intra-dialytic hypotension or cardiovascular instability during haemodialysis according to the treating nephrologist Patients who are currently taking triptans, dopamine antagonists, tramadol, sedative and opioid analgesics Patients who have a known diagnosis or have other psychiatric conditions, including severe depression, bipolar affective disorder, severe anxiety, panic disorder, substance misuse or psychosis. Currently involved in another intervention study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The control group will be at the standard dialysate temperature of 36.5 °C (which is the standard of care in the sites), 3 times a week for 12 months. In the intervention group, patients will receive haemodialysis with a dialysate temperature of 35 degree centigrade. The intervention group will start off using a dialysate temperature that is 36 °C. Thereafter the dialysate temperature will be reduced every two week by 0.5 °C until 35 °C or the lowest tolerated temperature reached. Patients who would fail to tolerate the temperature of 35 °C, the lowest tolerated temperature will be carried over to the end of the study. The intervention group is split into 3 brackets, stratified by age group (patients under 55 years of age, 55-75 and above 75). A third group will also be recruited, but not randomised, consisting of the primary carers (family, friends, etc) of the patients in the other two group to measure the burden they feel in caring for a patient with renal problems.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control Group<br>The control group will be at the standard dialysate temperature of 36.5 °C (which is the standard of care in the sites), 3 times a week for 12 months | |
| Experimental: Lower Temperature Group<br>These patients will receive haemodialysis with a dialysate temperature of 35 degree centigrade. The intervention group will start off using a dialysate temperature that is 36 °C. Thereafter the dialysate temperature will be reduced every two week by 0.5 °C until 35 °C or the lowest tolerated temperature reached. Patients who would fail to tolerate the temperature of 35 °C, the lowest tolerated temperature will be carried over to the end of the study. | Procedure: Lower Temperature Group<br>* Dialysate temperature of 35 degree centigrade. The intervention group will start off using a dialysate temperature that is 36 °C. Thereafter the dialysate temperature will be reduced every two week by 0.5 °C until 35 °C or the lowest tolerated temperature reached.<br>|
| No Intervention: Caregivers<br>Patients, who consent for the study, will be asked to identify the most suitable carer to participate in the study who could be approach in person, over the phone or by post as deemed suitable by the research team and convenient by the carer. Patient's permission to contact their identified carer will be recorded. Carers of consenting patients will be approached in the same manner as above after obtaining patients consent to contact their carers. Patients will still be able to take part in the study even if their carer declines consent. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigation of lower temperatures of dialysis and cognitive decline | To assess whether lower temperatures of dialysis fluid prevents the decline in cognitive function via utilisation of the Montreal Cognitive Assessment (MOCA) v7.2. The MOCA includes activities relating to Visuospatial / Executive (score out of 5); Naming (score out of 3); Memory (score of of 10); Attention (score out of 6); Naming (score out of 3) Abstraction (score out of 2); Delayed Recall (score out of 5) and Orientation (score out of 6). 1 point is given for each correct answer, and a higher score represents normal cognitive function, whilst lower scores represent possible cognitive decline. A total of 30 points can be achieved. | 1.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of intradialytic hypotension | To measure the frequency of intradialytic hypotension as an explanatory outcome | 1.5 years | 
| Recruitment rates | To measure recruitment to inform the design of a larger clinical trial | 1.5 years | 
| Attrition Rates | To measure attrition rates to inform the design of a larger clinical trial | 1.5 years | 
| Non-recruitment reasons | To record reasons for non-recruitment and study attrition to inform the design of a larger clinical trial. | 1.5 years | 
| Depression rates | To measure depression in targeted population to be able to estimate exclusion rates of patients who would be suffering from Depressive Pseudo Cognitive Impairment from the future trial | 1.5 years | 
| Outcomes from Burden questionnaire to assess burden in patients and carers | To assess the burden of study-related interventions and assessments on patients and carers | 1.5 years | 
| Cognitive battery outcome | To assess the administration, suitability and adherence of the chosen cognitive method for patients, especially those from ethnic minorities | 1.5 years | 
| Carers Burden assessment | To assess the administration and suitability of the chosen method for measuring carers' burden in this group. | 1.5 years | 
| Quality Of Life outcomes | To assess the administration and suitability of the Assessment of Quality of Life 6 (AQoL-6) for quality of life measures and activities of daily living in haemodialysis participants. The AQoL-6 is a likert scale ranging from 'Never' (=1), 'Rarely' (=2) 'Some of the Time' (=3) 'Often' (=4) and 'Nearly All of the Time' (=5) - there are 20 items so a total score of 100 can be obtained. A score of 100 represents very poor quality of life, where as a score of 0 indicates very good quality of life. | 1.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haemodialysis, Kidney Disease, Mental Health, Cognitive Impairment