Clinical trial NCT03645733: Evaluation of the Effect of Cooled Haemodialysis on Cognitive Function in Patients Suffering With End-stage KD
Official title: Evaluation of the Effect of Cooled Haemodialysis on Cognitive Function in Patients Suffering With End-stage Kidney Disease: Feasibility Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cognitive Impairment
Keywords: Haemodialysis
Kidney Disease
Mental Health
Cognitive Impairment
Lead sponsor: Heart of England NHS Trust
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research, United Kingdom
First posted: 2018-08-24
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Patient is aged \>18 years.
2. Receiving haemodialysis three (3) times per week for ESKD, for at least 3 months
3. Having proven mental capacity to understand the study and give informed consent

Exclusion Criteria:

1. Established diagnosis of dementia in a memory clinic or specialised service.
2. Receiving Acetylcholine Esterase Inhibitors
3. Receiving antipsychotic or antidepressants unless stable on treatment for at least 6 weeks
4. Current participation in a study of an investigational medicinal product
5. Inter-current infection
6. An operation date for a living donor kidney transplant within the period of the trial
7. Patients expected to survive less than 1 year according to the treating nephrologist
8. Patients prone to intra-dialytic hypotension or cardiovascular instability during haemodialysis according to the treating nephrologist
9. Patients who are currently taking triptans, dopamine antagonists, tramadol, sedative and opioid analgesics
10. 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.
11. Currently involved in another intervention study

Primary outcomes:
measure: Investigation of lower temperatures of dialysis and cognitive decline
timeFrame: 1.5 years
Secondary outcomes:
measure: Frequency of intradialytic hypotension
timeFrame: 1.5 years
measure: Recruitment rates
timeFrame: 1.5 years
measure: Attrition Rates
timeFrame: 1.5 years
measure: Non-recruitment reasons
timeFrame: 1.5 years
measure: Depression rates
timeFrame: 1.5 years
measure: Outcomes from Burden questionnaire to assess burden in patients and carers
timeFrame: 1.5 years
measure: Cognitive battery outcome
timeFrame: 1.5 years
measure: Carers Burden assessment
timeFrame: 1.5 years
measure: Quality Of Life outcomes
timeFrame: 1.5 years
Other outcomes:
Locations:
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: West Midlands
Study officials:
affiliation: University Hospital Birmingham NHS Foundation Trust
name: George Tadros, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dasgupta I, Odudu A, Baharani J, Fergusson N, Griffiths H, Harrison J, Maruff P, Thomas GN, Woodhall G, Youseff S, Tadros G. Evaluation of the effect of Cooled HaEmodialysis on Cognitive function in patients suffering with end-stage KidnEy Disease (E-CHECKED): feasibility randomised control trial protocol. Trials. 2020 Sep 30;21(1):820. doi: 10.1186/s13063-020-04725-0.