Identifying Therapeutic Hemodialysis Targets Through Cerebrovascular Reactivity; RESPIRACT 2

Patients with chronic kidney disease receiving hemodialysis (HD) suffer from higher rates of brain vascular disease and decreased cognition than the general population. One way to assess brain vascular health and response to HD stress, is to test how the brain's blood flow responds to carbon dioxide (CO2) to measure Cerebrovascular Reactivity (CVR). In this study, the investigators will compare the magnitude and speed of the brain's blood flow response to a step-wise change in CO2 with hemodynamic, dialysis, and cognitive parameters. The goal of the study is to establish therapeutic targets that can be altered during the dialysis procedure to protect the brain from HD stress.

This is a follow-up study previously conducted by our lab group titled: "Hemodialysis Patients Have Impaired Cerebrovascular Reactivity to CO2 Compared to Chronic Kidney Disease Patients and Healthy Controls: A Pilot Study". It was determined that individuals who receive hemodialysis (HD) exhibited significant differences in their Cerebrovascular Reactivity (CVR) when compared to both healthy controls, and patients with kidney disease not yet on HD.

In this study, the aim is to determine if the degree of cognitive impairment is related to the degree of impaired brain blood flow response in order to determine therapeutic targets that may be altered during the dialysis procedure in order to preserve cognitive functioning in the patient's receiving HD, building upon the previous feasibility study.

This study will require 4 assessments over the course of 2 dialysis treatments (2 assessments per dialysis treatment \[ie. pre and post HD assessments\]). The subsequent dialysis treatment assessments will be completed in the course of a month to mitigate learning effects with regards to the cognitive assessment.

The study assessment includes:

1. Measuring cerebrovascular reactivity (CVR) before and after hemodialysis (HD):

   CVR will be measured using two specialized devices: RespirActTM in combination with Transcranial Doppler before and after an HD session. Specifically, the RespirActTM device is an automated breathing circuit that uses a gas bladder to control and deliver carbon dioxide (CO2). It has various gas cylinders that are used in order to obtain the correct increase in CO2 in each patient. This type of gas manipulation was selected because it is a more accurate measure of CVR, while also reducing between-subject variability.

   Transcranial Doppler is used in conjunction with the RespirActTM to allow insight into cerebral blood flow, by measuring the middle cerebral artery's blood flow velocity.

   During the CVR measurement, the RespirActTM will be connected to a facemask, and the Transcranial Doppler will be positioned on the trans-temporal window.

   During the diagnostic assessment there will be three steps:
   1. Baseline: Measurement of CVR and hemodynamics with no CO2 stimulus applied. Will take approximately 5 minutes.
   2. CO2 Diagnostic Assessment: Inducement of hypercapnia by raising baseline CO2 levels to 5-10 mmHg above baseline. This causes controlled stress, allowing insight into how the brain responds to stress. This increase will be sustained for approximately 5 minutes.
   3. Return to baseline: CO2 stimulus is removed and the patient is monitored until levels return to baseline. Will take roughly 5 minutes.

   Note: time intervals may be shortened or lengthened if the patient feels uncomfortable, asks to cease the application of CO2, or needs longer to return to baseline.
2. Identification of potential hemodynamic and dialysis targets:

   By investigating hemodynamic and specific HD parameters, identifiable targets may be ascertained that can be used to protect the brain during HD by investigating CVR before and after an HD session. To measure hemodynamic parameters the Finapres NOVA, a finger cuff device that allows for non-invasive real-time capture and recording of heart rate, blood pressure, and mean arterial pressure will be implemented. Blood samples will also be collected pre and post HD (done through the dialysis access point), which will give insight into potential dialysis targets such as sodium, calcium, magnesium, acid-base balance, and inflammation with respect to CVR.
3. Determining how CVR, cognitive impairment, and the HD process are related:

By performing a cognitive assessment before and after the HD treatment, it will allow insight into how the brain is affected by the HD process, along with how it is related to CVR. The cognitive assessment battery selected is as follows:

1. A web based cognitive assessment: The Cambridge Brain Sciences (CBS) is a computerized cognitive assessment that can be self-administered. The version that entails 6 tasks which primarily measure verbal ability, short term memory, and reasoning skills has been selected for this study. The CBS will be used in conjunction with a dementia screening tool Montreal Cognitive Assessment (MoCA), as earlier work demonstrated that CBS helps screening tools differentiate cognitive impairment while providing a more comprehensive insight into cognitive impairment, particularly with individuals who demonstrated borderline impairment.
2. A traditional screening tool: The MoCA is a quick dementia screening instrument that can detect mild cognitive impairment by assessing different cognitive domains, such as attention, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation, but still gives an overall assessment of global cognitive function. The MoCA has a maximum score of 30 with traditionally scores below 26 (1 standard deviation (SD)) indicating mild cognitive impairment (MCI), however a cut-off of 1.5SD for a measure of MCI, which has been derived from the diagnostic criteria from the Cardiovascular Health Cognition Study and the Mayo Clinic Study of Aging.
3. A commonly used attention and executive function assessment in those with kidney disease: The Trails Making Test (TMT) is composed of 2 subtests: TMTA and TMTB. In the TMTA the patient is asked to connect the numbers 1 through 25 as quickly as possible. It is a measure of visuomotor tracking, scanning, and attention. Alternatively, the TMTB adds an extra layer to the TMTA in that the patient is now asked to alternate numbers and letters (1-A-2-B-3-C etc.) which requires thinking flexibility and mental shifting and executive function.

In total this assessment should take 45 minutes to complete each time.

Eligibility Criteria:
Inclusion Criteria:

* Patients ≥ 18 years old, receiving hemodialysis treatment at least 3 times per week at a London Health Sciences Centre facility
* English proficiency

Exclusion Criteria:

* Mental incapacity to consent
* Declined to participate
* Severe chronic obstructive lung disease (COPD) /Asthma
* History of cerebrovascular accident (stroke, transient ischemic attack)
* Previous neurosurgery
* History of carotid stenosis or carotid surgery
* History of vasculitis
* Documented Dementia
* Pregnancy
* Not fluent in English