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Current Research Studies

Evaluation of kidney medullary sodium content using sodium-23 magnetic resonance imaging to understand and predict diuretic resistance

 

Principal Investigator: Dr. Christopher McIntyre

 

Background: Heart failure leads to fluid retention, breathlessness and fatigue and is often associated with kidney failure; this is important because the interaction with kidney failure makes heart failure worse. When the kidneys fail, patients eliminate less water and salt that end up accumulating in the body, increasing the risk of fluid retention and its side effects (i.e. swelling). Diuretics such as Furosemide, also called Lasix, work on your kidneys by increasing the amount of water and salt elimination through your urine. Diuretic resistance occurs when you don’t get enough diuresis (production of urine), thereby failing to achieve a decrease in swelling caused by fluid retention despite being given the maximal dose of diuretic. When there is no or minimal response to diuretics, higher doses of diuretics are often necessary. Diuretic resistance makes it much more difficult for patients to manage water and salt well. At the moment, we have no way of predicting how heart and kidney failure patients will respond to diuretics, and how high a dose they will need. We plan to measure salt content in the kidneys with MRI in order to study the difference in salt content between heart failure patients who respond to diuretics and those who do not respond to diuretics.

 

This study will tell us whether kidney sodium content can predict diuretic response in heart failure, and whether sodium MRI can be routinely employed to improve management of diuretic therapy in the future. Seven participants have been scanned to determine the feasibility of the hardware being used. We are now validating that what we have seen in our preliminary work is visualized in patients.

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

Preclinical investigation of the effects of hemodialysis on microvascular perfusion

 

Principal Investigator: Dr. Christopher McIntyre
Co-Investigator: Dr. Barry Janssen

 

Background: Patients suffering from kidney disease rely on hemodialysis (HD) for renal replacement therapy. It provides life-saving treatment for kidney failure for around three million people globally and typically consuming 5-10% of the total healthcare budget. Unfortunately, the quality of life in patients is poor and mortality is high, with cardiovascular disease (CVD) being the leading cause of death. Although this high CVD mortality in renal patients usually directly results from a higher prevalence of an underlying cardiovascular pathology, research has shown that this is further compounded by the additional physiological stress from the HD procedure itself. Research shows that HD induces a maldistribution of blood flow in the microcirculation of tissues, leaving significant areas in the tissues devoid of blood flow. As such, HD can induce recurrent and cumulative ischemic injury to vital organs like the heart, brain, liver and kidney, resulting in cardiac failure and arrhythmia, cognitive impairment, reduced toxin clearance and a reduction of residual renal function, respectively.
 
Investigation of the microcirculation requires the use of intravital microscopy to observe the flow of blood of the small capillaries in the tissue. We developed a small animal model that allows us to investigate blood flow during an HD procedure using customized mini-dialyzers.

The versatility of the small animal model allows for a detailed pre-clinical investigation of how HD affects microvascular blood flow in tissues. With this model we will investigate how different treatment procedures, new dialyzer designs, membrane materials, or new pharmacological treatment strategies can affect the efficiency of HD. Moreover, in light of the recent COVID19 pandemic, we investigated whether modification of the HD procedure can be used to mitigate the hyperinflammatory response. For results of that study, please see Initial evaluation of extracorporeal immunomodulatory therapy for the treatment of critically ill COVID-19 infected patients | Scientific Reports (nature.com).

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

Fluid intake after hemodialysis: Investigating the relationship between time and weight gain during the interdialytic interval

 

Principal Investigator: Dr. Christopher McIntyre

 

Background: Interdialytic weight gain determines how much fluid (ultrafiltration) has to be removed during each hemodialysis session. High ultrafiltration volumes stress the organism and lead to a higher risk of death. Thirst is the main driving factor of interdialytic weight gain, and thirst is mainly driven by salt intake, molecules that increase blood tonicity (such as sugar in diabetics) and fluid loss (such as in dehydration and blood loss). It has been speculated that fluid loss during hemodialysis could increase the sense of thirst immediately following dialysis, but this statement requires further evidence. 

Hypothesis: We hypothesize that a significant portion of interdialytic weight gain occurs in the first hours following hemodialysis to compensate for the fluid loss. Therefore, in this observational study, we will have a sample of approximately 20 non-diabetic patients, on standard hemodialysis, self-monitor their weight gain and blood pressure during the intervals between hemodialysis sessions for a week. Demographics, anthropometrics, questionnaires, hemodialysis prescription and treatment information will also be recorded. Study participants will be provided a digital scale and a blood pressure monitor, and will be asked to prospectively record weight changes and blood pressure four times a day for a week.

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

 

Improving the outcomes of peritoneal dialysis (PD) catheter insertion

 

Principal Investigator: Dr. Arsh Jain

 

One in five patients on peritoneal dialysis (PD) will experience a PD catheter complication in the first 6 months following insertion. The goal of this research study is to improve the outcomes of PD catheter insertions and to maximize the safe and effective use of PD therapy.

 

Specific aims of this study are:

1) To determine if the method of insertion is associated with PD catheter complications

2) To determine what operator and center characteristics and practices are associated with insertion-related complications, with a focus on operator volume

3) To achieve expert consensus on optimal practices for PD catheter insertion and care using a data driven approach

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

Sodium assessment of the cardiac tissue using sodium magnetic resonance imaging

 

Principal Investigator: Dr. Christopher McIntyre

 

Background: Chronic kidney disease (CKD) is extremely prevalent worldwide and affects around 10% of people living in developed health economies. Patients with CKD have damaged kidneys that are not able to filter their blood as well as healthy individuals. The most critical ion that is excreted and regulated by the kidneys is sodium. In patients with CKD, their damaged kidneys can cause inadequate removal and accumulation of sodium. This has been found to occur in the heart muscle and could drive the development of fibrosis which contributes to heart failure.

Using sodium magnetic resonance imaging (MRI), it is possible to measure the sodium content in the cardiac tissue of patients with kidney disease.

 

Study Objective: We will investigate whether the elevated levels of sodium in patients with kidney disease is also present in their cardiac tissues, and if so, whether this relates to cardiac abnormalities. Cardiac sodium MRI images of healthy volunteers, hemodialysis patients, and CKD patients, stage 1-5, will be analyzed for sodium content. This sodium information will then be compared to the biomarkers of fibrosis measured from each patient’s proton MRI images in order to establish a possible correlation. This research has the potential to precede additional studies that may investigate the effect of diuretics on the cardiac tissue of kidney disease patients.

 

Hypotheses: 

  • CKD and HD patients have larger cardiac sodium deposits compared with healthy individuals

  • Cardiac sodium deposits are correlated with left ventricular mass and cardiac T1 and T2 times

  • Cardiac sodium deposits are correlated with male sex, older age, dialysate composition, serum biomarkers of kidney function, inflammation, microvascular and cardiac function

 

Study Design: This is a single center observational pilot study

 

Once recruited, participants will undergo one study visit (on a non-dialysis day for hemodialysis patients). Each study visit will include: blood pressure and heart rate measurements, measurement of advanced glycation end products (AGEs), blood work, a spot urine test, a sodium intake questionnaire, a single time to recovery question, a proton MRI scan, and an MRI scan of the cardiac tissue detecting sodium content.

 

Study Population: We will include healthy individuals with no known kidney impairment, and patients with various stages of chronic kidney disease

Intervention: MRI scan (1H & 23Na) of the kidneys

Primary Outcome: Difference in cardiac sodium signal between:

  • Chronic in-center hemodialysis patients

  • CKD stage 3-5 patients

  • Sex and age-matched healthy adult controls

Secondary Outcomes: Correlation between cardiac sodium signal and:

  • Demographics (i.e. Age, Sex)

  • Dialysate composition (in HD patients)

  • Left ventricular mass

  • Left ventricular volume

  • Left atrial volume

  • Septal T1 and T2 times

  • Total body water and extracellular volume (bioimpedance spectroscopy)

  • Biochemistry biomarkers: uremic toxins, inflammatory, cardiac and microvascular biomarkers, serum albumin, estimated glomerular filtration rate (cystatin C) and high-sensitivity troponin T

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

Kidney sodium functional imaging: evaluation of kidney medullary sodium content using 23Na MRI in kidney disease

 

Principal Investigator: Dr. Christopher McIntyre

 

Background: Maintenance of the corticomedullary gradient (CMG) is required for urine concentration and is one of the most important tubular functions allowing humans to live in a warm environment. However, functional tubular parameters to assess direct CMG are lacking. Sodium magnetic resonance imaging (23Na MRI) is a non-invasive tool that has successfully measured direct CMG dynamic changes in healthy volunteers. Because CMG measurement may provide a relevant assessment of tubular dysfunction independently of glomerular alteration, we propose to explore CMG in patients with a large range of kidney disease, from chronic kidney disease to dialysis or transplanted patients.
 

Study Objective: To determine the corticomedullary gradient in patients with different types and levels of kidney disease and provide the first application of renal tubular functional MRI.

Hypothesis: 23Na kidney MRI will provide functional MR of the kidney as a non-invasive tool to describe medullary function in order to improve management of chronic and acute kidney disease.

Study Design: Pilot, cross-sectional, observational study

 

Study Protocol: Once enrolled, participants will undergo one study visit (on a non-dialysis day for hemodialysis patients). The study visit will include: blood pressure and heart rate measurements, measurement of advanced glycation end products (AGEs) using an AGE Reader, blood work, urine collection, 24 hr urine volume test for patients who have had kidney stones, and an MRI scan of the kidneys detecting sodium content.

Study Population: Patients with various stages of chronic kidney disease, transplanted patients, dialysis patients (peritoneal and hemodialysis), patients with autosomal dominant polycystic kidney disease (ADPKD), patients with nephrolithiasis, and healthy individuals with no kidney impairment.

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Intervention: Sodium content measurement in the cortex and medulla with 23Na MRI

Primary Outcome: Exploratory cortico-medullary gradient measurement in a large range of kidney disease by measuring sodium medullary to cortex ratio with 23Na kidney MRI in:

  • Stage 1-5 CKD patients

  • Transplanted patients

  • Dialysis patients (HD and PD)

  • Patients with acute kidney injury

  • ADPKD patients

  • Nephrolithiasis patients (characteristically associated with salt loading)

  • Healthy controls

 

Secondary Outcomes:

  • To evaluate the relationship between sodium medullary to cortex ratio and urinary osmolarity

  • To evaluate the relationship between sodium medullary to cortex ratio and renal function

  • To compare sodium medullary to cortex ratio between native kidneys and transplanted kidneys

  • To compare sodium medullary to cortex ratio between transplanted kidneys and kidney biopsies

  • To evaluate the accuracy to detect acute kidney injury with 23NaMRI

  • To evaluate sodium medullary to cortex ratio in dialysis patients and renal residual function

  • To compare sodium medullary to cortex ratio between healthy controls and patients who have nephrolithiasis

  • To evaluate the ability to measure sodium medullary to cortex ratio in autosomal dominant polycystic kidney disease

  • To determinate sodium medullary to cortex ratio measurement is meaningful in clinical practice

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

Trial of intradialytic cycling as kidney exercise rehabilitation for cardiac stunning in hemodialysis (TICKERS HD)

 

Principal Investigator: Dr. Christopher McIntyre

 

Background: People with kidney failure receiving chronic hemodialysis (HD) suffer from fatigue post treatment, poor functional status, and high rates of cardiac failure and death. Previous work has shown that these outcomes are correlated with recurrent ischemic cardiac injury (myocardial stunning) that occurs during HD treatments. Myocardial stunning, identified by cardiac regional wall motion abnormalities (RWMAs), is common during HD. Intradialytic cycling (during HD) decreases HD-induced stunning, and may improve adverse outcomes associated with stunning. We will use echocardiography (echo) and a validated cardiac biomarker to understand the effects of intradialytic aerobic exercise on myocardial stunning and HD-related symptoms.

Research Question: Compared to current standard of care, does participation in a 12-week aerobic exercise program during HD decrease HD-induced myocardial stunning as measured by the change in number of cardiac RWMAs from baseline to peak HD stress (last 30 minutes of HD)?

Hypothesis: Intradialytic aerobic exercise will provide protection against HD-induced myocardial stunning immediately after starting the exercise program. Furthermore, exercise training for 12 weeks will lead to progressive decline in HD-induced myocardial injury, HD-related fatigue, and symptom burden, and will result in improved cardiac function over time.

Primary Objective: To determine the effect of 12-weeks of intradialytic cycling on HD-induced myocardial stunning in adults on chronic HD.

 

Secondary Objectives:

  • To correlate HD-induced myocardial stunning with high-sensitivity troponin T (hsTnT), a validated biomarker for cardiac injury

  • To characterize the effect of 12 weeks of intradialytic cycling on post-HD fatigue and symptom burden

  • To explore the “off treatment effect” of intradialytic cycling on HD-induced myocardial stunning

  • To gather feasibility data to inform the design of an innovative multi-center clinical trial investigating the effect of exercise during HD on long term cardiac outcomes

 

Study Design: Multi-center, assessor blinded RCT with 1:1 parallel group design, and allocation concealment comparing change in HD-induced myocardial stunning in 80 HD patients participating in 12 weeks of cycling during HD, compared to 80 HD patients receiving standard HD care.

Study Population: All adults receiving chronic HD (3 times/week) at in-center HD units in the 7 participating sites will be eligible.

Intervention: Participants will receive baseline exercise counselling as per controls and then participate in a supervised 12-week intradialytic cycling program.

 

Primary Outcome: Change in HD-induced myocardial stunning measured by change in number of RWMAs at peak HD stress (~30 minutes before the end of HD) from baseline to 12 weeks as measured by intradialytic echo.

 

Secondary Outcomes:

  • Change in pre-HD hsTnT level from baseline to 12 weeks as measured by Roche High-Sensitivity Troponin TTM assay at each site

  • Change in severity of post-hemodialysis fatigue will be assessed by the self-reported answer to the question: “How long does it take you to recover from a dialysis session and resume your normal, usual activities?”

  • Symptom burden measured using the Dialysis Symptom Index Severity Score

  • Exercise capacity measured by Incremental Shuttle Walk Test

  • Change in physical activity behavior patterns assessed using total active minutes per day, as measured by multi-directional accelerometry

  • Assess how exercise training affects HD-related myocardial stunning over time

  • Feasibility data collected will include eligibility, recruitment, adherence to exercise, retention rates and site-specific barriers

 

Results and associated papers will be linked once study is complete and all data is analyzed.

Prospective study of long-term vascular burden in TTP/aHUS patients
 

Principal Investigator: Dr. Susan Huang
 

Background: Idiopathic thrombotic thrombocytopenia purpura (TTP) is a rare, life-threatening disorder characterized by unexplained hemolytic anemia (early destruction of red blood cells) and thrombocytopenia (low blood platelet count). TTP was originally thought to be almost universally fatal; however, treatment with plasma exchange has transformed the disease in terms of survival, with 80% of patients now surviving an acute episode (the short and sudden period of time when a disease is at its worst). Past research has focused on achieving remission and reducing mortality in TTP patients during TTP episodes, but there are few studies that look at the longer-term outcomes of TTP on the body. Previous studies have shown that long-term vascular burden (blood vessel damage over time) is higher in people with TTP, but how these vascular problems develop in TTP patients is not well understood.


The aim of this study is to: understand the structural and functional sequelae of successfully treated idiopathic thrombotic thrombocytopenic purpura (TTP), assess the interaction between treatments and long-term consequences of idiopathic TTP, to distinguish the factors that are associated with macro and microvascular recovering, and to identify the therapeutic opportunities to improve chronic management of idiopathic TTP.


Study Design: A prospective cohort study at the London Health Sciences Centre, Ontario, Canada. We will identify 15 idiopathic TTP patients with the first episode of TTP who are in remission within the last 30 days. They will be followed for 12 months from the time of their remission. All patients will be treated with standard of care plasma exchange therapy at the London Health Sciences Centre, as well as have MRI and CT of the brain and echocardiography completed at various time points during the study.

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

An extension of an interventional study to assess the effect of expanded dialysis (HDx-Theranova) on patient reported symptoms using London Evaluation of Illness (LEVIL)


Study design: Interventional Trial (100 participants - 3 Canadian sites)

 

Background: The accumulation and retention of uremic toxins in chronic kidney disease have been associated with chronic inflammation, cardiovascular disease, high morbidity, and mortality. Conventional hemodialysis can remove small solutes and smaller-sized middle molecules; however, it is not effective in the removal of large middle molecules which are highly indicative of suboptimal outcomes and mortality. There is currently a new class of dialysis membrane that is more permeable than conventional high-flux filters and allows the passage of large middle molecules. This progressive and innovative concept is labelled “expanded” (HDx) with the use of medium cut-off dialyzers. 

 

Hypothesis: We hypothesize that the clearance of large middle molecules will have a direct and translatable effect on patient reported symptoms

 

Primary Objective:

  • Determine if the clearance of larger middle molecular weight toxins using a medium-cut-off dialyzer (HDx- Theranova) effects patient reported symptoms as reported by LEVIL

 

Secondary Objectives:

  • Determine if the clearance of larger middle molecular weight toxins using a medium-cut-off dialyzer (HDx-Theranova) effects cognition and sexual desire in hemodialysis patients

 

Study Protocol: The purpose of this study is to determine the effect of the HDx therapy (Theranova) on hemodialysis patient’s symptom burden, hemodialysis related quality of life, cognition, and sexual desire compared to their usual high-flux dialyzer. Theranova will be used in place of the usual high-flux dialyzer during the patient’s scheduled hemodialysis treatments for 24 weeks. We will be assessing symptom burden using LEVIL where patients self-report their symptoms with at least one hemodialysis treatment each week during the entire study period. Cognition testing, sexual desire, and recovery time will be assessed at baseline (weeks 1-4) and repeated after 24 weeks of HDx therapy (week 28 of the study). 

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

To learn more about our previous studies on HDx (Theranova), please refer to the following papers:

 

Impact of Expanded Hemodialysis Using Medium Cut-off Dialyzer on Quality of Life: Application of Dynamic Patient-Reported Outcome Measurement Tool - ScienceDirect

 

POS-604 MIDDLE MOLECULE CLEARANCE & EXPANDED DIALYSIS: WHAT IS THE IMPACT ON PATIENT-REPORTED SYMPTOM BURDE, THROUGH THE LENS OF THE LONDON EVALUATION OF ILLNESS (LEVIL) - ScienceDirect

 

Pruritus: Is there a grain of salty truth? - Penny - 2021 - Hemodialysis International - Wiley Online Library

 

P1062EXPANDED DIALYSIS (HDX): IS THERE AN IMPACT ON PATIENT REPORTED SYMPTOM? | Nephrology Dialysis Transplantation | Oxford Academic (oup.com)

 

Identifying therapeutic hemodialysis targets through cerebrovascular reactivity: RESPIRACT 2

 

Study design: A prospective observational study with 30 hemodialysis patients

 

Background: 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 blood flow responds to carbon dioxide (C02). In this study, we will compare the magnitude and speed of the brain blood flow response to a step-change in C02 with hemodynamic, dialysis, and cognitive parameters. The goal of this study is to establish therapeutic targets that can be altered during the dialysis procedure to protect the brain from HD stress. 

 

Hypothesis: We hypothesize that there will be identifiable factors that can be modified through the investigation of cerebrovascular reactivity (CVR) which will provide an understanding of the factors which are driving the pathological response in patients receiving HD. This will allow for the identification of relevant alterations to the HD procedure to provide protection against the negative effects of HD on the brain. 

 

Primary Endpoints:

  • Cerebrovascular reactivity (CVR) measured as a percent change in cerebral blood flow (CBF) divided by mmHg changes in C02 from baseline to hypercapnic stage

  • Dynamics of CBF response measured as time constant of change in CBF from baseline to hypercapnic stage

  • Cognitive impairment - Creyos (formerly “Cambridge Brain Sciences”) computer based neuropsychological assessment, The Montreal Cognitive Assessment (MoCA), and Trails Making test form A and B

 

Secondary Endpoints:

  • Identification of hemodynamic and dialysis parameters, which can be modified to protect the brain from the stress of HD

 

Study Intervention: Measurement of CBF response with transcranial doppler to a step increase in C02 from baseline to +5-10 mmHg and then back down to baseline (with each level of C02 lasting up to 5 minutes depending on patient tolerance). Patients will complete this 15-minute protocol before and after their hemodialysis treatment, during both their long and short interval dialysis days (2 study visits total). 

 

This study is significant in that currently, the problem of HD-induced brain injury is not well recognized, understood, or the focus of care during HD treatments. Therefore, optimizing dialysis to minimize harm by understanding the HD treatment-based factors determining CVR will identify additional therapeutic targets. This has the potential to be used alone or in combination with other dialysis-based interventions to allow patients to tolerate HD and maximize their quality of life, whilst maintaining cognitive vitality and independence.

 

Results and associated papers will be linked once study is complete and all data is analyzed.

 

To learn more about our previous study on cerebrovascular reactivity in chronic kidney disease patients, please refer to the following paper:

 

Hemodialysis Patients Have Impaired Cerebrovascular Reactivity to CO2 Compared to Chronic Kidney Disease Patients and Healthy Controls: A Pilot Study - ScienceDirect

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