Research Studies

A Phase 1 Interventional Study to Test Short-Term Safety, Tolerability, and Preliminary Efficacy of Sodium-Free Intraperitoneal 30% Icodextran/10% Dextrose Solution in Peritoneal Dialysis Patients

Principal Investigator: Dr. Christopher McIntyre

Currently used peritoneal dialysis solutions consist of high levels of salt, which in turn limits the removal of sodium. This can lead to the accumulation of sodium in the skin and other soft tissues. Over time, this accumulation of sodium leads to long-term adverse outcomes for dialysis patients. Additionally, conventional peritoneal solutions may also be insufficient at removing extracellular fluid, adding to the complications and adverse outcomes patients experience. Therefore, PD solutions optimized to improve extracellular volume and sodium management are needed.

The aim of this study will be to see if a single 8-hour dwell of 500 mL if intraperitoneal sodium-free 30% Icodextran/10% Dextrose solution is safe, tolerable, and effective in achieving sodium and fluid removal in peritoneal dialysis patients. This is a significant area of study as sodium and volume balance in kidney failure patients is critical. Extracellular volume overload has been consistently associated with cardiovascular morbidity and mortality.

Patients will undergo 1 single 8-hour dwell (using their current PD catheter) and will be monitored the entire treatment and for 1-hour post drain at the end of the 8 hours. During the dwell, patients will have the following data collected: pain scores (infusion, dwell, and drain pain assessments), hemodynamic stability (continuous blood pressure monitoring etc. using a Finapes), blood work at different intervals including glucose and serum sodium levels as well as other biomarkers, dialysate and urine samples at different intervals, and UF (with weights pre and post intervention).

The SCUF-WAK Pilot Study (Slow Continuous Ultrafiltration Wearable Artificial Kidney)

Principal Investigators: Dr. Robert Lindsay and Dr. Susan Huang

During standard intermittent hemodialysis (3x/week for 3-4 hours each time), a large volume of fluid is removed in a short period of time. Current evidence suggests that both volume overload (prior to a dialysis treatment) and aggressive fluid removal (during dialysis) can induce circulatory stress and multi organ injury. More frequent dialysis treatments results in better outcomes. The ideal renal replacement therapy would provide continuous compensation for the impaired kidneys, but is not a viable option with standard dialysis machines, as they are bulky and stationary. This idea necessitates a compact, “wearable” renal replacement therapy.

The few groups working on the concept of a “Wearable Artificial Kidney” (WAK) are encountering the major problem requirement for dialysate and its regeneration. No group has considered the addition of an ultrafiltration day time therapy by WAK to an already established dialysis regime. This pilot study will employ the addition of slow continuous ultrafiltration (SCUF) in addition to standard intermittent hemodialysis treatments. The clinical goal for this therapy is to provide a more steady state fluid volume for patients while also increasing uremic toxin removal. However, the purpose of this pilot study is to solely establish the safety and acceptability of the SCUF-WAK prototype.

Evaluation of Sodium Deposition in Soft Tissues of Patients with Kidney Disease and its Association

Principal Investigator: Dr. Christopher McIntyre

Our body maintains sodium (salt) balance by getting rid of excess sodium through urine. When the kidneys stop working, sodium accumulates in the skin and muscles. We already know that sodium accumulation is higher in men, older patients, and patients with high blood pressure, and that sodium accumulation may have a number of other side effects such as inflammation. We are measuring sodium content in the tissues with magnetic resonance imaging (MRI) in patients at various stages of chronic kidney disease (CKD), on various dialysis therapies, and in patients with heart failure. Based on earlier findings, we know that high sodium concentration is linked to age, high blood pressure, diabetes, and CKD. The threshold of sodium accumulation in peadiatric patients is likely lower, but it has never been explored. Therefore, we began to scan healthy children and those with CKD to determine tissue sodium level. More recently, we have observed more salt in the skin in patients on dialysis and more salt in the skin and muscle in CKD patients stage 1-4. We also observed that skin sodium is higher in patients who have a higher sodium dialysate concentration. Our next question will be, “Is salt in the skin higher in patients who have heart failure with renal dysfunction compared to patients with only heart failure.”

To view articles from this study and about this topic please click the following links:

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.

Interventional Study to Assess the Effect of Extended Dialysis using the Theranova Dialyzer on Patient Reported Symptoms using the London Evaluation of Illness (LEVIL)

Principal Investigator: Dr. Christopher McIntyre

We know that many patients who are on dialysis suffer from the burden of unwanted symptoms, which can affect quality of life. In this study, we look at symptom burden using the London Evaluation of illness “LEVIL,” an application based platform where patients can self-report their symptoms with each hemodialysis treatment using an iPad or mobile phone. We look at 9 different symptom domains including general well-being, pain, energy, sleep quality, shortness of breath, appetite, bodily itch, restless legs, and time to recovery.

The Theranova dialyzer is capable of removing large middle molecules (15,000 - 60,000 Da) because of its highly permeable membrane that have been linked to the development of complications such as cardiovascular disease. At this time, enrolment, treatment, and data collection are ongoing and 29 hemodialysis patients have completed the study. We are excited to see if symptoms are related to an increased amount of these uremic toxins in the blood.

To view articles from this study and about this topic please click the following links:

Investigation of Electrophysiological Substrate of Arrhythmia in Hemodialysis patients

Principal Investigator: Dr. Christopher McIntyre

Computed tomography (CT) imaging is a useful tool in studying blood flow defects in organs such as the lungs and heart during dialysis treatment. In this study, our aim is to observe the changes in blood flow in the heart muscle during hemodialysis and determine whether or not this response is related to irregular heart rhythms in patients on hemodialysis treatment.

To detect irregular heart rhythms, patients enrolled in this study have a small implantable loop recorder (heart monitoring device) placed directly under the skin near the heart. By doing this, we are able to study a patient’s heart rhythm continuously for up to one year.

Currently, 7 patients have completed the imaging sessions and 3 of these patients have had the loop recorder implanted. Based on the results thus far, there is a general decrease in blood flow in the heart muscle that is strongly evident at 3 hours into dialysis treatment. To relate these blood flow defects to heart rhythm, we will continue to remotely monitor the data obtained from those with the implanted loop recorder.

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.

Initial feasibility pilot study of interdialytic peritoneal ultrafiltration to manage volume status in hemodialysis patients

Principal Investigator: Dr. Christopher McIntyre

Tissue sodium deposition is harmful to patients on chronic hemodialysis. A sample of 10 chronic hemodialysis patients will undergo a 5-week, pilot, interventional study to test the efficacy of tissue sodium removal in-between hemodialysis sessions, twice per week, for three weeks. Tissue sodium removal will be achieved with a 10% dextrose solution by peritoneal dialysis - all patients will undergo the surgical insertion of a peritoneal dialysis catheter. Patients will undergo symptomatic and hemodynamic monitoring throughout the study for safety assessment. Total tissue sodium removal will be assessed at the beginning and at the end of the study with sodium magnetic resonance imaging.

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.

Renal Community Photo Initiative

Principal Investigator: Dr. Christopher McIntyre

This collaborative research effort between the Kidney Clinical Research Unit and the Visual Arts Department at Western University is underway to understand how persons with chronic kidney disease, persons receiving chronic dialysis treatments or those who have received a kidney transplant respond to treatment through imagery. Participants are invited to photograph, share and discuss their photos, and experience the images of other participants.

The goals of this project are:
i) to explore how photographic image-making and the use of different camera types can influence the patient photographer, the types of photographs that are produced and those with whom the photos are shared, and
ii) to share these photographs and artistic representations in order to educate, inform and raise awareness among caregivers, healthcare providers, those overseeing policy and funding and key stakeholders.

39 subjects selected one of 4 different cameras or cyanotype paper and participated in the main study with 12 of these participants also in the sub-study. The sub-study was designed to obtain participant feedback regarding use of these images to obtain the study objective. Such visuals include large banners, a “post-card” display, “Bringing Healing into Focus” - a site created by Schulich School of Medicine and Dentistry for their website, media attention from CTV London and a blog written for Home Dialysis Central. Recruitment continues while the study group also explores options to potentially “archive” the images and further share them with a number of communities.

This study is complete – to view publications related to this study, please click the following links:

Reducing hemodialysis induced recurrent brain injury to improve patients' lives

Principal Investigator: Dr. Christopher McIntyre

Chronic kidney disease patients undergoing hemodialysis often begin to experience difficulties with executive function, and the ability to plan and make decisions. These cognitive changes are associated with abnormalities in their brain scans. We believe this arises from issues with blood flow to the brain during and following hemodialysis sessions.

Our group is testing a new therapy which may protect the brain by priming the body with restrictions in blood flow in the lower leg for a few minutes, administered monthly before dialysis treatment. This is safe and it has been shown to prevent injury in other organs, including the liver, kidneys, and heart. The study involves cognitive tests and brain scans before and during dialysis, twice over the course of one year. Follow up scans will help us determine if the new therapy helps to maintain brain health. As well, hemodialysis treatment is often associated with negative complications related to microcirculatory stress (blood vessel injury). It is already shown that cells within the blood vessels respond to injury by releasing biological factors. Of these biological factors in the blood are microparticles, which are fragments of injured cells.

We are currently conducting a research project that focuses on measuring microparticles within the blood of patients who are undergoing hemodialysis. Our research aims to understand if microparticles can be used as an indicator of microcirculatory stress brought upon by dialysis, and to determine whether they can be used to identify if patients are responding to different dialysis modalities.

Does peritoneal dialysis preserve blood brain flow, maintain structure and prevent injury? A neuroimaging study.

Principal Investigator: Dr. Arsh Jain

Abnormalities of cognitive impairment (predominately in decision making) are almost universal in dialysis patients and appear early after starting dialysis. Around 75% of hemodialysis patients’ exhibit mild cognitive impairment (MCI) and a high proportion (~ 15%) have dementia. The injury is multifactorial, and amendable to HD-based intervention. Although the effects of hemodialysis on cerebral blood flow have been well studied, the effects of peritoneal dialysis on cerebral blood flow remain unclear. There is evidence that hemodialysis and peritoneal dialysis may affect the brain differently. In observational studies, peritoneal dialysis compared to hemodialysis is associated with a 16% lower risk of hemorrhagic stroke and a 25% lower risk of a new diagnosis of dementia. It may be that peritoneal dialysis offers a gentler alternative for cerebral blood flow with less acute hemodynamic changes. The purpose of this study is to measure how peritoneal dialysis affects the brain using Magnetic Resonance Imaging (MRI). We plan on recruiting 25 patients from London, Ontario to undergo two study visits, one year apart. There will be two MRI scans at each visit – the first will occur before PD treatment, and the second will occur during PD treatment. Scans will capture images of brain structure, blood flow, and injury. These results will be compared to HD patients. To date, we have recruited 3 patients.

Assessment of Telehome Monitoring in Patients on Peritoneal Dialysis (CONNECT Trial): A Multicentre Randomized Controlled Trial

Principal Investigator: Dr. Arsh Jain

One in 10 Canadians has kidney disease and 39,000 are being treated for complete kidney failure, requiring renal replacement therapy through dialysis or kidney transplantation. The most common forms of dialysis are in-centre hemodialysis and home-based peritoneal dialysis. Peritoneal dialysis (PD) has been shown to have early survival advantage compared to hemodialysis (HD), along with improved quality of life. It has also been found to be the least costly of form of dialysis (suggested savings of about $50,000 per patient per year). However, only 18% of dialysis patients in Canada currently use PD and approximately 10-30% of these patients switch from PD to HD each year. Patients primarily leave PD due to issues with infections and lack of home support. Telehome monitoring, which involves the sharing of digital patient health information between the patient and care provider, is a solution which addresses these two issues. We have implemented a telehome monitoring solution, eQ Connect™, which provides a platform for instructional media and training content, clinical data entry, and video communication, ultimately eliminating barriers for PD retention. This program is delivered on an iPad which replaces the traditional paper and pen PD record. This randomized control trial is taking place at 11 sites across Canada, and began in June 2016 at Victoria Hospital in London. To date, we have recruited 467 participants.

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.

The Peritoneal Dialysis Outcomes and Practice Patterns Study Phase 2 (PDOPPS2)

Principal Investigator: Dr. Arsh Jain

PDOPPS 2 is a prospective, observational cohort study of PD subjects and facilities in participating countries. It is designed to advance the understanding of optimal practices for peritoneal dialysis (PD) patients worldwide. The study is designed to increase the appropriate use of PD, extend technique survival, reduce mortality, and improve quality of life for PD patients.

Novel extracorporeal treatment to modulate hyperinflammation in COVID-19 patients

Principal Investigator: Dr. Christopher McIntyre

We are facing a global COVID-19 outbreak that has forced the majority of the population to stay home. Unfortunately, in severe cases, COVID-19 causes a potentially fatal condition known as acute respiratory distress syndrome (difficulty to breathe). Patients who suffer from severe respiratory illness are admitted to the ICU due to worsening health because of the virus. It is thought that worsening health is caused by a “cytokine storm”. Cytokines are small proteins secreted by cells of the immune system that control inflammation. A cytokine storm refers to an overproduction of these small proteins, which occurs when too many white blood cells (help the body fight infection and other diseases) are activated. In turn, these small proteins activate more white blood cells leading to a vicious cycle. This huge stimulation of inflammation can become damaging to a patient’s organs, leading to multi-organ injury (i.e. lung, heart etc…).

We configured a dialysis machine to hopefully decrease this cytokine storm by inactivating white blood cells through a dialysis circuit. Seven patients have been enrolled in the study in the intensive care unit. When the team started treatment on the first positive COVID-19 patient, they had around a 98% chance of dying and when the team recalculated the score after treatment was complete the patient had about a 30% of dying. We would like to study approximately 40 patients total (20 controls and 20 in the intervention group). If proven successful, the therapy would allow for a reduced intubation time, length of hospital admission, and a decrease in mortality rates.

To view articles from this study please click the following links:

Completed.

Check out the latest story here or below 'Canadian research team becomes first in the world to treat COVID-19 patients with dialysis'

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.

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.

ALXN1210-NEPH-202 Ravulizumab in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN)

Principal Investigator: Dr. Susan Huang

IgAN is a condition that causes chronic kidney disease. Overtime, some patients develop end-stage renal disease (ESRD) requiring dialysis or kidney transplant. This study involves an investigational treatment called ALXN1210 which is also known as Ravulizumab (study treatment). It is being developed for the treatment of IgAN. The study treatment binds to the C5 protein of the complement system. The complement system is a part of the body’s immune system. Dysregulation of the complement system is a contributing factor for the cause of IgAN. The study treatment works by reducing complement activity.

The purpose of this study is to evaluate the safety and efficacy of the study treatment in participants with IgAN. It is expected that approximately 60 participants aged at least 18 years will participate in this study at about 105 sites around the world. There will be approximately 3 sites participating in Canada. We plan to enroll up to 10 participants.

ALXN1210 has been approved for the treatment of adult patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) and adult and pediatric patients with atypical hemolytic uremic syndrome (aHUS) under the brand name Ultomiris®. ALXN1210 is also being studied in participants with Lupus Nephritis (LN), Generalized Myasthenia Gravis, Amyotrophic Lateral Sclerosis (ALS), and Neuromyelitis Optica Spectrum Disorder. Health Canada has issued a No Objection Letter to the Sponsor, authorizing the research study to be conducted in Canada. Participants will be randomly assigned to either the study treatment (Ravulizumab) or placebo and the study duration is approximately 86 weeks.

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.

A Simple Exercise Program for Patients with End Stage Kidney Disease to Improve Strength and Quality of Life: A Feasibility Study

Principal Investigator: Dr. Louise Moist

End-stage kidney disease (ESKD) is a major health problem. There are more than 25,000 Canadians receiving dialysis. People receiving dialysis are hospitalized approximately twice yearly and deal with chronic fatigue, other unrelenting symptoms, and reduced quality of life. Several factors are responsible for the poor quality of life and impaired function in people on dialysis including other diseases, dialysis-related side effects, and overwhelming fatigue. In other chronic disease populations, increasing physical activity through exercise can improve quality of life, physical function and reduce hospitalization. A recent survey showed that those with ESKD would like to increase their physical activity, but deal with barriers such as lack of physician advice, lack of safe and convenient programs, and cost. Together with exercise specialists and patients, we have developed an exercise program that addresses the barriers and will be simple to implement.

The purpose of this study, called a ‘pilot study’ or a ‘feasibility study, is to test whether a simple, prescribed exercise program can be easily adopted by dialysis programs and people on dialysis, and whether the program is sustainable and cost-effective. The results may be used as a guide for larger studies, although there is no guarantee that they will be conducted. It is anticipated that about 150 people will take part in this study, from 4 centers located in Canada. 50 of these patients will be local participants from London Health Sciences Centre. The study will recruit participants over a period of 27 months. Participants will be given a pedometer and walking poles (depending on which group they are randomized into) and will be given an exercise prescription to meet a target number of step counts.

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

Principal Investigator: Dr. Louise Moist

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

A Phase 1 Interventional Study to Test Short-Term Safety, Tolerability, and Preliminary Efficacy of Sodium-Free Intraperitoneal 30% Icodextran/10% Dextrose Solution in Peritoneal Dialysis Patients

Principal Investigator: Dr. Christopher McIntyre

Preclinical investigation of the effects of hemodialysis on microvascular perfusion

Principal Investigator: Dr. Christopher McIntyre

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

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