Preclinical investigation of the effects of hemodialysis on microvascular perfusion.

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 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 in the small capillaries in the tissue. We developed a small animal model that allows to investigate blood flow during a HD procedure using customized mini-dialyzers.

Projects: The versatility of the preclinical small animal model allows for a detailed preclinical investigation of how HD affect microvascular blood flow in tissue. 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 are currently investigating if a modification of the HD procedure can be used to mitigate the hyperinflammatory response.

MyTEMP: Major outcomes with personalized dialysate TEMPerature (MyTEMP): A pragmatic, registry-based, cluster randomized controlled trial

Small randomized trials demonstrated that a lower compared with higher dialysate temperature reduced the average drop in intradialytic blood pressure. Some observational studies demonstrated that a lower compared with higher dialysate temperature was associated with a lower risk of all-cause mortality and cardiovascular mortality. There is now the need for a large randomized trial that compares the effect of a low vs high dialysate temperature on major cardiovascular outcomes. The purpose of this study is to test the effect of outpatient hemodialysis centers randomized to (1) a personalized temperature-reduced dialysate protocol or (2) a standard-temperature dialysate protocol for 4 years on cardiovascular-related death and hospitalizations.

The MyTEMP trial is a pragmatic, registry-based, open-label, cluster randomized controlled trial being conducted at 84 hemodialysis centres in Ontario, Canada. These hemodialysis centers will care for approximately 15500 patients and provide over 4 million dialysis sessions over a 4-year follow-up. If effective in reducing cardiovascular-related death or hospitalization, a personalized dialysate temperature can be scaled and delivered on all hemodialysis machine in Ontario (and worldwide) at no added cost.

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

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.”

Evaluation of Kidney Medullary Sodium Content using Sodium-23 Magnetic Resonance Imaging to understand and predict diuretic resistance

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 is 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 salt 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. This project is active, and recruitment will begin in the near future.

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

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. Enrolment, treatment, and data collection are ongoing at this time with 14 hemodialysis patients currently receiving therapy. We are excited to see if symptoms are related to an increased amount of these uremic toxins in the blood.

Multimodal assessment of dyspnea, cardio-pulmonary structure and function in chronic hemodialysis patients

Sodium may drive asthma and shortness of breath. We know that an increase in salt leads to a decrease in a hormone produced by the body which in turn leads to an increase in bronchial spasms, which are constrictions of the smooth muscle cells of the bronchioles. We also know that any increase in salt levels increases calcium ions and this causes vasoconstriction within the lung cells.

Shortness of breath is common among patients on dialysis, however it is not well understood. This study explores the causes of shortness of breath in the hemodialysis population by measuring lung structure and function. Enrolment and data collection are currently ongoing with 7 patient participants having completed the study to date.

Investigation of Electrophysiological Substrate of Arrhythmia in Hemodialysis patients

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, 4 patients have completed the CT imaging and 2 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.

Reducing hemodialysis induced recurrent brain injury to improve patients' lives

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.

Novel extracorporeal treatment to modulate hyperinflammation in COVID-19 patients

We are currently 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. Two patients have received treatment 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.

Head to to read the full story - ‘Canadian team first in world to treat COVID-19 with specialized dialysis.’

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

Principal Investigator: Dr. 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.

Improving the Outcomes of Peritoneal Dialysis (PD) Catheter Insertion

Principal Investigator: Dr. 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 insertion and to maximize the safe and effective use of PD therapy. Specific aims are: 1) To determine if 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 to achieve expert consensus on optimal practices for PD catheter insertion and care.

MyCOG: Protecting against hemodialysis induced neuro-cognitive injury using personalized dialysate temperature

Recent research has shown that roughly 87% of patients on hemodialysis suffer from some level of lowered brain function. Hemodialysis has been shown to cause injuries to the brain. It is hypothesized that a reduced hemodialysis temperature may prevent injuries to the brain that may result in cognitive impairments. In Ontario, hemodialysis centres are involved in a large study (MyTEMP) to determine the effects of dialysate temperatures on rates of cardiovascular death and disease. Eight of these hemodialysis centres that are under the care of nephrologists at LHSC, were selected for MyCOG in order to recruit an equal number of participants to both the intervention and standard of care arms. Eligible participants included those > 18 years of age without pre-existing diagnosis of dementia, no communication impairment at baseline, with a reasonable use of the English language, who received hemodialysis treatment for < 12 months and were allocated to the assigned treatment dialysate temperature were invited to complete a cognitive assessment. This assessment was designed by researchers at the Brain and Mind Institute at Western University and required approximately 45 minutes of the participant’s time. The test could be assigned, accessed and completed via the participant’s smart phone or home computer (desktop, tablet, laptop) and was to be completed the day following dialysis treatment. For individuals who did not have access to such a device, a tablet was provided to them during their hemodialysis treatment, in order to complete the cognitive assessment. Results of the two study arms (standard of care dialysate temperature vs cooler dialysate temperature) are compared to determine if there is a difference in performance outcomes. This pilot study may inform a larger scale study. Preliminary results of this pilot study were presented as an abstract at the 2019 ASN meeting and are being further analyzed.

Renal Community Photo Initiative

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.


PI: Dr. Jain
Full Title: Assessment of Telehome Monitoring in Patients on Peritoneal Dialysis (CONNECT Trial): A Multicentre Randomized Controlled Trial
Background: 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.

Intervention: 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.

Recruitment: 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.

Brain Imaging in Peritoneal Dialysis Patients

PIs: Dr. Jain & Dr. Chiu
Full Title: Does peritoneal dialysis preserve blood brain flow, maintain structure and prevent injury? A neuroimaging study.
Background: 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.

Purpose: The purpose of this study is to measure how peritoneal dialysis affects the brain using Magnetic Resonance Imaging (MRI).

Recruitment: 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.