2017

Dr. Ioan-Andrei Iliuta
University Health Network, Ontario
Supervisors: Dr. York Pei, Dr. James W. Scholey

KRESCENT POST-DOCTORAL FELLOWSHIP 2017-2020
Partnership with: Otsuka Pharmaceuticals Canada and the PKD Foundation of Canada

After having received his medical degree at Laval University in 2010, Dr. Iliuta completed residency training in internal medicine (2010-2013) and nephrology (2013-2015) in Quebec City. He then pursued a fellowship in Hereditary Kidney Disease under the supervision of Dr. York Pei at Toronto General Hospital, University Health Network, while undergoing graduate training in the Translational Research Program at the Institute of Medical Science, University of Toronto. His clinical interests range from autosomal dominant polycystic kidney disease to tuberous sclerosis complex and inherited tubulopathies. His current research focuses on investigating novel disease-modifying therapies for the treatment of polycystic kidney disease. In the fall, he will be starting a PhD in Biomedical Science at the University of Toronto, with a focus on the therapeutics of AMP kinase in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited form of kidney disease manifesting in adults, in which numerous cysts enlarge progressively until they cause severe kidney failure requiring dialysis or a transplant. Although ADPKD is a major cause of kidney failure in North America, effective treatments to slow disease progression are lacking. By acting on specific pathways involved in the metabolism (specifically, energy sensing and production) of cyst cells in APDKD, either through drug combinations or dietary changes, we hope to attenuate the severity of renal disease: this would result in smaller kidneys, better quality of life, and a longer interval to kidney failure.

Dr. Thomas Kitzler, MD
Boston Children’s Hospital – Harvard Medical School
Supervisor: Dr. Friedhelm Hildebrandt

KRESCENT POST-DOCTORAL FELLOWSHIP 2017-2020

Dr. Thomas Kitzler will complete his research fellowship under the supervision of Dr. Friedhelm Hildebrandt at Boston Children’s Hospital – Harvard Medical School. His project focuses on the discovery and characterization of novel kidney disease genes by means of whole-exome sequencing and zebrafish animal models. These models will then be used to screen for novel targeted therapies. Dr. Kitzler completed his medical residency at the department of Medical Genetics at McGill University where he was also involved in basic research in the field of Nephrology. Dr. Kitzler obtained his degree at the Medical University of Graz, Austria.

Nephronophthisis (NPHP) is an autosomal-recessive cystic kidney disease and it is the most frequent genetic cause of chronic kidney disease (CKD) in the first three decades of life. In recent years, it has been demonstrated that NPHP shows a high degree of genetic heterogeneity. Elucidating the underlying genetic and molecular pathomechanisms of hereditary kidney disease is paramount for identifying at-risk individuals and for the development of novel targeted therapies to alter or hopefully even reverse disease progression.

Dr. Kitzler will characterize novel NPHP candidate genes. He will then use zebrafish models to screen for novel targeted therapies for genetic causes of kidney disease, for which currently no treatment exists.

Dr. Friedhelm Hildebrandt at the Boston Children’s Hospital is a world leader at identifying new genes which cause kidney disease when changed. The goal of Dr. Kitzler’s project in his laboratory is firstly, to better understand the role of a recently identified kidney-disease gene discovered in a family from Montreal. He will use Dr. Hildebrandt’s database of more than 1,500 families with unsolved cases of kidney disease to screen for other families with changes in this gene. To do this, he will use state-of-the-art technology, such as whole- exome capture and next-generation sequencing. Both methods allow us to look at a vast amount of genes in an efficient manner. He will then use well-known animal models of nephronophthisis, such as zebrafish, to further detail how this gene causes kidney disease and use these animal models to screen for new therapies. This work will hopefully lead to the development of new treatment options for genetic forms of kidney disease.

Dr. Caroline Lamarche, MD, MSc
BC Children Hospital / University of British Columbia
Supervisor: Dr. Megan Levings

KRESCENT POST-DOCTORAL FELLOWSHIP 2017-2020

Dr. Lamarche will complete her post-doctoral fellowship under the supervision of Dr. Megan Levings at BC Children Hospital/University of British Colombia where she will work on a way to tailor antigen-specific regulatory T cells for their use in transplantation.

Transplantation is the best and sometimes only treatment for end-stage organ failure. In the last ten years, the lives of more than 20,000 Canadians have been improved, extended, or saved by donated organs. lmmunosuppressive drugs make transplantation possible, but since these drugs cannot suppress just the cells reactive to the transplanted organ but suppress the entire immune system, these drugs come at the price of an increase in infection and cancer risk. The drugs are also not perfect; many organs are still lost to rejection.

Our goal is to improve the success of transplantation, by finding ways to re-educate the recipient's immune system to tolerate the transplanted organ. Our strategy is to harness the natural immunosuppressive properties of a type of white blood cell called T regulatory cells (Tregs). Tregs naturally regulate immune responses by ensuring the immune system attacks infectious or harmful substances without over-reacting to self or non-harmful foreign proteins. In the last 10 years, research has shown that Tregs could be used as a cell-based therapy to induce immune tolerance and prevent organ rejection. The efficacy of Treg cell therapies can be significantly enhanced if the cellular product is enriched for Tregs that recognize an target that is specific to the transplanted organ. Dr Levings' lab developed a method to improve the potency of Tregs by engineering them to express a protein that activates them when they are in the presence of a transplant. My goal is thus to study the potential of those engineered Tregs to control allograft rejection and lower the chances that transplant recipients will reject the donor organ.

Dr. Matthew Lanktree
University Health Network, Ontario
Supervisors: Dr. Andrew D. Paterson, Dr. York Pei

KRESCENT POST-DOCTORAL FELLOWSHIP 2017-2019

Dr. Matthew Lanktree began research training during an undergraduate degree in bioinformatics at University of Waterloo, then completed a combined MD/PhD degree at University of Western Ontario studying complex disease genetics. Moving to McMaster University, he completed Internal Medicine residency and a clinical fellowship in Nephrology, before moving to University of Toronto to pursue a post doctoral research fellowship in heritable kidney diseases including polycystic kidney disease. Dr. Lanktree has received funding from the Canadian Institutes of Health Research, and the American Society of Nephrology, and is a member of the Canadian Kidney Foundation KRESCENT program. Over the last 15 years, Dr. Lanktree has published over 50 articles in high impact journals in genetics and medicine, and has set his goal to improve outcomes for patients with polycystic kidney disease.

Therapies for polycystic kidney disease attempt to maintain kidney function and slow progression towards kidney failure which requires dialysis or kidney transplantation. Patients at highest risk of disease progression have the most to benefit from early initiation of aggressive therapy. Large kidney size can help identify patients at high risk of progression, as can identification of the responsible genetic mutation. We seek to incorporate both these data sources, imaging and genetics, as well as clinical risk factors, to improve our ability to identify patients at highest risk of kidney failure. Additionally, using genetic and molecular tests of blood, urine and kidney cyst fluid, and “big data” from international collaborations, we will further stratify patients, and attempt to identify new treatments and possibly a cure for polycystic kidney disease.

Dr. Mathieu Lemaire
The Hospital for Sick Children, Research Institute, Ontario

KRESCENT NEW INVESTIGATOR AWARD 2017-2010
KRESCENT INFRASTRUCTURE AWARD 2017-2018

Dr. Mathieu Lemaire finished his medical training at McGill University in 2004 and then moved to Toronto to learn Paediatrics and Nephrology at The Hospital for Sick Children. Then, he went to Yale University (New Haven, CT) to pursue a PhD in Investigative Medicine under the supervision of Dr Richard P. Lifton as a KRESCENT post-doctoral fellow.

Blood vessels are like roads that can reach any cell of our body. We call the cells that line blood vessels "endothelial cells". Blood flows fast in normal blood vessels, but it is slow when there is damage. It forms a blood clot. This is similar to a “good traffic jam”: it helps repair injured blood vessels. The body must control the machines that help with repair to avoid “bad traffic jams”. Healthy blood vessels don't need blood clots.

In the lab, we study the function of endothelial cells in the kidneys. We work on a disease called "atypical hemolytic-uremic syndrome". For simplicity, we call it "aHUS". Patients with aHUS get kidney failure. Why? Blood clots form in the blood vessels of the kidneys. These clots prevent normal blood flow in kidneys. Blood flow is important to deliver food and oxygen to the kidneys.

We found that mutations in the gene diacylglycerol kinase epsilon (DGKE) can cause aHUS. Each cell in the body contains DNA, a code made of genes. Genes make proteins—the building blocks of cells. Mutations are changes in the DNA that cause abnormal function of a protein. For our patients, the mutations prevent DGKE from working well.

This project will tackle four different tasks to help us understand better DGKE function in endothelial cells:

1. Figure out how a deficiency in DGKE leads to abnormal AKT function in endothelial cellsFind out how
2. abnormal eNOS function affects the function of blood vessels that have no DGKE protei
3. nDetermine how DGKE deficiency prevents endothelial cell to withstand normal blood flowStudy how DGKE
4. mutations found in patients with aHUS affect the function and structure of DGKE enzymes

This research is important so we can start thinking about new treatment for this disease. Studies on the function and structure of DGKE could be helpful to diagnose patients with new mutations. It will also teach us a lot about how normal blood vessels prevent blood clot formation.

Ms. Vinusha Kalatharan
University of Western Ontario, Ontario
Supervisors: Dr. Amit Garg, Dr. York Pei

KRESCENT ALLIED HEALTH DOCTORAL AWARD 2017-2018

Ms. Vinusha Kalatharan will complete her fellowship under the supervision of Drs. Amit Garg and York Pei at The University of Western Ontario, where she is currently pursuing her PhD in Epidemiology and Biostatistics.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder with no cure. Urinary tract stones are five to ten times more common in patients with ADPKD compared to the general population, and increase morbidity by causing pain and accelerating disease progression. For these reasons, stones require effective management in patients with ADPKD. Recurrent pain, blood in urine, urinary tract obstruction, or infection caused by stones may demand an urgent intervention to remove the stone. However, the reduced kidney function and distorted kidney anatomy in this population may make performing these interventions more challenging than the general population. Strong evidence on the safety and efficacy of urological interventions, as well as the associated operative and post-operative healthcare costs for urinary tract stone removal in patients with ADPDK is lacking. Ms. Kalatharan aims to: 1) describe and compare the incidence of urological interventions for urinary tract stone removal in patients with ADPKD to non-ADPKD counterparts; 2) describe and compare the 30-day incidence of complications following a urological intervention for stone removal in patients with ADPKD to non-ADPKD counterparts; and 3) describe and compare the operative and perioperative healthcare costs of urological intervention for stone removal in patients with ADPKD to non-ADPKD counterparts. She will conduct several population-based studies using the Ontario’s healthcare administrative databases held at the Institute for Clinical Evaluative Sciences and statistical and health economical analyses to address these objectives. Research findings from these studies may help modify and inform future clinical practice guidelines on the management of urinary tract stones in ADPKD.