Awardees
 

Supervisor: Dr. Robert Kleta; Dr. Rulan Parekh
Award: KRESCENT Post-Doctoral Fellowships
Institution: University College London
Year: 2020-2022

Study title: Using genetics for precision medicine in nephrotic syndrome

Biography
Dr. Mallory Downie is currently pursuing her PhD in bioinformatics and genetics at University College London, UK. She received her MD from the University of Toronto and completed her general paediatrics and clinical nephrology training at the Hospital for Sick Children, Toronto. She is currently investigating the genetic contributors to childhood steroid sensitive nephrotic syndrome, one of the most common kidney diseases in children worldwide. Using genetic association studies in multi-ethnic populations, she aims to identify the genetic changes that make children at risk for developing more severe forms of disease and/or responding less well to treatment. Ultimately, Dr. Downie hopes that this work will contribute to establishing more individualized genetic risk profiles and more tailored treatments for children with steroid sensitive nephrotic syndrome.  

Lay Summary
Nephrotic syndrome is the most common kidney disease in children worldwide, with up to 3000 Canadian children newly diagnosed each year. In nephrotic syndrome, the kidneys leak protein into the urine which causes the patient’s body to swell. This can lead to complications like infection, blood clots, and kidney injury. Currently, the treatment for nephrotic syndrome is with medications commonly referred to as “steroids”, which can stop the kidney from leaking. Patients that respond to this treatment have “steroid sensitive nephrotic syndrome.” However, these and other medications used can have severe side effects, and the response to them is quite variable. In addition, even if treatment is initially successful, the disease can recur and eventually become chronic, lasting for decades. We also know that children of South Asian ethnicity are more likely to get nephrotic syndrome but we do not yet know why. 

Dr. Downie’s goal with this project is to understand why the standard treatments work differently for individual patients, what causes some patients to relapse, and why some children are more susceptible to developing nephrotic syndrome so that we can optimize treatment of this disease. Individual differences in disease severity and response to medications are at least partially determined by our genes. Each person has 30,000 genes which provide the instructions for making the proteins in the body. Each person has two copies of each gene, one inherited from each biological parent. While most genes are the same between all people, a small fraction varies. Sometimes a small change in a gene can cause it to stop working properly which can contribute to disease. Genetic studies in European children have found that multiple “poorly working” genes added together can increase an individual’s risk for steroid sensitive nephrotic syndrome. Yet we still do not know which genetic changes cause some individuals to respond poorly to treatment, or which changes increase disease risk in South Asian patients. 

To answer these questions, Dr. Downie will use a database of 1200 European and South Asian children with steroid sensitive nephrotic syndrome to 1) relate changes in their genes to their clinical features of disease (e.g. treatment response), and 2) compare the genetic information from children of South Asian background with and without disease. By looking at the genetic information of patients with steroid sensitive nephrotic syndrome, her data data will identify genetic changes that make patients at risk for developing more severe disease and poorer response to treatment. This can then be used to identify an individual’s genetic risk profile in order to plan their individualized treatment. In this way, she will use their genetic information to develop a “precision medicine” based approach to their disease management. Ultimately, her work will translate into optimal treatment with minimal medication side effects for children with nephrotic syndrome.