Robert Myette | Children's Hospital of Eastern Ontario Research Institute

Precision medicine for pediatric nephrotic syndrome: Podocyte extracellular vesicle proteomics as a novel marker to guide personalized therapy

Co-Applicant(s):  Mayra Trentin Sonoda, Tyler Cooper

Lay Abstract

Background: Nephrotic syndrome (NS) is one of the most common kidney diseases in children. NS is associated with significant protein loss in the urine. This leads to several complications, including swelling, increased risk of infection, blood clots, and early heart disease. This also results in a significant burden for not only the children affected, but also their families, and the health care system. The main cause of NS is unknown, but our treatment is standardized: children are treated with large doses of steroids. This often leads to unpleasant side effects, including weight gain, and mood changes. It is unclear who will go on to need only a single treatment, and who will need many courses of steroids. We must diagnose and treat NS better and decrease steroid use to minimize these significant side effects.

Purpose: To do this, we aim to better understand the podocyte, or "foot cell”, a sieve-like kidney cell that is responsible for filtering blood and creating urine. Foot cells are also responsible for keeping protein in the bloodstream and preventing its loss in the urine. NS is a disease of the foot cell. Interestingly, when stressed, these foot cells release small particles, called ectosomes (ECs), into the urine that allows us to study what is happening in the foot cell without needing to do an invasive biopsy. Our group has already shown that children with NS have higher levels of foot cell ECs in their urine. We will next aim to better understand what is inside the ECs by using foot cells in the lab, as well as urine samples from children. By doing this, we aim to develop a non-invasive marker of steroid responsiveness. Methods: Our first aim is directed at understanding protein signals within the ECs from foot cells in the lab. Secondly, we aim to determine if ECs from patient urine samples also have the same signatures (discovery and validation groups). Our hope is this comparison and correlation between laboratory foot cell ECs and human urinary ECs will allow us to develop a urine-based, non-invasive marker of steroid responsiveness.

Anticipated Outcomes: Building on our existing work which has already shown that foot cell ECs are elevated in the urine of children with NS, we anticipate that these ECs differ in their protein profiles between disease and remission. Further, we expect that we will be able to better understand why the podocyte cell releases these ECs during times of stress, and what that means in the context of steroid responsiveness in children.

Patient Engagement: Through engagement with our Nephrology Clinic at CHEO, particularly through discussions with the families and children with nephrotic syndrome, and by leveraging the well-developed family research leadership program at the CHEO Research Institute, we will ensure that the work we do is patient-centered and important for families and children with lived experience. Further, we will develop ways to effectively communicate the findings to not only the scientific community, but also the patient community (lay summaries and infographics of results and impact).

Relevance to Patients and Communities: This work is specifically relevant for children and families affected by NS. This disease has an unclear cause, and treatment approaches include high dose steroids which result in significant side effects, not to mention that 10-20% of children may be steroid resistant. By working to better understand this disease, we hope to reduce the amount of steroids children with NS are exposed to, provide more clarity as to why this disease occurs, and develop new diagnostic and treatment approaches.

Conclusion: This research is very new; however, we expect to build on our existing results to better understand foot cell ECs in NS, not only as non-invasive biomarkers of steroid responsiveness (as outlined here), but also as roadmaps to understand “distress beacons” within the foot cell. This information could change the way we approach treatment for children and youth with NS. This research is particularly important to me as I work with these children and their families in the clinic while I treat their NS. We owe it to them to find more effective and personalized treatment approaches.