Supported Research

Lay Abstract

For children with end-stage kidney failure, a kidney transplant is life-saving. Although there has been improvement in how long a transplant will last (graft survival), nearly 40% of children will lose their transplant within 10 years. This means that most children transplanted in early childhood should expect to need another transplant before they even reach adult age. The leading cause of transplant failure is chronic rejection. Inflammation infiltrating areas of scarring within the kidney transplant (known as i-IFTA) has been identified as a cardinal sign of chronic rejection. This i-IFTA inflammation can lead to progressive kidney failure and graft loss. The biology of i-IFTA is still poorly understood. There are not yet any proven treatments for i-IFTA, but there a many potential treatments that could be tried, if only we knew more about how i-IFTA works! A major problem for finding early signs of chronic rejection is the need for a kidney biopsy. Because kidney function only starts to get worse after there has been a lot of kidney tissue injury, this type of chronic damage from i-IFTA is picked up very late. That late detection means that the disease is already more established, which may make it harder to treat and more difficult to regain function that has already been lost. A better understanding of immune changes with i-IFTA would make it possible to identify i-IFTA much earlier with new tests for use in the clinic – and at a stage where it may be much more effectively treated. The field “omics” technologies is ideally suited for this purpose. It describes different ways of testing for multiple substances at the same time, and to look for patterns that may be typical for the disease we are interested to study. In this study, we look at genes that are active in biopsy tissue (aka “Transcriptomics”), immune proteins called cytokines that are in the urine (aka “proteomics”), and small molecules in the urine that are related to tissue metabolism (aka “metabolomics”). We can look at them each type of data separately to identify typical features (patterns of different substances) that tell us about the disease, and we can also look at how changes are inter-related. This process can help us not only to better understand the tissue changes with i-IFTA, but also help to identify potential new urine tests to use for screening in clinic, and to identify the types of immune reactions that are happening – so that we can decide what new treatment options might work the best! This study will use already collected kidney biopsies from over 100 patients, and urine samples from our biobank to evaluate differences between samples with/without i-IFTA. We will re-test all of the biopsies to carefully define which ones have i-IFTA and how severe the changes are. We will look to see what genes are activated differently in i-IFTA directly from the biopsy tissue. And we will examine the urine to identify the different cytokines and metabolites that can tell the difference between people with i-IFTA and people who are not affected. This information will be refined to propose new tests that can be used to screen i-IFTA and monitor treatment. It will also be used to identify what existing medications might work to treat i-IFTA and prevent kidney failure. Once we understand how their substances are related to i-IFTA, we will have both a better understanding of how this progressive kidney transplant disease works, how to develop better tests for diagnosis and develop better treatments!