Pediatric Renal Transplant Optimization with Biomarkers Examining Urine Multicentre Cohort (PROBE)

Project Summary

This project will address a critical clinical need in pediatric kidney transplantation, which is the current lack of an efficient, predictive and non-invasive method to detect signs of acute rejection.

Kidney transplantation is a life-saving treatment for children with end-stage kidney failure. A major threat to success is rejection, where the body’s immune system attacks and destroys the transplanted kidney. If rejection isn’t treated early, it results in permanent injury that can lead to loss of the transplant and a return to dialysis. Currently, tests that monitor kidney function will miss early or mild rejection. Instead, we screen with repeated kidney biopsies, which are risky and unpleasant. This research program will use proven techniques to identify signs of kidney injury and rejection in the urine of children who have had a kidney transplant. It will focus on the first year after transplant, since this is the highest risk for rejection. We will look for metabolites and chemokines that we have tested before to identify when injury or rejection is present. 

Metabolites are small molecules produced by our cells as part of their function or as waste products. Chemokines are a different type of molecule that is produced by our immune system to signal inflammation. We already know some of the changes that occur with rejection. We now plan to validate that the same changes are present in other Canadian children with kidney transplants.

We will ask children with a new kidney transplant and their families to participate in this study. They will provide a urine sample for analysis whenever they have a kidney biopsy and also at regular intervals after transplant. We will verify the metabolite and chemokine levels that are linked to rejection, and could predict rejection in other children. Once it has been refined, we will determine whether it improves outcome by using it as a test for real-time monitoring and limit our use of regular kidney biopsies. We hope to demonstrate that this will improve the accuracy to detect rejection early, reduce the number of biopsies and improve the health and long-term kidney function of children with a transplant.

This study is a multi-centre cohort study being conducted by the Blydt-Hansen Research Team at BC Children's Hospital, which is the primary site for this study. It includes participation from all major pediatric transplant centers in Canada.

It is funded by the Canadian Institutes of Health Research, with additional funding from Astellas Canada.

Project Status

Status: Active, data collection completed
Study Start Date: October 22, 2014
Study End Date:

Study Enrolment Status: Closed
Start Date: October 2014
End Date: October 2017

Project Team

Principal Investigator

Tom Blydt-Hansen
 
Co-Investigators

Dr. Julie Ho
Dr. David Wishart
Dr. David Rush
Dr. Ian Gibson
Dr. Atul Sharma
Dr. Beth Foster
Dr. Peter Nickerson 

Research Team Members

Mike Guron, Research Assistant and Data Coordinator
Julie Matheson, Research Coordinator
Samantha Lang, Master Student

Enrolment Eligibility Criteria
  1. Less than 22 years old at time of enrolment
  2. Listed for a kidney transplant or has recently (within the last month) received a kidney transplant
  3. At least 1 year of follow-up at the pediatric transplant center in Canada
Participate

For more information, or if you are interested in participating, contact us at sotresearch@bcchr.ca.

Publications
  1. Blydt-Hansen TD, Sharma A, Gibson IW, Wishart DS, Mandal R, Ho J, Nickerson P, Rush D. Urinary Metabolomics for Noninvasive Detection of Antibody-Mediated Rejection in Children After Kidney Transplantation. Transplantation. 2017 Oct;101(10):2553-2561. doi: 10.1097/TP.0000000000001662. PMID: 28121909.
     
  2. Mockler C, Sharma A, Gibson IW, Gao A, Wong A, Ho J, Blydt-Hansen TD. The prognostic value of urinary chemokines at 6 months after pediatric kidney transplantation. Pediatr Transplant. 2018 Aug;22(5):e13205. doi: 10.1111/petr.13205. Epub 2018 May 7. PMID: 29733487.
     
  3. Landsberg A, Sharma A, Gibson IW, Rush D, Wishart DS, Blydt-Hansen TD. Non-invasive staging of chronic kidney allograft damage using urine metabolomic profiling. Pediatr Transplant. 2018 Aug;22(5):e13226. doi: 10.1111/petr.13226. Epub 2018 May 31. PMID: 29855144.
     
  4. Archdekin B, Sharma A, Gibson IW, Rush D, Wishart DS, Blydt-Hansen TD. Non-invasive differentiation of non-rejection kidney injury from acute rejection in pediatric renal transplant recipients. Pediatr Transplant. 2019 May;23(3):e13364. doi: 10.1111/petr.13364. Epub 2019 Feb 4. PMID: 30719822.
     
  5. Hoffmann AJ, Gibson IW, Ho J, Nickerson P, Rush D, Sharma A, Wishart D, Blydt-Hansen TD. Early surveillance biopsy utilization and management of pediatric renal allograft acute T cell-mediated rejection in Canadian centers: Observations from the PROBE multicenter cohort study. Pediatr Transplant. 2021 Mar;25(2):e13870. doi: 10.1111/petr.13870. Epub 2020 Oct 7. PMID: 33026135.
     
  6. Blydt-Hansen TD, Sharma A, Gibson IW, Wiebe C, Sharma AP, Langlois V, Teoh CW, Rush D, Nickerson P, Wishart D, Ho J. Validity and utility of urinary CXCL10/Cr immune monitoring in pediatric kidney transplant recipients. Am J Transplant. 2021 Apr;21(4):1545-1555. doi: 10.1111/ajt.16336. Epub 2020 Oct 30. PMID: 33034126.
     
  7. Lang S, Sharma A, Foster B, Gibson IW, Ho J, Nickerson P, Wishart D, Blydt-Hansen T. Age and sex determine conversion from immediate-release to extended-release tacrolimus in a multi-center cohort of Canadian pediatric renal transplant recipients. Pediatr Transplant. 2020 Dec 23:e13959. doi: 10.1111/petr.13959. Epub ahead of print. PMID: 33368914.
Acknowledgements

This project would not have been possible without the contributions of the 101 children, parents and caregivers, and their commitment to providing samples and data that were vital to its success. We are grateful for the project leadership and dedication of Lise Bourrier, site coordination of Susan McMurrich and data stewardship of Mike Guron, and indeed the investigators at each of the participating sites and coordinators who supported their work.

IWK Halifax – Dr. Phil Acott
Montreal Children’s Hospital – Dr. Beth Foster
CHU Sainte-Justine – Dr. Veronique Phan
Children’s Hospital of Eastern Ontario – Dr. Janusz Feber
Hospital for Sick Children – Dr. Valerie Langlois, Dr. Chia Wei Teoh
McMaster Children’s Hospital – Dr. Steve Arora
London Health Sciences Center – Dr. Ajay Sharma
Jim Pattison Children’s Hospital – Dr. Robin Erickson, Michelle Ruhl
Stollery Children’s Hospital – Dr. Catherine Morgan
Alberta Children’s Hospital – Dr. Lorraine Hamiwka
Children’s Hospital-Health Sciences Center (Winnipeg) – Dr. Patricia Birk
BC Children’s Hospital – Dr. Cherry Mammen