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December 11, 2018

Project Title: PROBE Multicentre Study (Pediatric Renal transplant Optimization with BiomarkErs)

Principal Investigator: Tom Blydt-Hansen

Is the study funded?      Yes

Is the study open for recruitment?          Yes (until summer 2017)

Are you soliciting new sites to participate?           No

Brief description of project:

The overall objective of this project is to address the need for a reliable and noninvasive test for serial allograft injury surveillance and to guide treatment. We hypothesize that the monitoring of urine metabolites and chemokines is superior to renal biopsy for detection and treatment of renal allograft injury. Currently there are no validated biomarkers to detect rejection in children and measures of renal function are insensitive forcing reliance on invasive surveillance kidney biopsy to diagnose renal injury. Acute change in glomerular filtration rate (GFR) does not indicate the nature of underlying injury, and by contrast, less fulminant injury is masked by compensatory hyperfiltration of remaining glomeruli. Such injury is termed sub-clinical but has nonetheless major consequences for allograft damage and survival. The main clinical challenge in managing children after kidney transplantation remains to balance the need for timely diagnosis and treatment of serious allograft injury, against the damage associated with invasive testing or over-immunosuppression. The aims of this project are:

Aim 1. Characterize urine metabolite and chemokine changes associated with kidney allograft injury. We will focus on common types of kidney allograft injury including cell-mediated acute rejection, polyoma BK virus nephropathy, calcineurin-inhibitors and ischemic acute kidney injury, to expand on an existing repertoire of urine metabolite and chemokine candidate biomarkers of acute rejection. We will collect samples at the time of every kidney biopsy (surveillance and for indication) to develop robust classifiers that distinguish the tissue injury(metabolites) and immune activation (chemokine) phenotype of both clinical and sub-clinical allograft injury. Sensitivity analysis will be used to establish biomarker classifiers for real-time clinical monitoring.

Aim 2. Establish the impact of sub-clinical allograft injury on outcome. We will determine exposure to sub-clinical allograft injury over the first year post-transplantation by serial measurement of urine metabolite and chemokine biomarkers, and determine the impact of this injury on allograft function, fibrosis and tubular atrophy (histology), and alloimmune memory response (donor-specific antibodies). These outcomes will be considered irrespective of renal biopsy-driven treatments, seeking instead to measure impact of injury that currently remains undetected.

Aim 3. Test a personalized approach for noninvasive urine monitoring and intervention. Using these validated biomarkers, we will enroll a new prospective cohort to pilot an intervention strategy based on real-time serial monitoring of urine to identify sub-clinical allograft injury and recommend diagnostic kidney biopsy for confirmation of injury phenotype and treatment. Outcome will be compared with the previous observational cohort.

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