Trifecta-Kidney cfDNA-MMDx Study

Study Overview
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Brief Summary
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Demonstrate the relationship between DD-cfDNA levels and HLA antibodies in blood, and the Molecular Microscope® (MMDx) Diagnostic System results in indication biopsies.

Detailed Description
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There is a need for better screening of kidney transplant patients for rejection. Patients with kidney transplants are routinely tested (creatinine, urine protein, histology and donor specific antibody (DSA) as standard of care to detect rejection, but these tests are not adequate. Rejection is often missed by these tests (false negatives) and other processes such as acute kidney injury can produce false-positive results. Moreover, histology has a high interobserver disagreement diagnosing rejection, and cannot accurately assess acute injury. A definitive molecular assessment of rejection and injury in kidney biopsies has emerged - the Molecular Microscope® Diagnostic System (MMDx) - developed by the Alberta Transplant Applied Genomics Centre, University of Alberta. Now a new screening test is being introduced: the monitoring of donor-derived cell-free DNA (DD-cfDNA) released in the blood by the kidney during rejection. The Natera Inc DD-cfDNA Prospera® test is based on the massively multiplex PCR that targets 13,392 single nucleotide polymorphisms and targeted sequences are quantified by Next Generation Sequencing. The Prospera® test done on kidney transplant recipients detected active rejection and differentiated it from borderline rejection and no rejection. It is likely, however, that DD-cfDNA test may miss some T cell-mediated rejection (TCMR) cases and the distinction between early and fully developed antibody-mediated rejection (ABMR) was not tested. No study has actually examined the DD-cfDNA results in kidney transplants with acute or chronic kidney disease (AKI and CKD). DD-cfDNA measurements have only been correlated with histology, a flawed standard. DD-cf-DNA test must now be calibrated against MMDx that is based on global gene expression, the new standard for biopsy interpretation. The present study will calibrate centrally measured (Natera Inc) DD-cfDNA levels obtained at the time of an indication biopsy against the MMDx measurements of TCMR, and ABMR (early-stage, fully-developed, and late-stage), AK, and atrophy-fibrosis. We will compare blood DD-cfDNA measurements in 600 samples at the time of 300 indication biopsies to the MMDx results, as well as central assessment of HLA antibody (One Lambda) in 300 blood samples, interpreted centrally as DSA based on the tissue typing results. This study is an extension of the INTERCOMEX ClinicalTrials.gov Identifier: NCT01299168. We have collected 1014 kidney biopsies and corresponding blood samples. Due to considerable interest from participating centers, we extend this study to the total of 1300 biopsies and 3900 blood samples.

Official Title
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Trifecta-Kidney cfDNA-MMDx Study: Comparing the DD-cfDNA Test to MMDx Microarray Test, Central HLA Antibody Test, and Histology.

Conditions
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Kidney Transplant Rejection

Intervention / Treatment
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* Diagnostic Test: MMDx
* Diagnostic Test: Prospera
* Diagnostic Test: HLA antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All kidney transplant recipients undergoing a kidney biopsy for clinical indications, as determined by their physician or surgeon, will be eligible to enroll in the study. Exclusion Criteria: Patients will be excluded from the study if they decline participation or are unable to give informed consent or multiple organ recipients.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Kidney transplant biopsies for cause<br>The study population includes patients with a functioning kidney transplant undergoing a biopsy for clinical indications as standard of care. | Diagnostic Test: MMDx<br>* Portion of kidney transplant indication biopsy<br>Diagnostic Test: Prospera<br>* Transplant patient blood sample<br>* Other names: transplant patient blood sample;Diagnostic Test: HLA antibody<br>* Transplant patient blood sample<br>* Other names: transplant patient blood sample;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calibration of Prospera test for T cell-mediated rejection | Calibration of DD-cfDNA test cut-off values against the probability of T cell-mediated rejection in the biopsy as reported by MMDx. | 18 months | 
| Calibration of Prospera test for antibody-mediated rejection | Calibration of DD-cfDNA test cut-off values against the probability of antibody-mediated rejection in the biopsy as reported by MMDx. | 18 months | 
| Calibration of Prospera test for kidney injury | Calibration of DD-cfDNA test cut-off values against the probability of acute and chronic kidney injury in the biopsy as reported by MMDx. | 18 months | 
| Report calibrated Prospera test results for rejection | Report new DD-cfDNA test cut-off values for rejection | 6 months | 
| Report calibrated Prospera test results for kidney injury | Report new DD-cfDNA test cut-off values for acute and chronic kidney injury | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine if Prospera blood test can replace kidney biopsy test | Determine if Prospera test, as calibrated by this DD-cfDNA-HLA-MMDx study, will avoid need for indication biopsy when kidney transplant function deteriorates. This will be based on the consensus between participating clinicians. | 6 months | 
| Assessment of donor-specific antibody status | Report and compare the DSA status based on centralized and local HLA antibody measurement. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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donor derived cell-free DNA, blood, kidney biopsy