Clinical trial NCT04239703: Trifecta-Kidney cfDNA-MMDx Study
Official title: Trifecta-Kidney cfDNA-MMDx Study: Comparing the DD-cfDNA Test to MMDx Microarray Test, Central HLA Antibody Test, and Histology.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Kidney Transplant Rejection
Keywords: donor derived cell-free DNA
blood
kidney biopsy
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Natera, Inc.
name: One Lambda
First posted: 2020-01-27
Enrollment: 300
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population includes patients with a functioning kidney transplant undergoing a biopsy for clinical indications as standard of care to determine the cause of their graft dysfunction (deterioration in graft function, delayed graft function, proteinuria).

Brief summary: 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: 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 1203 kidney biopsies and 2422 corresponding blood samples. We extend this study to the total of 1400 biopsies and 2800 blood samples.

Eligibility criteria: 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.

Primary outcomes:
measure: Calibration of Prospera test for T cell-mediated rejection
timeFrame: 18 months
measure: Calibration of Prospera test for antibody-mediated rejection
timeFrame: 18 months
measure: Calibration of Prospera test for kidney injury
timeFrame: 18 months
measure: Report calibrated Prospera test results for rejection
timeFrame: 6 months
measure: Report calibrated Prospera test results for kidney injury
timeFrame: 6 month
Secondary outcomes:
measure: Determine if Prospera blood test can replace kidney biopsy test
timeFrame: 6 months
measure: Assessment of donor-specific antibody status
timeFrame: 6 months
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Baltimore
country: United States
facility: The Johns Hopkins University, School of Medicine
state: Maryland
city: Detroit
country: United States
facility: Detroit Medical Center, Harper University Hospital of Wayne State University
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital, Washington University at St. Louis
state: Missouri
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Ctr.
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Murray
country: United States
facility: Intermountain Transplant Services
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
city: Seattle
country: United States
facility: Division of Nephrology & UW Organ Transplant Center University of Washington
state: Washington
city: Melbourne
country: Australia
facility: Department of Nephrology, The Royal Melbourne Hospital 1 South East
city: Edmonton
country: Canada
facility: University of Alberta, Department of Medicine
state: Alberta
city: Vancouver
country: Canada
facility: ST. Paul's Hospital, 6A Providence Building, 1081 Burrard Street
state: British Columbia
city: Zagreb
country: Croatia
facility: University Hospital Merkur Renal Division
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine (IKEM)
city: Berlin
country: Germany
facility: Charite-Medical University of Berlin Department of Nephrology
city: Vilnius
country: Lithuania
facility: Centre of Nephrology, Vilnius University Hospital Santaros Klinikos
city: Białystok
country: Poland
facility: Department of Nephrology and Transplantation Medical University in Bialystok
city: Bydgoszcz
country: Poland
facility: University Hospital nr1 Bydgoszcz, Klinika Transplantologii
city: Gdańsk
country: Poland
facility: Medical University of Gdańsk Klinika Nefrologii Transplantologii i Chorób Wewnętrznych
city: Katowice
country: Poland
facility: Medical University of Silesia
city: Poznań
country: Poland
facility: Department of Transplantation and General Surgery, Wojewodzki Hospital
city: Szczecin
country: Poland
facility: Department of Nephrology, Transplantation and Internal Medicine, University Hospital n.2
city: Szczecin
country: Poland
facility: Pomeranian Medical University, Samodzielny Publiczny Woj. Szpital Zespolony, Oddzial Nefrologii i Transplantacji Nerek
city: Warsaw
country: Poland
facility: Medical University of Warsaw, Department of Transplantation Medicine, Nephrology and Internal Diseases
city: Warsaw
country: Poland
facility: Transplant Medicine & Nephrology Clinic, Medical University of Warsaw
city: Warsaw
country: Poland
facility: The Children's Memorial Health Institute, Department of Nephrology, Kidney Transplantation and Hypertension
city: Wrocław
country: Poland
facility: Wroclaw Medical University, Department of Nephrology and Transplantation Medicine
city: Ljubljana
country: Slovenia
facility: Department of Nephrology, University Medical Centre
city: Zürich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: University of Alberta
name: Philip F Halloran, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Madill-Thomsen KS, Halloran PF. Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope(R) Diagnostic System (MMDx). Clin Sci (Lond). 2024 Jun 5;138(11):663-685. doi: 10.1042/CS20220530.
citation: Halloran PF, Madill-Thomsen KS. Donor-derived Cell-free DNA: A Step Forward in the Quest for Transplant Truth. Transplantation. 2025 Jun 1;109(6):910-914. doi: 10.1097/TP.0000000000005332. Epub 2025 Jan 28. No abstract available.
citation: Halloran PF, Reeve J, Madill-Thomsen KS, Demko Z, Prewett A, Billings P; Trifecta Investigators. The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies. J Am Soc Nephrol. 2022 Feb;33(2):387-400. doi: 10.1681/ASN.2021091191. Epub 2022 Jan 20.
citation: Halloran PF, Reeve J, Madill-Thomsen KS, Demko Z, Prewett A, Gauthier P, Billings P, Lawrence C, Lowe D, Hidalgo LG; the Trifecta Investigators. Antibody-mediated Rejection Without Detectable Donor-specific Antibody Releases Donor-derived Cell-free DNA: Results From the Trifecta Study. Transplantation. 2023 Mar 1;107(3):709-719. doi: 10.1097/TP.0000000000004324. Epub 2023 Feb 21.
citation: Halloran PF, Madill-Thomsen KS, Reeve J. The Molecular Phenotype of Kidney Transplants: Insights From the MMDx Project. Transplantation. 2024 Jan 1;108(1):45-71. doi: 10.1097/TP.0000000000004624. Epub 2023 Dec 13.
citation: Halloran PF, Reeve J, Madill-Thomsen KS, Kaur N, Ahmed E, Cantos C, Al Haj Baddar N, Demko Z, Liang N, Swenerton RK, Zimmermann BG, Van Hummelen P, Prewett A, Rabinowitz M, Tabriziani H, Gauthier P, Billings P; Trifecta Investigators*. Combining Donor-derived Cell-free DNA Fraction and Quantity to Detect Kidney Transplant Rejection Using Molecular Diagnoses and Histology as Confirmation. Transplantation. 2022 Dec 1;106(12):2435-2442. doi: 10.1097/TP.0000000000004212. Epub 2022 Nov 22.
citation: Gauthier PT, Madill-Thomsen KS, Demko Z, Prewett A, Gauthier P, Halloran PF; Trifecta-Kidney Investigators. Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release From Kidney Transplants in Different Disease States. Transplantation. 2024 Apr 1;108(4):898-910. doi: 10.1097/TP.0000000000004877. Epub 2023 Dec 27.