Trifecta-Kidney cfDNA-MMDx Study

Официальное название

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

Обзор

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

Подробное описание

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. Investigators have collected 1195 kidney biopsies, 1103 blood samples for DD-cfDNA test and 1150 blood samples for One Lamba test, and will extend this study to the total of 1400 biopsies and 2800 blood samples.

Вмешательства

• Диагностический тест MMDx
  Portion of kidney transplant indication biopsy
• Диагностический тест Prospera
  Transplant patient blood sample
• Диагностический тест HLA antibody
  Transplant patient blood sample

Первичные конечные точки

• Calibration of Prospera test for T cell-mediated rejection [Срок оценки: 18 months]
• Calibration of Prospera test for antibody-mediated rejection [Срок оценки: 18 months]
• Calibration of Prospera test for kidney injury [Срок оценки: 18 months]
• Report calibrated Prospera test results for rejection [Срок оценки: 6 months]
• Report calibrated Prospera test results for kidney injury [Срок оценки: 6 month]

Вторичные конечные точки (2)

• Determine if Prospera blood test can replace kidney biopsy test [Срок оценки: 6 months]
• Assessment of donor-specific antibody status [Срок оценки: 6 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• Patients will be excluded from the study if they decline participation or are unable to give informed consent or multiple organ recipients.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 11 центров

• Tampa General Hospital — Tampa
• University of Maryland School of Medicine — Baltimore
• The Johns Hopkins University, School of Medicine — Baltimore
• Detroit Medical Center, Harper University Hospital of Wayne State University — Detroit
• Henry Ford Hospital — Detroit
• Barnes-Jewish Hospital, Washington University at St. Louis — St Louis
• University Hospitals Cleveland Medical Ctr. — Cleveland
• Cleveland Clinic — Cleveland
• … и ещё 3 центра

Польша · 11 центров

• Department of Nephrology and Transplantation Medical University in Bialystok — Bialystok
• University Hospital nr1 Bydgoszcz, Klinika Transplantologii — Bydgoszcz
• Medical University of Gdańsk Klinika Nefrologii Transplantologii i Chorób Wewnętrznych — Gdansk
• Medical University of Silesia — Katowice
• Department of Transplantation and General Surgery, Wojewodzki Hospital — Poznan
• Department of Nephrology, Transplantation and Internal Medicine, University Hospital n.2 — Szczecin
• Pomeranian Medical University, Samodzielny Publiczny Woj. Szpital Zespolony, Oddzial Nefro — Szczecin
• Medical University of Warsaw, Department of Transplantation Medicine, Nephrology and Inter — Warsaw
• … и ещё 3 центра

Канада · 2 центра

• University of Alberta, Department of Medicine — Edmonton
• ST. Paul's Hospital, 6A Providence Building, 1081 Burrard Street — Vancouver

Австралия · 1 центр

• Department of Nephrology, The Royal Melbourne Hospital 1 South East — Melbourne

Хорватия · 1 центр

• University Hospital Merkur Renal Division — Zagreb

Чехия · 1 центр

• Institute for Clinical and Experimental Medicine (IKEM) — Prague

Германия · 1 центр

• Charite-Medical University of Berlin Department of Nephrology — Berlin

Литва · 1 центр

• Centre of Nephrology, Vilnius University Hospital Santaros Klinikos — Vilnius

Словения · 1 центр

• Department of Nephrology, University Medical Centre — Ljubljana

Швейцария · 1 центр

• University Hospital Zurich — Zurich

Публикации

• 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. PMID 38819301
• 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. PMID 39883025
• 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. PMID 35058354
• 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. PMID 36190186
• 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. PMID 37310258
• 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. Transplan PMID 35765145
• 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. PMID 38150492
• Hidalgo LG, Madill-Thomsen KS, Reeve J, Mackova M, Gauthier P, Demko Z, Prewett A, Lee M, Alhamad T, Anand S, Arnol M, Baliga R, Banasik M, Blosser CD, Bobba S, Brennan D, Bromberg J, Budde K, Chamienia A, Chow K, Ciszek M, Costa N, Deborska-Materkowska D, Debska-Slizien A, Domanski L, Fatica R, Francis I, Fryc J, Gill J, Gill J, Glyda M, Gourishankar S, Gryczman M, Gupta G, Hruba P, Hughes P, Jit PMID 40854490

Идентификаторы

NCT: NCT04239703 · ATAGC05

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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