Marc E Richmond1, Steven D Zangwill2, Steven J Kindel3, Shriprasad R Deshpande4, Jacob N Schroder5, David P Bichell6, Kenneth R Knecht7, William T Mahle8, Mark A Wigger9, Nunzio A Gaglianello10, Elfriede Pahl11, Pippa M Simpson12, Mahua Dasgupta13, Paula E North14, Mats Hidestrand13, Aoy Tomita-Mitchell15, Michael E Mitchell16. 1. Department of Pediatrics, Division of Pediatric Cardiology, College of Physicians and Surgeons, Columbia University, New York, New York. 2. Division of Cardiology, Phoenix Children's Hospital, University of Arizona College of Medicine, Phoenix, Arizona. 3. Division of Pediatric Cardiology, Department of Pediatrics, Medical College of Wisconsin, Herma Heart Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin. 4. Division of Cardiology and Division of Cardiac Intensive Care, Children's National Hospital, Washington, District of Columbia. 5. Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University, Durham, North Carolina. 6. Division of Pediatric Cardiac Surgery, Department of Surgery, Vanderbilt University, Nashville, Tennessee. 7. Department of Pediatrics, Arkansas Children's Hospital, Little Rock, Arkansas. 8. Division of Cardiology, Department of Pediatrics, Emory University, Children's Healthcare of Atlanta, Atlanta, Georgia. 9. Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee. 10. Department of Medicine, Division of Cardiology Medical College of Wisconsin, Milwaukee, Wisconsin. 11. Ann & Robert H. Lurie Children's Hospital Chicago, Chicago, Illinois. 12. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin. 13. Division of Critical Care, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin. 14. Department of Pathology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin. 15. Division of Pediatric Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Herma Heart Institute, Milwaukee, Wisconsin. 16. Division of Pediatric Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Herma Heart Institute, Milwaukee, Wisconsin. Electronic address: mmitchell@chw.org.
Abstract
BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.
BACKGROUND: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample. METHODS: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAIHEART, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee. RESULTS: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection. CONCLUSIONS: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.
Authors: Peter J Kennel; Alexandre Yahi; Yoshifumi Naka; Donna M Mancini; Charles C Marboe; Klaas Max; Kemal Akat; Thomas Tuschl; Elena-Rodica M Vasilescu; Emmanuel Zorn; Nicholas P Tatonetti; Paul Christian Schulze Journal: ESC Heart Fail Date: 2021-03-13
Authors: Jeroen G H P Verhoeven; Dennis A Hesselink; Annemiek M A Peeters; Evert de Jonge; Jan H von der Thüsen; Ron H N van Schaik; Maja Matic; Carla C Baan; O C Manintveld; Karin Boer Journal: Transpl Int Date: 2022-03-21 Impact factor: 3.782
Authors: Marta Jiménez-Blanco Bravo; Laura Pérez-Gómez; Francisco J Hernández-Pérez; Carlos Arellano-Serrano; Mario Torres-Sanabria; Manuel Gómez-Bueno; Juan F Oteo-Domínguez; Susana Mingo-Santos; Javier Segovia-Cubero Journal: Front Cardiovasc Med Date: 2022-04-06