Michael Keller1, Errol Bush2, Joshua M Diamond3, Pali Shah4, Joby Matthew4, Anne W Brown5, Junfeng Sun6, Irina Timofte7, Hyesik Kong8, Ilker Tunc9, Helen Luikart10, Aldo Iacono7, Steven D Nathan5, Kiran K Khush10, Jonathan Orens4, Moon Jang8, Sean Agbor-Enoh11. 1. Laborarory of Applied Precision Omics (APO), Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland; Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland; Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland. 2. Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland; Inova Fairfax Hospital, Falls Church, Virginia. 3. Division of Pulmonary and Critical Care Medicine, University of Maryland Medical Center, Baltimore, Maryland. 4. Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland; Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland. 5. Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland; Bioinformatics and Computation Core, NHLBI, Bethesda, Maryland. 6. Pulmonary and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland. 7. Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland; Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California. 8. Laborarory of Applied Precision Omics (APO), Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland. 9. Laborarory of Applied Precision Omics (APO), Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Pulmonary, Allergy, and Critical Care Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 10. Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland. 11. Laborarory of Applied Precision Omics (APO), Lung and Blood Institute (NHLBI), National Institutes of Health, Bethesda, Maryland; Genomic Research Alliance for Transplantation (GRAfT), National Heart, Lung and Blood Institute, Bethesda, Maryland; Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland. Electronic address: sean.agbor-enoh@nih.gov.
Abstract
BACKGROUND: Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD. METHODS: This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not. RESULTS: On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median [IQR]: 12.2% [8.2, 22.0] vs 8.5% [5.6, 13.2] p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed ∼2-times higher %ddcfDNA levels than patients who did not develop CLAD (median [IQR]: 22.4% [11.8, 27.6] vs 9.9% [6.7, 14.9], p = 0.007). CONCLUSION: PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone. Published by Elsevier Inc.
BACKGROUND: Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD. METHODS: This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not. RESULTS: On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median [IQR]: 12.2% [8.2, 22.0] vs 8.5% [5.6, 13.2] p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed ∼2-times higher %ddcfDNA levels than patients who did not develop CLAD (median [IQR]: 22.4% [11.8, 27.6] vs 9.9% [6.7, 14.9], p = 0.007). CONCLUSION: PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone. Published by Elsevier Inc.
Authors: E M Gielis; K J Ledeganck; B Y De Winter; J Del Favero; J-L Bosmans; F H J Claas; D Abramowicz; M Eikmans Journal: Am J Transplant Date: 2015-07-16 Impact factor: 8.086
Authors: Geert M Verleden; Allan R Glanville; Erika D Lease; Andrew J Fisher; Fiorella Calabrese; Paul A Corris; Christopher R Ensor; Jens Gottlieb; Ramsey R Hachem; Vibha Lama; Tereza Martinu; Desley A H Neil; Lianne G Singer; Greg Snell; Robin Vos Journal: J Heart Lung Transplant Date: 2019-04-03 Impact factor: 10.247
Authors: Roy D Bloom; Jonathan S Bromberg; Emilio D Poggio; Suphamai Bunnapradist; Anthony J Langone; Puneet Sood; Arthur J Matas; Shikha Mehta; Roslyn B Mannon; Asif Sharfuddin; Bernard Fischbach; Mohanram Narayanan; Stanley C Jordan; David Cohen; Matthew R Weir; David Hiller; Preethi Prasad; Robert N Woodward; Marica Grskovic; John J Sninsky; James P Yee; Daniel C Brennan Journal: J Am Soc Nephrol Date: 2017-03-09 Impact factor: 10.121
Authors: Iwijn De Vlaminck; Lance Martin; Michael Kertesz; Kapil Patel; Mark Kowarsky; Calvin Strehl; Garrett Cohen; Helen Luikart; Norma F Neff; Jennifer Okamoto; Mark R Nicolls; David Cornfield; David Weill; Hannah Valantine; Kiran K Khush; Stephen R Quake Journal: Proc Natl Acad Sci U S A Date: 2015-10-12 Impact factor: 11.205
Authors: Ankit Bharat; Kishore Narayanan; Tyler Street; Ryan C Fields; Nancy Steward; Aviva Aloush; Brian Meyers; Richard Schuessler; Elbert P Trulock; G Alexander Patterson; Thalachallour Mohanakumar Journal: Transplantation Date: 2007-01-27 Impact factor: 4.939
Authors: Sean Agbor-Enoh; Yan Wang; Ilker Tunc; Moon Kyoo Jang; Andrew Davis; Iwijn De Vlaminck; Helen Luikart; Pali D Shah; Irina Timofte; Anne W Brown; Argit Marishta; Kenneth Bhatti; Sasha Gorham; Ulgen Fideli; Jennifer Wylie; David Grimm; Natalie Goodwin; Yanqin Yang; Kapil Patel; Jun Zhu; Aldo Iacono; Jonathan B Orens; Steven D Nathan; Charles Marboe; Gerald J Berry; Stephen R Quake; Kiran Khush; Hannah A Valantine Journal: EBioMedicine Date: 2019-01-26 Impact factor: 8.143
Authors: Michael B Keller; Rohan Meda; Sheng Fu; Kai Yu; Moon Kyoo Jang; Ananth Charya; Gerald J Berry; Charles C Marboe; Hyesik Kong; Helen Luikart; Ileana L Ponor; Pali D Shah; Kiran K Khush; Steven D Nathan; Sean Agbor-Enoh Journal: Am J Transplant Date: 2022-04-12 Impact factor: 9.369
Authors: Justin P Rosenheck; David J Ross; Mena Botros; Alexander Wong; Jonathan Sternberg; Yen-An Chen; Nathan Liang; Amy Baer; Ebad Ahmed; Ryan Swenerton; Bernhard G Zimmermann; Gordon Fehringer; Zachary P Demko; Michael Olymbios; Paul R Billings; Brian C Keller Journal: Transplant Direct Date: 2022-03-25
Authors: Emmanuel Schneck; Ingolf Askevold; Ramona Rath; Andreas Hecker; Martin Reichert; Stefan Guth; Christian Koch; Michael Sander; Werner Seeger; Konstantin Mayer; Winfried Padberg; Natascha Sommer; Stefan Kuhnert; Matthias Hecker Journal: J Clin Med Date: 2022-07-16 Impact factor: 4.964
Authors: Elizabeth A Belloli; Tian Gu; Yizhuo Wang; Dharshan Vummidi; Dennis M Lyu; Michael P Combs; Aamer Chughtai; Susan Murray; Craig J Galbán; Vibha N Lama Journal: Am J Respir Crit Care Med Date: 2021-10-15 Impact factor: 30.528