Sean Agbor-Enoh1, Annette M Jackson2, Ilker Tunc3, Gerald J Berry4, Adam Cochrane5, David Grimm6, Andrew Davis3, Pali Shah2, Anne W Brown7, Yan Wang8, Irina Timofte8, Palak Shah7, Sasha Gorham3, Jennifer Wylie6, Natalie Goodwin6, Moon Kyoo Jang3, Argit Marishta3, Kenneth Bhatti3, Ulgen Fideli3, Yanqin Yang3, Helen Luikart6, Zeling Cao8, Mehdi Pirooznia9, Jun Zhu3, Charles Marboe10, Aldo Iacono7, Steven D Nathan7, Jonathan Orens2, Hannah A Valantine11, Kiran Khush12. 1. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Department of Medicine, Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA; Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. 2. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Department of Medicine, Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA. 3. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. 4. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. 5. Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA. 6. Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. 7. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Department of Medicine, Inova Fairfax Hospital, Fairfax, Virginia, USA. 8. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Department of Medicine, University of Maryland Medical Center, Baltimore, Maryland, USA. 9. Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. 10. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Department of Pathology, New York Presbyterian University Hospital of Cornell and Columbia, New York, New York, USA. 11. Genomic Research Alliance for Transplantation (GRAfT), National Institutes of Health, Bethesda, Maryland, USA; Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA. Electronic address: hannah.valantine@nih.gov. 12. Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address: kiran@stanford.edu.
Abstract
BACKGROUND: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.
BACKGROUND: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation. METHODS: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR+ LTRs. RESULTS: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels. CONCLUSION: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.
Authors: Robin Schmitz; Zachary W Fitch; Paul M Schroder; Ashley Y Choi; Annette M Jackson; Stuart J Knechtle; Jean Kwun Journal: Transpl Int Date: 2020-01 Impact factor: 3.782
Authors: Andrew M Courtwright; Severine Cao; Isabelle Wood; Hari R Mallidi; Jared Kawasawa; Anna Moniodis; Julie Ng; Souheil El-Chemaly; Hilary J Goldberg Journal: Ann Am Thorac Soc Date: 2019-09
Authors: Sean Agbor-Enoh; Michael A Solomon; Samuel B Brusca; Jason M Elinoff; Yvette Zou; Moon Kyoo Jang; Hyesik Kong; Cumhur Y Demirkale; Junfeng Sun; Fayaz Seifuddin; Mehdi Pirooznia; Hannah A Valantine; Carl Tanba; Abhishek Chaturvedi; Grace M Graninger; Bonnie Harper; Li-Yuan Chen; Justine Cole; Manreet Kanwar; Raymond L Benza; Ioana R Preston Journal: Circulation Date: 2022-08-25 Impact factor: 39.918
Authors: Katrina Bazemore; Michael Rohly; Nitipong Permpalung; Kai Yu; Irina Timofte; A Whitney Brown; Jonathan Orens; Aldo Iacono; Steven D Nathan; Robin K Avery; Hannah Valantine; Sean Agbor-Enoh; Pali D Shah Journal: J Heart Lung Transplant Date: 2021-05-30 Impact factor: 10.247
Authors: Moon Kyoo Jang; Ilker Tunc; Gerald J Berry; Charles Marboe; Hyesik Kong; Michael B Keller; Pali D Shah; Irina Timofte; Anne W Brown; Ileana L Ponor; Cedric Mutebi; Mary C Philogene; Kai Yu; Aldo Iacono; Jonathan B Orens; Steven D Nathan; Sean Agbor-Enoh Journal: J Heart Lung Transplant Date: 2021-04-24 Impact factor: 13.569
Authors: Michael Keller; Errol Bush; Joshua M Diamond; Pali Shah; Joby Matthew; Anne W Brown; Junfeng Sun; Irina Timofte; Hyesik Kong; Ilker Tunc; Helen Luikart; Aldo Iacono; Steven D Nathan; Kiran K Khush; Jonathan Orens; Moon Jang; Sean Agbor-Enoh Journal: J Heart Lung Transplant Date: 2021-02-20 Impact factor: 13.569
Authors: Joshua Y C Yang; Stijn E Verleden; Arya Zarinsefat; Bart M Vanaudenaerde; Robin Vos; Geert M Verleden; Reuben D Sarwal; Tara K Sigdel; Juliane M Liberto; Izabella Damm; Drew Watson; Minnie M Sarwal Journal: J Clin Med Date: 2019-02-13 Impact factor: 4.241