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J Heart Lung Transplant. 2018 Jul;37(7):925-932. doi: 10.1016/j.healun.2018.01.1305. Epub 2018 Jan 31.

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis.

Author information

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02423070 NCT01985412.

KEYWORDS:

cell-free DNA; clinical AMR; early diagnosis of AMR; molecular diagnosis; precision medicine; subclinical allograft injury

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