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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of Heart and Lung TransplantationAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Course of FEV(1) after onset of bronchiolitis obliterans syndrome in lung transplant recipients.Am J Respir Crit Care Med. 2007; 175: 1192-1198
- An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome.Eur Respir J. 2014; 44: 1479-1503
- International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010.J Heart Lung Transplant. 2010; 29: 717-727
- Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation.J Heart Lung Transplant. 2017; 36: 540-545
Islam AK, Sinha N, DeVos JM, et al. Early clearance vs persistence of de novo donor-specific antibodies following lung transplantation [e-pub ahead of print]. Clin Transplant. http://dx.doi.org/10.1111/ctr.13028, accessed February 15, 2018.
- De-novo donor-specific anti-HLA antibodies 30 days after lung transplantation are associated with a worse outcome.J Heart Lung Transplant. 2016; 35: 1067-1077
- Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation.J Heart Lung Transplant. 2016; 35: 397-406
- Antibody-mediated rejection in lung transplantation: clinical outcomes and donor-specific antibody characteristics.Am J Transplant. 2016; 16: 1216-1228
- De novo donor HLA-specific antibodies predict development of bronchiolitis obliterans syndrome after lung transplantation.J Heart Lung Transplant. 2014; 33: 1273-1281
- De Novo DQ Donor-specific antibodies are associated with chronic lung allograft dysfunction after lung transplantation.Am J Respir Crit Care Med. 2016; 194: 596-606
- Lung intragraft donor-specific antibodies as a risk factor for graft loss.J Heart Lung Transplant. 2016; 35: 1418-1426
- Acute antibody-mediated rejection after lung transplantation.J Heart Lung Transplant. 2013; 32: 1034-1040
- Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation.J Heart Lung Transplant. 2013; 32: 70-77
- Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.Chest. 2013; 143: 1717-1724
- Nodular endocardial infiltrates (Quilty lesions) cause significant variability in diagnosis of ISHLT Grade 2 and 3A rejection in cardiac allograft recipients.J Heart Lung Transplant. 2005; 24: S219-S226
- Late antibody-mediated rejection after heart transplantation following the development of de novo donor-specific human leukocyte antigen antibody.Transplantation. 2012; 93: 650-656
- Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation.J Heart Lung Transplant. 2017; 36: 1004-1012
- Cell-free DNA and active rejection in kidney allografts.J Am Soc Nephrol. 2017; 28: 2221-2232
- Noninvasive monitoring of infection and rejection after lung transplantation.Proc Natl Acad Sci USA. 2015; 112: 13336-13341
- Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection.Sci Transl Med. 2014; 6: 241ra77
- Validation of a clinical-grade assay to measure donor-derived cell-free DNA in solid organ transplant recipients.J Mol Diagn. 2016; 18: 890-902
- Universal noninvasive detection of solid organ transplant rejection.Proc Natl Acad Sci USA. 2011; 108: 6229-6234
- Pathology of pulmonary antibody-mediated rejection: 2012 update from the Pathology Council of the ISHLT.J Heart Lung Transplant. 2013; 32: 14-21
- A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients.J Heart Lung Transplant. 2011; 30: 361-374
- Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection.J Heart Lung Transplant. 2007; 26: 1229-1242
- Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.J Heart Lung Transplant. 2011; 30: 735-742
- A new classification system for chronic lung allograft dysfunction.J Heart Lung Transplant. 2014; 33: 127-133
- Donor-derived cell-free DNA is a novel universal biomarker for allograft rejection in solid organ transplantation.Transplant Proc. 2015; 47: 2400-2403
- The molecular phenotype of kidney transplants.Am J Transplant. 2010; 10: 2215-2222
- Identification and classification of acute cardiac rejection by intragraft transcriptional profiling.Circulation. 2011; 123: 2236-2243
Article Info
Publication History
Published online: February 03, 2018
Identification
Copyright
© 2018 Published by Elsevier Inc. on behalf of International Society for the Heart and Lung Transplantation
