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

Sean Agbor-Enoh, Annette M. Jackson, Ilker Tunc, Gerald J. Berry, Adam Cochrane, David Grimm, Andrew Davis, Pali Shah, Anne W. Brown, Yan Wang, Irina Timofte, Palak Shah, Sasha Gorham, Jennifer Wylie, Natalie Goodwin, Moon Kyoo Jang, Argit Marishta, Kenneth Bhatti, Ulgen Fideli, Yanqin YangHelen Luikart, Zeling Cao, Mehdi Pirooznia, Jun Zhu, Charles Marboe, Aldo Iacono, Steven D. Nathan, Jonathan Orens, Hannah A. Valantine, Kiran Khush

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)925-932
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume37
Issue number7
DOIs
StatePublished - Jul 2018

Keywords

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

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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