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
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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
