Molecular criteria for pulmonary antibody-mediated rejection are associated with an increased risk of allograft failure.

Abstract

Background: Current International Society for Heart and Lung Transplantation (ISHLT) criteria for pulmonary antibody-mediated rejection (AMR) is predicated on a constellation of clinical, laboratory and histopathological parameters, including the presence of donor-specific antibodies (DSA). However, molecular evidence of allograft injury is not considered. The aim of this study was to investigate if allograft injury on the molecular level, as measured by donor-derived cell-free DNA (dd-cfDNA), identifies DSA positive patients experiencing a form of AMR associated with increased risk of chronic lung allograft dysfunction (CLAD) or death.

Methods: This multicenter, observational analysis included adult lung transplant recipients from two prospective cohort studies. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. Molecular AMR was defined as the presence of DSA and dd-cfDNA level >1% occurring > 30 days post-transplant. Clinical AMR was defined using ISHLT criteria. Time-dependent multivariable Cox regression models were used to determine the association of Clinical AMR or Molecular AMR with the composite outcome of CLAD or death.

Results: The final analysis included 209 subjects. Sixty-one subjects met criteria for molecular AMR. Molecular AMR captured 42/46 (91%) of patients who experienced Clinical AMR. Molecular AMR was associated with an increased risk of CLAD or death (HR 2.00, 95% CI: 1.18 - 3.38, p = 0.010). The results remained consistent analyzing Molecular AMR subjects without concomitant ISHLT Clinical AMR, acute rejection, or infection (HR 2.45, 95% CI: 1.01 - 5.94, p = 0.047).

Conclusions: Molecular AMR identifies a population of lung transplant recipients potentially experiencing antibody-mediated rejection not captured by current ISHLT criteria.