Levels of Cell-free DNA at the Diagnosis of Antibody-mediated Rejection Predict Poor Outcomes in Lung Transplant Recipients

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Abstract Rationale: Lung transplant recipients (LTRs) with antibody-mediated rejection (AMR) are at increased risk of chronic lung allograft dysfunction (CLAD) and early death. Currently, few methods exist to risk-stratify AMR patients for poor outcomes. We hypothesized that the degree of allograft injury at diagnosis of AMR is associated with an increased risk of CLAD/death. We tested this hypothesis using donor-derived cell-free DNA (dd-cfDNA), a sensitive molecular biomarker of allograft injury previously shown to risk-stratify LTRs in other disease states, such as acute cellular rejection. Methods: This analysis included 221 LTRs from two prospective cohort studies. Patients underwent serial plasma collection, bronchoscopy, and transbronchial biopsy at pre-specified timepoints and at times of concern for allograft dysfunction. Dd-cfDNA was measured from plasma by shotgun sequencing. AMR was diagnosed by adjudication committee according to International Society of Heart and Lung Transplantation criteria. Univariate logistic and Cox regression analyses determined the association of %dd-cfDNA levels at diagnosis of AMR with the risk of developing the primary, composite outcome of CLAD/death. Results: Fifty-six of 221 subjects had clinical AMR. Sixteen subjects were excluded due to missing %dd-cfDNA assessments or censorship, leaving 40 subjects for final analysis. Twenty-two of 40 patients had >1 episode of AMR, resulting in 71 AMR timepoints at a median of 12 months (IQR 4.7-19.9) post-transplant. Median %dd-cfDNA was 7-fold higher in AMR patients at time of their diagnosis compared with stable controls: 1.84 (0.75-6.51) versus 0.27 (0.11-0.58), p < 0.0001 (Figure 1A). Twenty-six of the 40 patients developed CLAD/death at a median of 9.5 months (4.0-23.2) from AMR diagnosis. At time of their diagnosis, median %dd-cfDNA was 0.91 (0.26-2.64) for AMR subjects that lived versus 2.24 (1.23-7.19) for those with CLAD/death, p = 0.007 (Figure 1B). In univariate analyses, higher levels of %dd-cfDNA at diagnosis of clinical AMR were associated with an increased risk of developing the composite outcome of CLAD/death with an odds ratio of 1.20 (95% CI 1.03-1.49), p = 0.048 and a hazard ratio of 1.06 (95% CI 1.004 – 1.109), p = 0.023. Conclusions: We have demonstrated that higher levels of %dd-cfDNA at the diagnosis of AMR are associated with an increased risk of CLAD and death. Ongoing studies will include multivariable analyses to adjust for confounders and further assess this association. This study adds to the growing body of literature demonstrating that dd-cfDNA is a potential clinical tool that can be used to risk-stratify post-transplant complications.

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