*Purpose: Chronic lung allograft dysfunction (CLAD) is the primary etiology of graft failure and associated with poor survival post lung transplantation (LT). Risk factors for the development of CLAD include antibody mediated rejection (AMR), acute cellular rejection (ACR), donor specific antibodies (DSA), GERD, and infection. With clinical and histological assessment having poor reproducibility, earlier identification of high-risk patients for graft failure remains challenging. Donor-derived cell-free DNA (dd-cfDNA) is a biomarker for tissue damage. The determination of thresholds for clinical utilization of dd-cfDNA in LT have yet to be defined. The aim of this pilot study was to provide insight into allograft injury using dd-cfDNA (AlloSure) and determine its relationship to various pathologies as well as characterize its natural history.

*Methods: 23 LT recipients with various pathologies had single-point testing using AlloSure dd-cfDNA for initial assessment. Diagnoses were confirmed following full assessments with other investigations, imaging and medical history reviewed.

*Results: All patients with stable graft function had dd-cfDNA <0.15% (n=4). CLAD (n=6) patients had a median dd-cfDNA level of 0.85% (0.8-1.27), with 1 outlier <0.15%. Patients with CLAD and AMR (n=6) had a median of 1.2% (0.74-1.75). Patients with infection (n = 3) had median of 0.82% (0.58-1.01).

*Conclusions: Stable LT patients appear to have a baseline dd-cfDNA of < 0.15%. Increased dd-cfDNA was observed in CLAD, AMR and LT infection, and ACR. Early identification and distinction between AMR/ACR, infection and other types of acute injury is important as earlier treatment of these entities may prevent CLAD progression. Results suggest not all CLAD may be associated with elevated dd-cfDNA. Defined phenotypes: bronchiolitis obliterans syndrome and restrictive allograft syndrome exist but further phenotypes may be differentiated with larger studies using dd-cfDNA in prospective surveillance.

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