There was no known link between the donor-derived cell-free DNA fraction (dd-cfDNA[percent]) in plasma in kidney transplant patients at the time of indication biopsy and gene expression in the biopsied allograft. For a study, researchers obtained tissue from 300 biopsies from 289 kidney transplant recipients in the prospective, multicenter Trifecta research to compare genome-wide gene expression in biopsies with dd-cfDNA(%) in matched plasma samples drawn soon before the biopsy. Rejection was evaluated utilizing the microarray-based Molecular Microscope Diagnostic System, which uses automatically assigned rejection archetypes and molecular report sign-outs, as well as histological assessments that adhered to Banff recommendations.

The median period of biopsy after transplantation was 455 days (5 days to 32 years), with a case-mix comparable to prior studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. All 20 top probe sets associated with dd-cfDNA(%) in genome-wide mRNA measurements have previously been annotated for connection with ABMR and all forms of rejection, whether natural killer (NK) cell-expressed (e.g., GNLY, CCL4, TRDC, and S1PR5) or IFN-–inducible (e.g., PLA1A, IDO1, CXCL11, and WARS). dd-cfDNA(%) linked extremely highly with ABMR and all forms of rejection, moderately strongly with active TCMR, and weakly with inactive TCMR, renal damage, and atrophy fibrosis among gene set and classifier scores. Active ABMR, mixed, and active TCMR had the greatest dd-cfDNA(%), whereas late-stage ABMR and less-active TCMR had lower dd-cfDNA(%). Molecular rejection factors predicted dd-cfDNA(%) better than histologic variables using multivariate random forests and logistic regression. The presence of dd-cfDNA (%) at the time of indicated biopsy highly corresponds with active molecular rejection and has the potential to avoid needless biopsies.