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Distinct molecular processes mediate donor-derived cell-free DNA release from kidney transplants in different disease states.

ABSTRACT: Background: Among all biopsies in the Trifecta kidney study (ClinicalTrials.gov #NCT04239703), elevated plasma dd-cfDNA correlated most strongly with molecular antibody-mediated rejection (ABMR) (JASN 33:387, 2022), but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. Results: In all 604 biopsies, dd-cfDNA was elevated in ABMR, TCMR, and AKI. Within ABMR biopsies, dd-cfDNA correlated with ABMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as NRNI, dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (e.g., the TCMRProb classifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. Conclusions. In kidney transplants, elevated plasma dd-cfDNA is associated with three distinct molecular states in the donor tissue: ABMR, recent parenchymal injury, including cell cycling, and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305222 | GEO | 2025/08/22

REPOSITORIES: GEO

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The Trifecta study: comparing plasma donor-derived cell-free DNA levels with the molecular phenotype of kidney transplant biopsies

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