Defining the relationships among four tests for assessing antibody-mediated rejection in heart transplants in a...

Four tests assess antibody-mediated rejection (ABMR) in heart transplants: standard of care local endomyocardial biopsy (EMB) histology, EMB molecular analysis (Molecular Microscope® Diagnostic System - MMDx), donor-derived cell-free DNA (dd-cfDNA), and donor-specific antibody (DSA). These tests have become critical for the development and use of novel therapies for ABMR. The Trifecta-Heart study (NCT04707872) aimed to define the relationships among these tests.

The study compared standard of care local histology diagnosis to the results of three central tests assessing ABMR: central DSA (One Lambda Inc.), dd-cfDNA (Natera, Inc.), and MMDx rejection assessments in 214 EMBs. Results were primarily expressed as positive-negative to facilitate analysis and to simulate the way all tests are used for clinical decision-making.

MMDx diagnosed more ABMR, TCMR, and No rejection (NR) than histology, a pattern confirmed in a validation set from the larger INTERHEART study (NCT02670408). When correlations and partial correlation modeling were used to defined the hierarchy of relationships among all tests, MMDx ABMR correlated more strongly with dd-cfDNA and DSA than did histologic ABMR. In MMDx-histology discrepancies, biopsies with no histologic rejection but with MMDx ABMR had elevated DSA and dd-cfDNA, and biopsies with MMDx NR but histology ABMR had low DSA and dd-cfDNA. DSA-negative ABMR by MMDx or histology had elevated dd-cfDNA, similar to DSA-positive ABMR. Most cases with molecular injury and high dd-cfDNA also had concurrent molecular rejection.

These inter-test relationships will be useful in guiding ABMR management, including monitoring of treatment responses and relapses, especially when discrepancies occur.