*Purpose: There is growing interest in using transcriptomics to complement histologic evaluation of allograft hearts. The present study scrutinizes discrepancies between histologic and MMDx® systems and provides a logical framework to understand the underlying reasons.

*Methods: Sixty-two allograft biopsies from 22 pediatric HT recipients were clinically graded using the International Society of Heart Transplantation (ISHLT) 2005 criteria. Grade 1R biopsies were further subcategorized into grades 1A, 1B and 2, and grade 2R biopsies into grade 3A and higher, using ISHLT 1990 criteria. Antibody mediated injury was graded as pAMR (0), pAMR (1h+), pAMR (1i+) and pAMR (2). Typically, 2 fragments of tissue from each biopsy were sent for MMDx® analysis by clinical protocol among recipients with clinical concern for rejection (symptoms, new graft dysfunction, increase in DSA, or immediate prior biopsy ≥1B and/or pAMR1h+ or pAMR2-3. Histologic and gene expression findings were correlated and compared with the clinical parameters.

*Results: All biopsies without histologic evidence of TCMR and ABMR were also characterized as such by MMDx® (n = 30). MMDx® reported no TCMR in 15/15 biopsies with ISHLT grade 1A and 10/12 grade 1B TCMR (see Table) . The single grade 2 TCMR biopsy in our dataset was interpreted as molecular TCMR. Amongst the 4 biopsies with grade 3A TCMR, 2 were classified as molecular TCMR, one as molecular mixed ABMR/TCMR, and one with neither TCMR nor ABMR. Amongst 36 biopsies with pAMR (0), 8 were classified as molecular ABMR and all patients had concurrent circulating DSA, despite the negative C4d staining. Among biopsies graded pAMR 1h+, 11/18 had molecular findings interpreted as ABMR. MMDx® did not classify ABMR in 5 biopsies (two patients) with pAMR 2 histology, including one with diffuse C4d staining and circulating DSA. However, these biopsies were classified as showing severe injury phenotype.

*Conclusions: In this pediatric HTx cohort, MMDx® did not identify TCMR in biopsies with grade 1A, most grade 1B, and occasional grade 2 or 3A rejection. This may reflect lower sensitivity, an arbitrary threshold setting for molecular diagnosis, or misclassification by histologic grading. Detection of ABMR by MMDx® on biopsies graded pAMR0 with circulating DSA highlights the challenges of histology-based diagnosis of ABMR. While these diagnostic discrepancies demonstrate the need for further investigation, they may also suggest that histology and molecular analyses have complementary roles.

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