*Purpose: The ISHLT classification of rejection in heart allograft biopsies is independent of DSA status. There is only limited data on the prevalence of DSA in biopsies falling into specific histologic diagnostic categories for T-cell mediated rejection (TCMR) and antibody mediated rejection (AMR). The extent to which a random section taken from the tissue block for molecular studies reflects the overall pathologic diagnosis has also not been formally evaluated.

*Methods: Heart allograft biopsies obtained for clinical diagnostic purposes were subjected to a standard histopathologic examination. In-situ complement deposition was evaluated by immunohistochemistry for C4d. Medical records were reviewed for the presence of class I and class II anti-HLA donor specific antibodies (DSA) in the same time frame as the biopsy.

*Results: Examining 1 of 3 available tissue sections from 211 biopsies led to differences of at least one ISHLT 1990 rejection grade in 10% of biopsies with Quilty lesions, 42% with grade 1R, 13% with grade 2R and 31% with antibody mediated rejection grade pAMR (2) (Figure 1). A positive DSA test was obtained in 15/49 (31%) of TCMR grade 1R, 15/51 (29%) of grade 2R, 33/39 (85%%) of pAMR (1h+), and 23/27 (85%) of pAMR 2 biopsies. DSA test was negative in 62/72 (86%) pAMR (1i+) biopsies, but these could represent incipient AMR since 20/72 (28%) patients became DSA positive on subsequent follow up.

*Conclusions: (1). Rejection associated lesions are not uniformly distributed in myocardial tissue sections. This can explain why in some molecular studies that analyze limited biopsy tissue (eg PMID 28662985) up to 44% of grade 2/3 TCMRs are interpreted as ‘No Rejection’ and the corresponding archetype score is almost as high as that for histologic ABMR (0.36 vs 0.39). (2). Biopsies with histologic TCMR have concurrent DSA positivity in 29-31% biopsies, and these should be excluded from training sets used to develop molecular classifiers. (3) pAMR (1h+) biopsies may represent C4d negative ABMR in 85% of samples.

Fig. 1 Differences in degree & localization of inflammation across different biopsy fragments (upper panel). Biopsy sites, pericardium, intramyocardial fat, chordae tendineae & papillary muscle tissue can further confound the results of molecular analysis of randomly chosen tissue fragments (lower panel).

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