Evolving the surveillance and workup of heart transplant rejection: A real-world analysis of the Molecular Microscope Diagnostic System

Abstract

The Molecular Microscope Diagnostic System (MMDx) analyzes RNA transcripts of transplanted heart tissue to differentiate among T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), injury, and healthy tissue. However, little is known about its performance in relation to other modalities in a real-world heart transplant population. We evaluated whether MMDx performs in agreement with other validated modalities. Two hundred and twenty-eight corresponding endomyocardial biopsies (EMBx) and MMDx specimens from 135 adult heart transplant patients were retrospectively reviewed with correlating donor-derived cell-free DNA (dd-cfDNA).Rejection was classified on EMBx in 29 specimens (TCMR ≥ 2R and/or AMR ≥ 1), on MMDx in 56 specimens, and in 74 values with dd-cfDNA ≥0.20%. Despite moderate agreement between EMBx and MMDx (84% agreement, Cohen's kappa, 0.48, p < .001), systematic differences were observed (McNemar's test, p < .001) where MMDx classified 32 of 37 discordant cases as rejection. MMDx and dd-cfDNA demonstrated slight agreement (72% agreement, Cohen's kappa, 0.39, p < .001); however, systematic differences were also apparent where MMDx classified 12 of 50 discordant specimens as rejection when dd-cfDNA was <0.20% (McNemar's test, p < .001).Our findings provide insight on the performance of MMDx relative to other modalities in a heart transplant cohort and have implications on the surveillance and workup of allograft rejection in heart transplantation.

Relationship Between Donor Derived Cell-Free DNA and Tissue-Based Rejection-Related Transcripts In Heart Transplantation

“…However, there is a paucity of data assessing the relationship between dd-cfDNA and MMDx. In a recent single-center study, Alam et al elegantly showed that the concordance across all three diagnostic modalities (dd-cfDNA, MMDx, and traditional microscopy) was quite low (61%), but the comparison between two modalities, the percent agreement was relatively high (70-84%) (10). Similar to their study, our work also shows that the agreement between modalities was substantial (67-75%).…”

“…There is limited literature investigating the relationship between dd-cfDNA and MMDx, particularly in heart transplantation (10)(11)(12). Recently, a single-center study showed moderate agreement between MMDx and dd-cfDNA (10).…”

“…There is limited literature investigating the relationship between dd-cfDNA and MMDx, particularly in heart transplantation (10)(11)(12). Recently, a single-center study showed moderate agreement between MMDx and dd-cfDNA (10). In another study, when dd-cfDNA was used in conjunction with tissue RATs in kidney transplant patients, specificity to rule-in rejection was improved (12).…”

Anything But a Biopsy: The Quest for Noninvasive Alternatives in Heart Transplantation

“…17,18 It remains difficult to know what to do with discrepant information where cell damage/injury is seen in the absence of clear rejection or allograft dysfunction. [18][19][20] Given the cost, complexity, and uncertainties that exist coupled with the push to optimize noninvasive surveillance pathways, there remains keen interest in novel biomarker approaches.…”

“…17,18 It remains difficult to know what to do with discrepant information where cell damage/injury is seen in the absence of clear rejection or allograft dysfunction. 18-20…”