Molecular diagnosis of ABMR with or without donor-specific antibody in kidney transplant biopsies: Differences in timing and intensity but similar mechanisms and outcomes

Abstract

We studied the clinical, histologic, and molecular features distinguishing DSA‐negative from DSA‐positive molecularly defined antibody‐mediated rejection (mABMR). We analyzed mABMR biopsies with available DSA assessments from the INTERCOMEX study: 148 DSA‐negative versus 248 DSA‐positive, compared with 864 no rejection (excluding TCMR and Mixed). DSA‐positivity varied with mABMR stage: early‐stage (EABMR) 56%; fully developed (FABMR) 70%; and late‐stage (LABMR) 58%. DSA‐negative patients with mABMR were usually sensitized, 60% being HLA antibody‐positive. Compared with DSA‐positive mABMR, DSA‐negative mABMR was more often C4d‐negative; earlier by 1.5 years (average 2.4 vs. 3.9 years); and had lower ABMR activity and earlier stage in molecular and histology features. However, the top ABMR‐associated transcripts were identical in DSA‐negative versus DSA‐positive mABMR, for example, NK‐associated (e.g., KLRD1 and GZMB) and IFNG‐inducible (e.g., PLA1A). Genome‐wide class comparison between DSA‐negative and DSA‐positive mABMR showed no significant differences in transcript expression except those related to lower intensity and earlier time of DSA‐negative ABMR. Three‐year graft loss in DSA‐negative mABMR was the same as DSA‐positive mABMR, even after adjusting for ABMR stage. Thus, compared with DSA‐positive mABMR, DSA‐negative mABMR is on average earlier, less active, and more often C4d‐negative but has similar graft loss, and genome‐wide analysis suggests that it involves the same mechanisms. Summary Sentence In 398 kidney transplant biopsies with molecular antibody‐mediated rejection, the 150 DSA‐negative cases are earlier, less intense, and mostly C4d‐negative, but use identical molecular mechanisms and have the same risk of graft loss as the 248 DSA‐positive cases.

Antibody-mediated Rejection Without Detectable Donor-specific Antibody Releases Donor-derived Cell-free DNA: Results From the Trifecta Study

“…[27][28][29] Archetypal analysis automatically assigns scores to each biopsy describing its relationship to each archetype group: no rejection, TCMR1 (active TCMR, often mixed), TCMR2 (less active TCMR), early stage AMR, fully developed AMR, and late-stage AMR, which is often relatively inactive. 20,29 Archetypes recognize only the dominant phenotype and do not designate a separate mixed category.…”

“…15,16 Another test widely used to assess risk of rejection is the donor-specific HLA antibody (DSA) to predict antibody-mediated rejection (AMR), but this has been complicated by the recognition of DSA-negative AMR. 17-20…”

WARS1, TYMP and GBP1 display a distinctive microcirculation pattern by immunohistochemistry during antibody-mediated rejection in kidney transplantation

“…Although all active ABMR cases had anti-HLA DSA in this study, WARS1 and TYMP showed a diffuse microcirculation pattern in most C4d negative cases, highlighting their potential interest in this context. As non-anti-HLA DSA are still not routinely tested, the diagnosis of such ABMR cases with no detectable anti-HLA DSA ultimately relies on C4d in daily practice, which is not known to perform well in this setting 33 , 34 , with up to 86% of C4d-negative cases in a recent transcriptomic study 35 . By highlighting a diffuse endothelial staining by immunohistochemistry, WARS1 and TYMP could be of great interest in these cases and this needs to be assessed in further studies.…”

Tocilizumab for the treatment of chronic antibody mediated rejection in kidney transplant recipients

“…Several studies have shown that DSA negative microvascular inflammation has a similar prognosis to DSA positive microvascular inflammation 29,30 . In addition, recent studies suggest that molecular signatures do not distinguish between HLA DSA positive and HLA DSA negative cases 31,32 . Since all the patients in our cohort had previously had DSA and the activated molecular pathways (presumably targeted by tocilizumab) are the same between DSA positive and DSA negative cases, we included all 38 cases in our study.…”