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Improving the histologic detection of DSA-negative antibody-mediated rejection in kidney transplants

ABSTRACT: Emerging treatments for antibody-mediated rejection (ABMR, NEJM391(2):122-132) have increased the importance of ABMR detection when donor-specific antibody (DSA) is negative. Lowering MFI cutoffs for DSA-positivity did not improve detection of DSA-negative ABMR. However, simply calling all DSA positive allowed Banff 2022 guidelines to identify 46% more ABMR cases with no measurable DSA, and per Net Reclassification Improvement increased agreement between histologic diagnoses and both dd-cfDNA (P=7.72E-7) and molecular ABMR (P=7.69E-7). New ABMR cases were as strongly positive for dd-cfDNA and molecular ABMR as those found using the conventional DSA interpretation. A validation set analysis using INTERCOMEX study data (ClinicalTrials.gov NCT#01299168) confirmed these findings, and found that the new DSA-negative ABMR cases identified by calling all DSA positive had the same risk for graft loss as those found with conventional DSA interpretation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303670 | GEO | 2026/01/16

REPOSITORIES: GEO

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Defining Relationships Among Tests for Kidney Transplant Antibody-Mediated Rejection

Project description:Effective therapies for kidney transplant antibody-mediated rejection (ABMR) (Mayer et al, 2024) will require accurate diagnoses plus assessment of ABMR activity, and the new tests that were used to show treatment effects in the clinical trial such as donor-derived cell-free DNA (dd-cfDNA) and molecular biopsy analysis (MMDx) could be useful. ). In a partial correlation network, all four tests were correlated, in a hierarchy of inter-test correlations: MMDx ABMR > dd-cfDNA > histology ABMR > and DSA. Surprisingly, DSA correlated at least as strongly with MMDx ABMR as with histologic ABMR, even though DSA is not used in MMDx. When expressed in the same six rejection classes, MMDx diagnosed ABMR more frequently than histology. When histology disagreed with MMDx ABMR, dd-cfDNA, and DSA correlated more strongly with MMDx assessment. However, histology also detected ABMR lesions in some cases that MMDx called no rejection, correlating with subthreshold molecular ABMR activity and dd-cfDNA and DSA (AJT 25:72-87, 2024). Thus, the four-way inter-test correlations extend below current thresholds for diagnosing ABMR. Molecular rejection predicted outcomes better than histologic rejection in Trifecta, confirmed in the earlier INTERCOMEX study. These results map a network of four ABMR-related tests that can add precision to ABMR assessment in trials and clinical management and highlight the need to establish the clinical significance of subthreshold ABMR activity.

2025-07-23 | GSE288273 | GEO

Distinct molecular processes mediate donor-derived cell-free DNA release from kidney transplants in different disease states.

Project description:Background: Among all biopsies in the Trifecta kidney study (ClinicalTrials.gov #NCT04239703), elevated plasma dd-cfDNA correlated most strongly with molecular antibody-mediated rejection (ABMR) (JASN 33:387, 2022), but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. Results: In all 604 biopsies, dd-cfDNA was elevated in ABMR, TCMR, and AKI. Within ABMR biopsies, dd-cfDNA correlated with ABMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as NRNI, dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (e.g., the TCMRProb classifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. Conclusions. In kidney transplants, elevated plasma dd-cfDNA is associated with three distinct molecular states in the donor tissue: ABMR, recent parenchymal injury, including cell cycling, and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.

2025-08-22 | GSE305222 | GEO

The Trifecta study: comparing plasma donor-derived cell-free DNA levels with the molecular phenotype of kidney transplant biopsies

Project description:Background. The Trifecta study (ClinicalTrials.gov #NCT04239703) is a prospective investigator-initiated trial to evaluate the relationship between plasma %dd-cfDNA at the time of indication biopsy and the molecular phenotype of the biopsy. Results. Median time of biopsy post-transplant was 455 days (5 days - 32 years), with case-mix similar to previous studies: 180 (60%) no rejection, 89 (30%) antibody-mediated rejection (ABMR), and 31 (10%) T cell-mediated rejection (TCMR) and mixed. In genome-wide mRNA measurements, all 20 top probesets correlating with %dd-cfDNA were previously annotated for association with ABMR and all rejection, either NK cell-expressed (e.g. GNLY, CCL4, TRDC, and S1PR5) or IFNG-inducible (e.g. PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, %dd-cfDNA correlated very strongly with ABMR and all rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury and atrophy-fibrosis. %dd-cfDNA was highest in active ABMR, mixed, and active TCMR but lower in late-stage ABMR and less active TCMR. By multivariate random forests and logistic regression, molecular rejection variables predicted %dd-cfDNA better than histologic variables. Conclusions. %dd-cfDNA at time of indication biopsy strongly correlates with active molecular rejection and has potential to reduce unnecessary biopsies.

2021-12-23 | GSE192444 | GEO

Transcriptomic profiling of blood memory B cell subsets in kidney transplant recipients

Project description:We compared the transcriptomic profile between patients without donor-specific antibodies (DSA-), patients with donor-specific antibodies without antibody-mediated rejection (DSA+ ABMR-) and patients with donor-specific antibodies and antibody-mediated rejection (DSA+ ABMR+). We found that patients with DSA+ ABMR+ had a distinct transcriptomic profile compared to DSA- and DSA+ ABMR- patients, characterized by upregulation of genes related to B cell activation and B cell effector functions.

2021-07-14 | GSE155670 | GEO

Transcriptomic profiling of circulating T follicular helper cells (cTFH) and activated memory B cells (ABC) in kidney transplant recipients

Project description:We compared the transcriptomic profile between patients without donor-specific HLA antibodies (DSA-), patients with donor-specific HLA antibodies without antibody-mediated rejection (DSA+ ABMR-) and patients with donor-specific HLA antibodies and antibody-mediated rejection (DSA+ ABMR+). We found that patient with DSA+ ABMR+ had a distinct transcriptomic profile compared to DSA- and DSA+ ABMR-, characterized by upregulation of genes encoding for germinal center T follicular helper cells function, T-B cell interaction and costimulatory molecules.

2020-11-09 | GSE145503 | GEO

Transcriptomic profiling of circulating T follicular helper cells in kidney transplant recipients

2021-07-01 | GSE134477 | GEO

Comparing plasma donor-derived cell-free DNA to gene expression in endomyocardial biopsies in the Trifecta-Heart study.

Project description:Background. Plasma donor-derived cell-free DNA (dd-cfDNA) is used to screen for rejection in heart transplants. We launched the Trifecta-Heart (ClinicalTrials.gov #NCT04707872), an investigator-initiated, prospective trial, to examine the correlations between genome-wide molecular changes in endomyocardial biopsies (EMBs) and plasma dd-cfDNA. The present report analyzes the correlation of plasma dd-cfDNA with the gene expression in EMBs from 4 vanguard centers and compared these correlations with those in 604 kidney transplant biopsies in the Trifecta-Kidney study (ClinicalTrials.gov #NCT04239703). Results. Top transcripts correlating with dd-cfDNA were related to genes increased in rejection such as IFNG-inducible genes (e.g., HLA-DMA), but also with genes induced by injury and expressed in macrophages (e.g., SERPINA1, HMOX1). In gene enrichment analysis, the top dd-cfDNA-correlated genes reflected inflammation and rejection pathways. Dd-cfDNA correlations with rejection genes in EMB were similar to those seen in kidney transplant biopsies, with somewhat stronger correlations for TCMR genes in hearts and ABMR genes in kidneys. However, the correlations with parenchymal injury-induced genes and macrophage genes were much stronger in hearts. Conclusions: In heart transplants in the Trifecta-Heart study, dd-cfDNA correlates significantly with molecular rejection but also with injury and macrophage infiltration, reflecting the proinflammatory properties of injured cardiomyocytes. The relationship supports the utility of dd-cfDNA in the clinical management of heart transplant recipients.

2024-07-19 | GSE272655 | GEO

Genomics of Chronic Rejection

Project description:We hypothesized that T cell-mediated immune mechanisms play a role in two conditions; 1: donor-specific antibody (DSA) negative transplant glomerulopathy (TGP) and 2: interstitial fibrosis and tubular atrophy (IFTA) with inflammation (i>0). We investigated gene expression profiles of those biopsies compared to biopsies with antibody-mediated rejection(ABMR) and to biopsies with non-specific IFTA and no inflammation. DSA negative TGP and IFTA with inflammation biopsies have a unique molecular signature distinct to that seen in biopsies with ABMR and IFTA without inflammation with significant expression of cytotoxic and regulatory T cells.

2017-01-17 | GSE93658 | GEO

Defining a NK cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies

Project description:In lung transplantation, antibody-mediated rejection (AMR) diagnosed by ISHLT criteria is uncommon compared to other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often DSA-negative and associated with NK cell transcripts. After optimizing rejection-selective transcript sets (RSTS) in a training set (n = 488), the resulting algorithms separated an NK cell-enriched rejection-like state (NKRL) from TCMR/Mixed in a test set (n = 488). Applying this approach to all 896 TBBs distinguished three groups - No rejection; TCMR/Mixed; and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with CLAD, reduced FEV1, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.

2025-07-24 | GSE303535 | GEO

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