Comparing plasma donor-derived cell-free DNA to gene expression in endomyocardial biopsies in the Trifecta-Heart study.
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PROVIDER: PRJNA1137896 | ENA |
REPOSITORIES: ENA
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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
Project description:The Trifecta study: comparing plasma donor-derived cell-free DNA levels with the molecular phenotype of kidney transplant biopsies
| PRJNA791412 | ENA
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
Project description:BackgroundThe relationship between the donor-derived cell-free DNA fraction (dd-cfDNA[%]) in plasma in kidney transplant recipients at time of indication biopsy and gene expression in the biopsied allograft has not been defined.MethodsIn the prospective, multicenter Trifecta study, we collected tissue from 300 biopsies from 289 kidney transplant recipients to compare genome-wide gene expression in biopsies with dd-cfDNA(%) in corresponding plasma samples drawn just before biopsy. Rejection was assessed with the microarray-based Molecular Microscope Diagnostic System using automatically assigned rejection archetypes and molecular report sign-outs, and histology assessments that followed Banff guidelines.ResultsThe median time of biopsy post-transplantation was 455 days (5 days to 32 years), with a case mix similar to that of 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 probe sets correlating with dd-cfDNA(%) were previously annotated for association with ABMR and all types of rejection, either natural killer (NK) cell-expressed (e.g., GNLY, CCL4, TRDC, and S1PR5) or IFN-γ-inducible (e.g., PLA1A, IDO1, CXCL11, and WARS). Among gene set and classifier scores, dd-cfDNA(%) correlated very strongly with ABMR and all types of rejection, reasonably strongly with active TCMR, and weakly with inactive TCMR, kidney injury, and atrophy fibrosis. Active ABMR, mixed, and active TCMR had the highest dd-cfDNA(%), whereas dd-cfDNA(%) was 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.ConclusionsThe dd-cfDNA(%) at time of indication biopsy strongly correlates with active molecular rejection and has the potential to reduce unnecessary biopsies.Clinical trial registration numberNCT04239703.
| S-EPMC8819982 | biostudies-literature
Project description:Donor organ shortage, growing waiting lists and organ discard rates are key problems in kidney transplantation. Donor organ quality is a critical factor determining post-transplant graft outcomes. However, organ quality is difficult to predict. Balancing the use of marginal donors without affecting outcomes is a main issue in the transplant field. The decision of acceptance of a kidney organ for transplantation is mainly based on donor organ biopsy findings, even though there are recognized limitations. The lack of better measures of organ quality at the time of transplantation as a predictor of performance graft outcome is a serious clinical challenge. Herein, we propose the use of a limited set of genes that captures intrinsic biology of kidney donor organs to improve available scoring systems. We studied gene expression in 192 deceased donor kidney biopsies and evaluated short-term outcomes which included delayed graft function and eGFR (high versus low) at 24 months for 168 kidney transplant recipients.
2022-06-13 | GSE147451 | GEO
Project description:Gene expression in donor kidney biopsies prior to kidney transplantation
| PRJNA614905 | ENA
Project description:summary : Tubulointerstitial transcriptome from ERCB subjects with chronic kidney disease and living donor biopsies. Samples included in this analysis have been previously analyzed using older CDF definitions and are included under previous GEO submissions - GSE47184 (chronic kidney disease samples), and GSE32591 (IgA nephropathy samples).
2018-01-24 | GSE104954 | GEO
Project description:Transcriptional profiling of adult mouse liver tissue comparing offspring derived from sperm and seminal plasma of normal protein diet fed males (controls, NN), sperm and seminal plasma from males fed a low protein diet fed males (LL), sperm from normal protein fed males and seminal plasma from low protein fed males (NL) or sperm from low protein diet fed males and seminal plasma from normal protein diet males (NL). The first letter denotes the diet of the sperm donor and the second letter the diet of the seminal plasma donor. Three-condition experiment: NN vs. LL, NN vs. NL, NN vs. LN. Adult offspring liver tissue. Biological replicates: 7 control (NN), 9 LL, 7 NL and 7 LN. One replicate per array chip.
2022-09-20 | GSE211520 | GEO
Project description:The presence of Donor-Specific anti-HLA Antibodies (DSA) is associated with an increased risk of both acute and chronic antibody-mediated rejection (AMR) in kidney allografts. AMR has remained challenging in kidney transplantation and is the major cause of late allograft loss. However, not all patients with DSA develop AMR, leading to the question of whether this represents accommodation, if other protective mechanisms exist or if this is actually a state of pre-rejection. Clinical and histological features, and gene expression profiles of kidney biopsy and blood samples of donor-specific antibody (DSA)+ patients without rejection were compared to antibody-mediated rejection (AMR) patients to elucidate the mechanisms involved in prevention of AMR. Of the 71 DSA+ patients, 46 had diagnosis of AMR and 25 did not show rejection. 50 DSA- patients without rejection were used as control. A subgroup of patients with available biopsy (n=61) and blood samples (n=54) were analyzed by microarrays. Both, DSA+/AMR+ and DSA+/AMR- biopsies showed increased expression of gene transcripts associated with cytotoxic T, natural killer cells, macrophages, interferon-gamma and rejection compared to DSA- biopsies. Regulatory T cell transcripts were up-regulated in DSA+/AMR+ and B cell transcripts in DSA+/AMR- biopsies. Whole blood gene expression analysis showed increased immune activity in only DSA+/AMR+ patients. There were no differentially expressed tolerant genes studied (n=14) in the blood or biopsy specimens of DSA+/AMR- patients. During a median 36 months follow-up, 4 DSA+/AMR- patients developed AMR, 12 continued to have DSAs but 9 lost DSAs. Gene expression profiles did not predict the development of AMR or persistence of DSAs. These results indicate increased immune activity in DSA+/AMR- biopsies despite lack of histologic findings of rejection.
2013-08-23 | GSE50084 | GEO
Project description:Expression profile of human donor lungs that have developed primary graft dysfunction (PGD) after lung transplantation and those that have not. In this study, we attempt to further our understanding of PGD by observing the changes in gene expression across donor lungs that developed PGD versus those that did not. Keywords: stress response
2007-06-06 | GSE8021 | GEO