MicroRNA Regulation in Blood Cells of Renal Transplanted Patients with Interstitial Fibrosis/Tubular Atrophy and Antibody-Mediated Rejection
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE115816 | GEO | 2018/08/20
REPOSITORIES: GEO
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Project description:Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
2024-09-04 | GSE275126 | GEO
Project description:The enigmatic natural killer (NK) cells mediate spontaneous cell-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity via cell surface Fc receptors. The dual functionality of NK cells may enable their participation in chronic active antibody-mediated rejection (CA-ABMR), wherein evidence for complement activation is inconsistent. We RNA sequenced 57 human kidney allograft biopsies to determine whether NK cell cytotoxicity pathway gene set enrichment is an attribute of CA-ABMR. Among the 15,910 intragraft-expressed genes, 60 were uniquely overexpressed in CA-ABMR compared to active antibody-mediated rejection (active-ABMR) or acute T cell-mediated rejection (TCMR), versus no rejection (NR) biopsies. Cell type annotation showed enrichment for T cells and NK cells, and molecular pathways related to T cells and NK cells in CA-ABMR versus active-ABMR biopsies. NK cell cytotoxicity gene set enrichment in CA-ABMR than in ABMR biopsies, but not in TCMR, was confirmed by gene set variation analysis. Cellular deconvolution analysis divulged a higher proportion of NK cells in CA-ABMR compared to active-ABMR, but not in TCMR; immunohistochemistry of 138 consecutive clinically indicated allograft biopsies validated a higher proportion of CD56+ NK cells in CA-ABMR. Principal component analysis of deconvolved immune cell transcriptomes separated CA-ABMR and TCMR from active-ABMR and NR biopsies. NK cell cytotoxicity pathway gene set was found to be enriched in rejection compared to no rejection biopsies in two publicly available kidney allograft microarray datasets. Altogether, CA-ABMR is exemplified by the overexpression of the NK cell pathway, and, surprisingly, compared to active-ABMR, is exemplified by key gene sets that are similar to TCMR.
2024-02-14 | GSE232825 | GEO
Project description:Molecular phenotyping of biopsies affords opportunities for increased precision and improved disease classification to address the limitations of conventional histologic diagnostic systems. We applied archetypal analysis, an unsupervised method similar to cluster analysis, to microarray data from 1208 prospectively collected kidney transplant biopsies from 13 centers. Seven machine learning-generated cross-validated classifier scores per biopsy were used as input for the archetypal analysis. Six archetypes representing extreme phenotypes were generated: no rejection; T cell-mediated rejection (TCMR); three phenotypes associated with antibody-mediated rejection (ABMR) - early-stage, fully-developed, and late-stage; and mixed rejection (TCMR plus early-stage ABMR). Each biopsy was assigned six scores, one for each archetype, that together represent a probabilistic assessment of that biopsy based on its rejection-related molecular properties. Viewed as clusters, the archetypes were similar to existing histologic Banff categories, but there was 32% disagreement, much of it probably reflecting the “noise” in the current histologic assessment system. Graft survival was worst for fully-developed and late-stage ABMR and was better predicted by molecular archetype scores than histologic diagnoses. The results provide a system for precision molecular assessment of biopsies and a new standard for recalibrating conventional diagnostic systems. (ClinicalTrials.gov NTC1299168) We applied archetypal analysis, an unsupervised method similar to cluster analysis, to microarray data from 1208 prospectively collected kidney transplant biopsies from 13 centers. This dataset is part of the TransQST collection.
2017-07-10 | E-GEOD-98320 | biostudies-arrayexpress
Project description:The first-generation Molecular Microscope® (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also detected acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov #NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used six rejection classifiers instead of RATs and generated seven rejection archetypes: No Rejection 48%; Minor 24%; TCMR1 2.3%; TCMR2 2.7%; TCMR/Mixed 2.7%; EABMR 3.9%; and FABMR 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long term risk. Graft survival and LVEF were reduced in hearts with TCMR, but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.
2024-04-02 | GSE262742 | GEO
Project description:Molecular phenotyping of biopsies affords opportunities for increased precision and improved disease classification to address the limitations of conventional histologic diagnostic systems. We applied archetypal analysis, an unsupervised method similar to cluster analysis, to microarray data from 1208 prospectively collected kidney transplant biopsies from 13 centers. Seven machine learning-generated cross-validated classifier scores per biopsy were used as input for the archetypal analysis. Six archetypes representing extreme phenotypes were generated: no rejection; T cell-mediated rejection (TCMR); three phenotypes associated with antibody-mediated rejection (ABMR) - early-stage, fully-developed, and late-stage; and mixed rejection (TCMR plus early-stage ABMR). Each biopsy was assigned six scores, one for each archetype, that together represent a probabilistic assessment of that biopsy based on its rejection-related molecular properties. Viewed as clusters, the archetypes were similar to existing histologic Banff categories, but there was 32% disagreement, much of it probably reflecting the “noise” in the current histologic assessment system. Graft survival was worst for fully-developed and late-stage ABMR and was better predicted by molecular archetype scores than histologic diagnoses. The results provide a system for precision molecular assessment of biopsies and a new standard for recalibrating conventional diagnostic systems. (ClinicalTrials.gov NTC1299168)
2017-07-10 | GSE98320 | GEO
Project description:Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces. All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified four idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal, T cell-mediated rejection (TCMR; T cell transcripts), antibody-mediated rejection (ABMR)-like (endothelial transcripts), and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population. Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or three pieces for each TBB will probably be needed to offset sampling variance.
2019-08-16 | GSE125478 | GEO
Project description:We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies (3BMBs). Unsupervised machine learning identified T cell-mediated rejection (TCMR) based on expression of validated rejection-associated transcripts (RATs). The relationship to patient outcomes is not known. We aimed to establish whether molecular TCMR in TBBs and 3BMBs has implications for future graft loss. Molecular TCMR scores assigned in all TBBs or high surfactant TBBs agreed closely, indicating that variation in alveolar content in TBBs does not prevent detection of TCMR. Molecular assessments of 3BMB-3BMB pairs showed less variation than TBB-TBB pairs. TBB TCMR scores correlated with those in 3BMB. In both formats, molecular TCMR was associated with increased risk of graft loss whereas the presence of histologic rejection or donor-specific antibodies was not. Molecular TCMR can be detected in TBBs or 3BMBs and is associated with future risk of graft loss. TCMR emerges as a n important contributor to risk of failure. ClinicalTrials.gov NCT02812290.
2020-10-07 | GSE150156 | GEO
Project description:Rationale: Interstitial fibrosis and tubular atrophy (IFTA) is found in ~25% of 1-year biopsies post-transplant(1, 2). It correlates with decreased graft survival when histological evidence of inflammation is present¬.(3-5) Identifying the etiology of IFTA is important because longterm graft survival has not changed as expected given improved therapies and a dramatically reduced incidence of acute rejection.(6-8) Methods: Gene expression profiles of 234 samples were obtained with matching clinical and outcome data (7 transplant centers). 81 IFTA samples were divided into subphenotypes by the degree of inflammation on histology: IFTA with acute rejection (AR), IFTA with inflammation and IFTA without inflammation. Samples with AR (n=54) and normally functioning transplants (TX; n=99) were used in comparisons. Conclusions: Gene expression profiling of all IFTA phenotypes were strongly enriched for cAR gene dysregulation pathways, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. We also found that the relative expression of AR-affiliated genes correlated with future graft loss in IFTA samples without inflammation. We conclude that undetected and/or undertreated immune rejection is leading to IFTA and graft failure. RNA was extracted from biopsy samples using the RNEasy kit (Qiagen), biotinylated cRNA prepared using Ambion MessageAmp Biotin II and hybridized to Affymetrix HG U133 Plus PM peg arrays (http://affymetrix.com/index.affx). Probe intensity data were log2–transformed and normalized using a custom-designed frozen Robust Multichip Average (fRMA). Low-variance and low signal probes were filtered according to industry standards, resulting in a filtered gene list with 17,564 transcripts. This dataset is part of the TransQST collection.
2016-01-15 | E-GEOD-76882 | biostudies-arrayexpress
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:Rationale: Interstitial fibrosis and tubular atrophy (IFTA) is found in ~25% of 1-year biopsies post-transplant(1, 2). It correlates with decreased graft survival when histological evidence of inflammation is present¬.(3-5) Identifying the etiology of IFTA is important because longterm graft survival has not changed as expected given improved therapies and a dramatically reduced incidence of acute rejection.(6-8) Methods: Gene expression profiles of 234 samples were obtained with matching clinical and outcome data (7 transplant centers). 81 IFTA samples were divided into subphenotypes by the degree of inflammation on histology: IFTA with acute rejection (AR), IFTA with inflammation and IFTA without inflammation. Samples with AR (n=54) and normally functioning transplants (TX; n=99) were used in comparisons. Conclusions: Gene expression profiling of all IFTA phenotypes were strongly enriched for cAR gene dysregulation pathways, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. We also found that the relative expression of AR-affiliated genes correlated with future graft loss in IFTA samples without inflammation. We conclude that undetected and/or undertreated immune rejection is leading to IFTA and graft failure.
2016-01-15 | GSE76882 | GEO