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Effect of Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Exposure on Intragraft Gene Expression of Kidney Transplant Patients

ABSTRACT: Treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been shown to have anti-inflammatory effects such as decreased growth factors and cytokines in animal models, this effect however, has not been investigated in kidney transplant recipients. We aimed to study the effect of ACEI or ARB treatment on intragraft gene expression profiles of transplant kidney biopsies using microarrays. Both groups had similar demographic characteristics in terms of age, race, sex, type of transplant, previous history of transplantation or acute rejection, panel reactive antibody levels, and immunosuppressive treatment. There were no differences in acute and chronic Banff allograft injury scores between the 2 Groups. Intragraft gene expression profiles of ACEI or ARB treated Group 2 biopsies showed decreased gene transcripts of interferon-gamma and rejection-associated transcripts (GRIT) and constitutive macrophage-associated transcripts (CMAT) compared to Group 1 biopsies. There were no statistically significant differences in expression of cytotoxic T cell (CAT), regulatory T cell (TREG), B-cell (BAT), natural killer cell (NKAT), or endothelial cell-associated transcripts (ENDAT) between the 2 Groups. Our data suggest that exposure to ACEI or ARB was associated with down-regulation of GRIT and CMAT. This anti-inflammatory effect of ACEI or ARB treatment could be an additional benefit in kidney transplant recipients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83095 | GEO | 2016/06/10

SECONDARY ACCESSION(S): PRJNA325105

REPOSITORIES: GEO

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Effect of Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Exposure on Intragraft Gene Expression of Kidney Transplant Patients

Project description:Treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) has been shown to have anti-inflammatory effects such as decreased growth factors and cytokines in animal models, this effect however, has not been investigated in kidney transplant recipients. We aimed to study the effect of ACEI or ARB treatment on intragraft gene expression profiles of transplant kidney biopsies using microarrays. Both groups had similar demographic characteristics in terms of age, race, sex, type of transplant, previous history of transplantation or acute rejection, panel reactive antibody levels, and immunosuppressive treatment. There were no differences in acute and chronic Banff allograft injury scores between the 2 Groups. Intragraft gene expression profiles of ACEI or ARB treated Group 2 biopsies showed decreased gene transcripts of interferon-gamma and rejection-associated transcripts (GRIT) and constitutive macrophage-associated transcripts (CMAT) compared to Group 1 biopsies. There were no statistically significant differences in expression of cytotoxic T cell (CAT), regulatory T cell (TREG), B-cell (BAT), natural killer cell (NKAT), or endothelial cell-associated transcripts (ENDAT) between the 2 Groups. Our data suggest that exposure to ACEI or ARB was associated with down-regulation of GRIT and CMAT. This anti-inflammatory effect of ACEI or ARB treatment could be an additional benefit in kidney transplant recipients. We identified 29 near normal biopsies with chronic sum allograft injury score (ct+ci+cv) â¤ 3 for gene expression profiling comparing 2 groups; Group 1 (n=16), patients with no exposure of ACEI or ARB treatment and Group 2 patients (n=13) with exposure to ACEI or ARB at least 6 months prior to kidney biopsy. Biopsies with a diagnosis of acute or chronic rejection, recurrent or de novo glomerular disease, or polyoma nephropathy were excluded.

2016-06-10 | E-GEOD-83095 | biostudies-arrayexpress

Molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation

Project description:The aim of this study was to investigate correlations between early subclinical findings (10 and 90 day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx). Our goal was threefold: first, to confirm that intragraft molecular changes at 12m post-transplant are associated with the observed histologic changes in SLK transplant recipients, compared with KTA transplant recipients; second, to ascertain whether specific molecular pathways/markers that are not accounted for by routine histology are differentially expressed in the kidney allografts of the SLK transplant recipients; and third, to determine whether a molecular signature that is uniquely associated with simultaneous liver transplantation can be identified in kidney allografts. Biopsy samples were from positive and negative crossmatch simultaneous liver-kidney transplant recipients (12 month protocol biopsies) were compared to control patient (positive and negative crossmatch) biopsies obtained at 12 months. This dataset is part of the TransQST collection.

2017-04-14 | E-GEOD-97780 | biostudies-arrayexpress

Intragraft Gene Expression in Positive Crossmatch Kidney Allografts: Ongoing Inflammation Mediates Chronic Antibody-Mediated Injury

Project description:We studied intragraft gene expression profiles of positive crossmatch (+XM) kidney transplant recipients who develop transplant glomerulopathy (TG) and those who do not. Whole genome microarray analysis and quantitative rt-PCR for 30 transcripts were performed on RNA from protocol renal allograft biopsies in 3 groups: 1) +XM/TG+ biopsies before and after TG; 2) +XM/NoTG; and 3) negative crossmatch kidney transplants (control). Microarray comparisons showed few differentially expressed genes between paired biopsies from +XM/TG+ recipients before and after the diagnosis of TG. Comparing +XM/TG+ and control groups, significantly altered expression was seen for 2,447 genes (18%) and 3,200 genes (24%) at early and late time points, respectively. Canonical pathway analyses of differentially expressed genes showed inflammatory genes associated with innate and adaptive immune responses. Comparing +XM/TG+ and +XM/NoTG groups, 3,718 probe sets were differentially expressed but these were over-represented in only 4 pathways. A classic accommodation phenotype was not identified. Using rt-PCR, the expression of inflammatory genes was significantly increased in +XM/TG+ recipients compared to control biopsies and to +XM/NoTG biopsies. In conclusion, pre-transplant DSA results in a gene expression profile characterized by inflammation and cellular infiltration and the majority of XM+ grafts are exposed to chronic injury. We analyzed gene expression from 2 groups of positive crossmatch kidney transplant recipients (+XM/TG+ and +XM/TG-). Patients in the +XM/TG+ group had 2 biopsies - prior to the development of transplant glomerulopathy on biopsy (Biopsy 1; cg=0; n=10) and after development of transplant glomerulopathy (Biopsy 2; cg>0; n=10). The +XM/TG- patients had only a Biopsy 2 (cg=0; n=11). A third patient group served as controls (n=10) and were from -XM recipients. This dataset is part of the TransQST collection.

2012-05-30 | E-GEOD-34748 | biostudies-arrayexpress

Mechanisms and rescue strategies of Calcineurin inhibitor mediated tolerance abrogation

Project description:To ensure safety tolerance induction protocols are accompanied by conventional immunosuppressive drugs IS. But IS such as calcineurin inhibitors CNI can interfere with tolerance induction. We investigated the effect of an additional CNI treatment on anti-CD4 mAb-induced tolerance induction upon rat kidney transplantation. Additional CNI treatment induced deteriorated graft function and chronic rejection characterised by alloantibody production, intragraft plasma cells and C3d deposition. Microarray analysis revealed enhanced intragraft expression of the B cell chemokine CXCL13 upon additional CNI treatment. In contrast PNOC, a B cell-related gene highly expressed in operational tolerant kidney transplant recipients, was decreased in grafts of anti-CD4 mAb+CsA-treated recipients suggesting an altered balance of B regulatory genes. Transient B cell depletion or transfer of Tregs three weeks after transplantation could inhibit intragraft B cell accumulation, alloantibody production and ameliorate chronic rejection. These data represent unexpected findings and should be taken into consideration when designing new clinical trials. To safe the benefit of CNI in controlling memory T cell responses we need strategies for a therapeutic optimization. We show here that early B cell depletion or transfer of Tregs may be one approach to arrest B cell accumulation, activation and graft destruction. comparative analysis of different immunosuppressive regimens on renal allograft gene expression versus untreated allografts

2013-09-01 | E-GEOD-40454 | biostudies-arrayexpress

The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study

Project description:Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. Groups differed in median time post-transplant e.g. R3injury 99 days vs. R4late 3117 days. R2TCMR biopsies expressed typical TCMR-related transcripts e.g. intense IFNG-induced effects. R3injury displayed increased expression of parenchymal injury transcripts (e.g. hypoxia-inducible factor EGLN1). R4late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2TCMR correlated with histologic rejection although with many discrepancies, and R4late with fibrosis. R2TCMR, R3injury, and R4late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2TCMR scores. No confirmed cases of clinical ABMR were present in the population, and strategies that previously revealed antibody-mediated rejection (ABMR) in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, molecular analysis of liver transplant biopsies detects rejection, has the potential to resolve ambiguities, and could assist with immunosuppressive management.

2020-05-06 | GSE145780 | GEO

Intragraft Gene Expression in Positive Crossmatch Kidney Allografts: Ongoing Inflammation Mediates Chronic Antibody-Mediated Injury

2012-05-30 | GSE34748 | GEO

Australian Chronic Allograft Dysfunction III

Project description:The Australian Chronic Allograft Dysfunction (AUSCAD) study is an ongoing single centre cohort study at Westmead hospital in Australia. In this section of the study, we aimed to identify biomarkers for allograft rejection in kidney transplant recipients, 3-months after their transplant. Our study recruited 123 patients, each having protocol renal allograft biopsies taken 3-months post transplantation.

2024-04-05 | GSE261892 | GEO

Molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation

2017-04-14 | GSE97780 | GEO

Landscape of innate immune system transcriptome and acute T-cell mediated rejection of human kidney allografts

Project description:Acute rejection of human allografts has been viewed mostly through the lens of adaptive immunity, and the intragraft landscape of innate immunity genes has not been characterized in an unbiased fashion. We did RNA sequencing of 34 kidney allograft biopsy specimens from 34 adult recipients; 16 were categorized as Banff acute T-cell mediated rejection (TCMR) and 18 as normal. Computational analysis of intragraft mRNA transcriptome identified significantly higher abundance of mRNA for pattern recognition receptors in TCMR compared to normal biopsies, as well as increased expression of mRNAs for cytokines, chemokines, interferons, and caspases. Intragraft levels of calcineurin mRNA were higher in TCMR biopsies suggesting under immunosuppression compared to normal biopsies. Cell-type enrichment analysis revealed higher abundance of dendritic cells and macrophages in TCMR biopsies. Damage associated molecular patterns, the endogenous ligands for pattern recognition receptors, as well markers of DNA damage were higher in TCMR. mRNA expression patterns supported increased calcium flux and indices of endoplasmic, cellular oxidative, and mitochondrial stress were higher in TCMR. Expression of mRNAs in major metabolic pathways were decreased in TCMR. Our global and unbiased transcriptome profiling identified heightened expression of innate immune system genes during an episode of TCMR in human kidney allografts.

2019-07-26 | GSE131179 | GEO

Mechanisms and rescue strategies of Calcineurin inhibitor mediated tolerance abrogation

2013-09-01 | GSE40454 | GEO

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