Molecular Evidence of Chronic Cellular Rejection in C4d and Microvascular Inflammation Negative Transplant Glomerulopathy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE93659 | GEO | 2017/01/17
SECONDARY ACCESSION(S): PRJNA361485
REPOSITORIES: GEO
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Project description:We investigated the clinical, histopathologic and genomic features of donor-specific antibody (DSA) +/C4d- and DSA-/C4d- transplant glomerulopathy (TGP) using microarrays. Comparison of the gene expression profiles of DSA-/C4d- TGP biopsies with ptc+g score > 1 to normal and IFTA (Interstitial Fibrosis and Tubular Atrophy) biopsies by microarrays revealed increased expression of quantitative cytotoxic T cell--associated transcripts (QCAT). However, CAMR (chronic antibody-mediated rejection) and DSA+/C4d- TGP had increased expression of QCAT, interferon-gamma and rejection induced, constitutive macrophage-associated, natural killer cell-associated, and DSA selective transcripts. B cell and endothelial cell associated transcripts expression were upregulated only in CAMR biopsies. Our results suggest that while DSA+/C4d- TGP should be classified under CAMR, DSA-/C4d- TGP with ptc+g score > 1 probably develops through a chronic cellular immune response. Total of 57 arrays included in this study. G1. Normal transplant kidney biopsies (N= 12); G2. Non-specific IFTA (N= 17); G3. TGP DSA-/C4d- (N=8); G4. TGP DSA+/C4d- (N= 9); G5. CAMR/TGP C4d+/DSA+ (N= 11)
2013-02-07 | E-GEOD-44131 | biostudies-arrayexpress
Project description:Kidney transplant biopsies showing transplant glomerulopathy (cg > 0) and microvascular inflammation (MVI) in the absence of C4d staining and DSAs do not fulfill the criteria for chronic active antibody-mediated rejection (CA-AMR) diagnosis or any other Banff category. In this multicenter intercontinental study including 36 cases, we compared, among other types of data, the transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString B-HOT panel. Due to lack of tissue, one sample was excluded from the transcriptomic analysis. In our analysis, nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, IFTA, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher activity of the T-cell receptor and B-cell associated transcripts. These results were coherent with those from our 5-plex immunofluorescence orthogonal analyses showing higher abundance of innate immune cells in the interstitium of CA-AMR DSA+/C4d+ samples when compared to cg+MVI DSA-/C4d- samples and a higher glomerular abundance of pan-T-cells in cg+MVI DSA-/C4d- samples when compared to CA-AMR DSA+/C4d+ samples. Here we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell-dominant phenotype.
2023-10-09 | GSE242984 | GEO
Project description:We investigated the clinical, histopathologic and genomic features of donor-specific antibody (DSA) +/C4d- and DSA-/C4d- transplant glomerulopathy (TGP) using microarrays. Comparison of the gene expression profiles of DSA-/C4d- TGP biopsies with ptc+g score > 1 to normal and IFTA (Interstitial Fibrosis and Tubular Atrophy) biopsies by microarrays revealed increased expression of quantitative cytotoxic T cell--associated transcripts (QCAT). However, CAMR (chronic antibody-mediated rejection) and DSA+/C4d- TGP had increased expression of QCAT, interferon-gamma and rejection induced, constitutive macrophage-associated, natural killer cell-associated, and DSA selective transcripts. B cell and endothelial cell associated transcripts expression were upregulated only in CAMR biopsies. Our results suggest that while DSA+/C4d- TGP should be classified under CAMR, DSA-/C4d- TGP with ptc+g score > 1 probably develops through a chronic cellular immune response.
2013-02-07 | GSE44131 | GEO
Project description:We study the global gene expression profiles of TGP patients with or without graft loss to determine if a clinical and/or gene expression profile can predict allograft survival. Transplant glomerulopathy (TGP) carries a poor prognosis and is associated with decreased allograft survival. In a large series of kidney transplant recipients, graft loss was observed in 38% of TGP patients at 5 years compared to 5% in patients without TGP. Among patients with TGP, predictors of poor outcome included C4d deposition in the peritubular capillaries, higher serum creatinine and proteinuria at diagnosis, the severity of interstitial fibrosis, and GBM duplication (higher Banff ‘chronic glomerulopathy [cg]’ score), and the presence of DSA. However, the importance of microvascular inflammation determined by peritubular capillaritis (ptc) and glomerulitis (g) scores and the strength of DSA has not been explored thoroughly. We have recently reported the intragraft gene expression profiles of TGP patients, with or without DSA. However, the association between gene expression profiles of biopsies and the allograft survival has not been investigated. In this study, in addition to known clinical and demographic factors associated with poor outcomes in TGP, we specifically aimed to investigate if intragraft gene expression profiles by microarrays, microvascular inflammation scores, and the strength of DSA determined by mean fluorescence intensity (MFI) values could predict allograft loss in TGP patients.
2014-06-18 | GSE58601 | GEO
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
Project description:We study the global gene expression profiles of TGP patients with or without graft loss to determine if a clinical and/or gene expression profile can predict allograft survival. Transplant glomerulopathy (TGP) carries a poor prognosis and is associated with decreased allograft survival. In a large series of kidney transplant recipients, graft loss was observed in 38% of TGP patients at 5 years compared to 5% in patients without TGP. Among patients with TGP, predictors of poor outcome included C4d deposition in the peritubular capillaries, higher serum creatinine and proteinuria at diagnosis, the severity of interstitial fibrosis, and GBM duplication (higher Banff M-bM-^@M-^Xchronic glomerulopathy [cg]M-bM-^@M-^Y score), and the presence of DSA. However, the importance of microvascular inflammation determined by peritubular capillaritis (ptc) and glomerulitis (g) scores and the strength of DSA has not been explored thoroughly. We have recently reported the intragraft gene expression profiles of TGP patients, with or without DSA. However, the association between gene expression profiles of biopsies and the allograft survival has not been investigated. In this study, in addition to known clinical and demographic factors associated with poor outcomes in TGP, we specifically aimed to investigate if intragraft gene expression profiles by microarrays, microvascular inflammation scores, and the strength of DSA determined by mean fluorescence intensity (MFI) values could predict allograft loss in TGP patients. The study population was derived from renal allograft biopsies diagnosed with TGP at Montefiore Medical Center, Bronx, NY from January 2009 to December 2012. All biopsies were clinically indicated for elevated creatinine or proteinuria. A retrospective chart review was conducted to record clinical, demographic, immunological, and histopathological parameters and graft outcomes. Graft loss was defined as requiring dialysis and/or retransplantation during follow-up. Of the 525 patients who underwent clinically indicated transplant kidney biopsies, 52 patients (10%) had diagnosis of TGP. Median follow up time after the biopsy was 23 months (range, 1-46). Seventeen patients (32%) lost their allografts (defined by return to dialysis or re-transplantation) at a median time of 16 months (range, 1-44). A subgroup of patients who were enrolled in the IRB-approved M-bM-^@M-^\Immune Monitoring StudyM-bM-^@M-^] and had clinically indicated biopsy samples were included in the analysis. A total of 28 biopsy samples (8 graft loss and 20 functioning allograft) were used for gene expression profiling.
2014-06-18 | E-GEOD-58601 | biostudies-arrayexpress
Project description:Kidney transplant recipients with biopsy-proven microvascular injury (MVI) have increased risk for allograft failure. MVI is often caused by antibody-mediated injury that is resistant to available treatments. Current diagnostic methods are also inadequate, with interobserver variability in traditional pathology reads, variable assessment of circulating donor-specific antibody between HLA laboratories, and peritubular capillary C4d staining. Molecular assessments of kidney biopsies can provide improved sensitivity for diagnosing MVI and other allograft pathology, while improving reproducibility and objectivity. Most molecular classifiers have been based on whole genome sequencing to develop diagnostic tests, but have provided limited therapeutic targets. In this study, we pursued a candidate gene approach to measure WNT pathway genes in residual clinical FFPE biopsies with and without MVI. We focused on the WNT pathway because of previous translational studies that implicated this pathway in chronic renal allograft injury as well as vascular injury in native chronic kidney disease.
2019-06-15 | GSE115989 | GEO
Project description:We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Immunohistochemistry for C4d was performed on paraffin-embedded sections. Of the 255 biopsies analyzed, 51% were C4d negative, 4% were minimal, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+. Minimal and focal/ diffuse PTC C4d+ staining were associated with a higher frequency of donor-specific anti-HLA antibodies (DSA) (67% vs. 82% vs. 25%), antibody mediated rejection (AMR) (66% vs. 89% vs. 19%) and mean glomerulitis (0.88 vs. 0.65 vs. 0.25, p=0.003), interstitial inflammation (1.25 vs. 1.41 vs. 0.79; p=0.003) and peritubular capillaritis scores (1.5 vs. 1.5 vs. 0.34; p < 0.001), compared to the C4d negative group, respectively. There were no differences in the DSA frequency, AMR rate, and Banff scores between isolated glomerular C4d+ and negative patients. While both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, and interferon-gamma and rejection induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis based transcripts, there was no activation of immune-response related genes in isolated glomerular C4d+ biopsies. In summary, minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR.
2012-05-29 | GSE38262 | GEO
Project description:We investigated the clinical and molecular significance of minimal peritubular capillary (PTC) and isolated glomerular C4d+ staining using microarrays. Immunohistochemistry for C4d was performed on paraffin-embedded sections. Of the 255 biopsies analyzed, 51% were C4d negative, 4% were minimal, 15% focal or diffuse PTC C4d+, and 31% isolated glomerular C4d+. Minimal and focal/ diffuse PTC C4d+ staining were associated with a higher frequency of donor-specific anti-HLA antibodies (DSA) (67% vs. 82% vs. 25%), antibody mediated rejection (AMR) (66% vs. 89% vs. 19%) and mean glomerulitis (0.88 vs. 0.65 vs. 0.25, p=0.003), interstitial inflammation (1.25 vs. 1.41 vs. 0.79; p=0.003) and peritubular capillaritis scores (1.5 vs. 1.5 vs. 0.34; p < 0.001), compared to the C4d negative group, respectively. There were no differences in the DSA frequency, AMR rate, and Banff scores between isolated glomerular C4d+ and negative patients. While both minimal and focal/diffuse C4d+ biopsies showed increased expression of genes related to the immune response, and interferon-gamma and rejection induced, cytotoxic T cell and constitutive macrophage-associated pathogenesis based transcripts, there was no activation of immune-response related genes in isolated glomerular C4d+ biopsies. In summary, minimal PTC C4d+ staining but not isolated glomerular C4d+ staining is associated with AMR. Total of 92 arrays included in this study. G1. Native pre-implantation biopsies (N= 10); G2. Focal or diffuse PTC C4d+ (N= 13); G3. Minimal PTC C4d+ (N=4); G4. Isolated glomerular C4d+ with glomerular disease (N= 13); G5. Isolated glomerular C4d+ staining without glomerular disease (N= 15); G6. C4d negative with glomerular disease (N= 12); G7. C4d negative biopsies without evidence of glomerular disease (N=25)
2012-05-28 | E-GEOD-38262 | biostudies-arrayexpress
Project description:Kidney transplant recipients with biopsy-proven microvascular injury (MVI) have increased risk for allograft failure. MVI is often caused by antibody-mediated injury that is resistant to available treatments. Current diagnostic methods are also inadequate, with interobserver variability in traditional pathology reads, variable assessment of circulating donor-specific antibody between HLA laboratories, and peritubular capillary C4d staining. Molecular assessments of kidney biopsies can provide improved sensitivity for diagnosing MVI and other allograft pathology, while improving reproducibility and objectivity. Most molecular classifiers have been based on whole genome sequencing to develop diagnostic tests, but have provided limited therapeutic targets. In this study, we pursued a candidate gene approach to measure WNT pathway genes in residual clinical FFPE biopsies with and without MVI. We focused on the WNT pathway because of previous translational studies that implicated this pathway in chronic renal allograft injury as well as vascular injury in native chronic kidney disease. Case-control study of 95 residual FFPE biopsies with MVI (g+ptc score >= 2, n=50) or Stable (g+ptc score < 2 and no other major abnormalities, n=45). Biopsies were retrieved from a biorepository of over 500 kidney transplant biopsies. We compared expression of 180 WNT pathway genes and 30 custom skipe-in targets (derived from previous studies of endothelial injury in transplantation) between MVI and Stable groups, with correction for multiple comparisons using FDR < 5%. This dataset is part of the TransQST collection.
2019-06-15 | E-GEOD-115989 | biostudies-arrayexpress