Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Intragraft anti-viral-specific gene expression as a distinctive transcriptional signature for polyomavirus-associated nephropathy

ABSTRACT: Polyoma virus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. Microscopic descriptions of PVAN are very similar to T-cell mediated rejection (TCMR) and have unclear underlying molecular mechanisms. To identify PVAN-specific gene expression, we analyzed 162 kidney biopsies with and without PVAN for global gene expression. Unsupervised hierarchical clustering analysis of all 162 biopsies revealed high similarity between PVAN and TCMR gene expression. Increasing the stringency for the specificity (p <0.001 and >2-fold expression) between PVAN and TCMR, 158 and 252 unique PVAN and TCMR injury-specific probesets were observed, respectively. While TCMR-specific probeset were overwhelmingly involved in immune response costimulation (CTLA4, CD28, CD86) and TCR (NFATC2, LCP2) signaling, PVAN-specific probesets were mainly related to viral replication process (IFITM1, LTF, NOSIP, RARRES3), RNA polymerase assembly (POLR2l, TAF10, RPS15) and pathogen recognition receptors (C1QA, C3, CFD). A principal component analysis using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific probesets (RPS15, CFD, LTF, and NOSIP) by QPCR and further confirmation by IHC of 2 PVAN-specific proteins with anti-viral function (LTF and IFITM1) was done, showing significantly higher expression within interstitial cellular infiltrates and in tubuli in PVAN specimens as compared to TCMR and NL kidney biopsies. In conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, particular PVAN-specific transcripts were identified with well-known anti-viral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design. A total of 168 kidney biopsies from kidney transplant patients were used. The kidney biopsies included renal biopsies from PVAN (n=10), T cell mediated cellular rejection (n=26), patients with IFTA (n=59), patients with stable grafts (STA) (n=73). This dataset is part of the TransQST collection.

ORGANISM(S): Homo sapiens

SUBMITTER: Tara Sigdel

PROVIDER: E-GEOD-72925 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy.

Sigdel Tara K TK Bestard Oriol O Salomonis Nathan N Hsieh Szu-Chuan SC Torras Joan J Naesens Maarten M Tran Tim Q TQ Roedder Silke S Sarwal Minnie M MM

Transplantation 20161001 10

<h4>Background</h4>Polyomavirus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. To identify PVAN-specific gene expression and underlying molecular mechanisms, we analyzed kidney biopsies with and without PVAN.<h4>Methods</h4>The study included 168 posttransplant renal allograft biopsies (T cell-mediated rejection [TCMR] = 26, PVAN = 10, normal functioning graft = 73, and interstitial fibrosis/tubular atrophy = 59) from 168 unique kidney allograft recipients. We per ...[more]

PMID: 27140517

Publication: 1/2

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Project description:Histologic diagnosis of T cell-mediated rejection in kidney transplant biopsies has limited reproducibility because it is based on non-specific lesions using arbitrary rules that are subject to differing interpretations. We used microarray results from 403 indication biopsies previously given histologic diagnoses to develop a molecular classifier that assigned a molecular T cell-mediated rejection score to each biopsy. Independent assessment of the biopsies by multiple pathologists confirmed considerable disagreement on the presence of TCMR features: 79-88% accuracy and 35-69% sensitivity. The agreement of the molecular T cell-mediated rejection score with the histology diagnosis was similar to agreement among individual pathologists: accuracy 89%, sensitivity 51%. However, the score also predicted the consensus among pathologists, being highest when all agreed. Many discrepancies between the scores and the histologic diagnoses were in situations where histology is unreliable e.g. scarred biopsies. The score correlated with histologic lesions and gene sets associated with T cell-mediated rejection. The transcripts most often selected by the classifier were expressed in effector T cells, dendritic cells, or macrophages or inducible by interferon-gamma. Thus the T cell-mediated rejection score offers an objective assessment of kidney transplant biopsies, predicting the consensus opinion among multiple pathologists, and offering insights into underlying disease mechanisms. Antibody-mediated rejection is a major cause of kidney transplant failure, but the current diagnostic system misses most cases due to dependency on subjective non-standardized tests. We hypothesized that molecular features could provide a test to address this problem. We classified 403 biopsies by a reference standard based on microcirculation lesions and donor-specific HLA antibody, and used microarray analysis to develop a classifier that assigned each biopsy a score reflecting the probability of antibody-mediated rejection. The scores correlated with donor-specific antibody and histologic lesions: 42/45 biopsies with antibody-mediated rejection scores >0.5 had both donor-specific antibody and microcirculation lesions. Intermediate scores (0.2-0.5) were more ambiguous, but became more specific combined with donor-specific antibody. Compared to diagnoses based on histology-plus-donor-specific antibody, the scores had sensitivity 0.67; specificity 0.90. Donor-specific antibody improved the specificity to 0.97. The score correlated not only with diagnoses of individual pathologists but with the consensus among multiple pathologists. The classifier used transcripts expressed in endothelial cells (e.g. CDH13, DARC, ROBO4) and NK cells (e.g. CX3CR1, FGFBP2), as well as IFNG-inducible transcripts e.g. CXCL11. Thus the molecular phenotype of antibody-mediated rejection provides not only an objective test that predicts microcirculation lesions and donor-specific HLA antibody, but also offers mechanistic insights. All consenting renal transplant patients undergoing biopsies for cause as standard of care. 403 samples and 8 controls (nephrectomies). This dataset is part of the TransQST collection.

Dataset Information

Intragraft anti-viral-specific gene expression as a distinctive transcriptional signature for polyomavirus-associated nephropathy

Publications

Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy.

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