title: Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy.
abstract: 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.
  
  
  
  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 performed gene expression assays and bioinformatics analysis to identify a set of PVAN-specific genes. Validity and relevance of a subset of these genes are validated by quantitative polymerase chain reaction and immunohistochemistry.
  
  
  
  Unsupervised hierarchical clustering analysis of all the biopsies revealed high similarity between PVAN and TCMR gene expression. Increased statistical stringency identified 158 and 252 unique PVAN and TCMR injury-specific gene transcripts respectively. Although TCMR-specific genes were overwhelmingly involved in immune response costimulation and TCR signaling, PVAN-specific genes were mainly related to DNA replication process, RNA polymerase assembly, and pathogen recognition receptors. A principal component analysis (PCA) using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific genes (RPS15, complement factor D, lactotransferrin, and nitric oxide synthase interacting protein) by quantitative polymerase chain reaction and confirmation by immunohistochemistry of 2 PVAN-specific proteins with antiviral function (lactotransferrin and IFN-inducible transmembrane 1) was done.
  
  
  
  In conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, PVAN-specific genes were identified with well-known antiviral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design.
authors.affiliation: 1 Department of Surgery, University of California, San Francisco, San Francisco, CA. 2 Kidney Transplant Unit, Bellvitge University Hospital, IDIBELL, UB, Barcelona, Spain. 3 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 4 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Tara K
authors.initials: TK
authors.lastname: Sigdel
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.forename: Nathan
authors.initials: N
authors.lastname: Salomonis
authors.forename: Szu-Chuan
authors.initials: SC
authors.lastname: Hsieh
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Maarten
authors.initials: M
authors.lastname: Naesens
authors.forename: Tim Q
authors.initials: TQ
authors.lastname: Tran
authors.forename: Silke
authors.initials: S
authors.lastname: Roedder
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
mesh_terms: D000293:Adolescent; D000328:Adult; D000943:Antigens, Differentiation / Q000235:genetics*; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D006084:Graft Rejection; D006801:Humans; D007223:Infant; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007781:Lactoferrin / Q000235:genetics*; D027601:Polyomavirus Infections / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000943:Antigens, Differentiation; C062010:leu-13 antigen; D007781:Lactoferrin