title: Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.
abstract: Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, 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. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: B D
authors.initials: BD
authors.lastname: Modena
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.|DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kurian
authors.affiliation: Department of Pathology, The Methodist Hospital, Houston, TX.
authors.forename: L W
authors.initials: LW
authors.lastname: Gaber
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: J
authors.initials: J
authors.lastname: Waalen
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
authors.forename: A I
authors.initials: AI
authors.lastname: Su
authors.affiliation: DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: T
authors.initials: T
authors.lastname: Gelbart
authors.affiliation: DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: T S
authors.initials: TS
authors.lastname: Mondala
authors.affiliation: DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: S R
authors.initials: SR
authors.lastname: Head
authors.affiliation: DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.
authors.forename: S
authors.initials: S
authors.lastname: Papp
authors.affiliation: Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.|Department of Transplant Nephrology, Mayo Clinic, Phoenix, AZ.
authors.forename: R
authors.initials: R
authors.lastname: Heilman
authors.affiliation: Northwestern Comprehensive Transplant Center, Northwestern University, Chicago, IL.
authors.forename: J J
authors.identifier: 0000-0002-9344-9928
authors.initials: JJ
authors.lastname: Friedewald
authors.affiliation: Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.|Glickman Urology and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH.
authors.forename: S M
authors.initials: SM
authors.lastname: Flechner
authors.affiliation: Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.|Scripps Center for Organ and Cell Transplantation, Scripps Health, La Jolla, CA.
authors.forename: C L
authors.initials: CL
authors.lastname: Marsh
authors.affiliation: Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.|Section of Transplant Surgery, University of Michigan, Ann Arbor, MI.
authors.forename: R S
authors.initials: RS
authors.lastname: Sung
authors.affiliation: Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.|Department of Surgery, St Vincent Medical Center, Los Angeles, CA.
authors.forename: H
authors.initials: H
authors.lastname: Shidban
authors.affiliation: Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.|Department of Transplant/Nephrology, University of Colorado, Aurora, CO.
authors.forename: L
authors.initials: L
authors.lastname: Chan
authors.affiliation: Northwestern Comprehensive Transplant Center, Northwestern University, Chicago, IL.
authors.forename: M M
authors.identifier: 0000-0001-9333-463X
authors.initials: MM
authors.lastname: Abecassis
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.|DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.|Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.
authors.forename: D R
authors.initials: DR
authors.lastname: Salomon
mesh_terms: D001284:Atrophy / Q000235:genetics / Q000401:mortality*; D005355:Fibrosis / Q000235:genetics / Q000401:mortality*; D020869:Gene Expression Profiling; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000235:genetics / Q000401:mortality*; D006085:Graft Survival; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000379:methods*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D009395:Nephritis, Interstitial / Q000235:genetics / Q000401:mortality*; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate
keywords: Interstitial fibrosis and tubular atrophy; basic (laboratory) research/science; genomics; graft survival; immunobiology; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; organ transplantation in general; rejection: T cell mediated (TCMR); translational research/science