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Am J Transplant. 2016 Jul;16(7):1982-98. doi: 10.1111/ajt.13728. Epub 2016 Mar 15.

Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

Author information

1
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA.
2
DNA Microarray and Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, CA.
3
Department of Pathology, The Methodist Hospital, Houston, TX.
4
Transplant Genomics Collaborative Group (TGCG), La Jolla, CA.
5
Department of Transplant Nephrology, Mayo Clinic, Phoenix, AZ.
6
Northwestern Comprehensive Transplant Center, Northwestern University, Chicago, IL.
7
Glickman Urology and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH.
8
Scripps Center for Organ and Cell Transplantation, Scripps Health, La Jolla, CA.
9
Section of Transplant Surgery, University of Michigan, Ann Arbor, MI.
10
Department of Surgery, St Vincent Medical Center, Los Angeles, CA.
11
Department of Transplant/Nephrology, University of Colorado, Aurora, CO.

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.

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

PMID:
26990570
PMCID:
PMC5501990
DOI:
10.1111/ajt.13728
[Indexed for MEDLINE]
Free PMC Article

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