Dataset Information

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.

SUBMITTER: Modena BD

PROVIDER: S-EPMC5501990 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Modena B D BD Kurian S M SM Gaber L W LW Waalen J J Su A I AI Gelbart T T Mondala T S TS Head S R SR Papp S S Heilman R R Friedewald J J JJ Flechner S M SM Marsh C L CL Sung R S RS Shidban H H Chan L L Abecassis M M MM Salomon D R DR

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20160315 7

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.ustransp ...[more]

PMID: 26990570

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Project description:Rationale: Interstitial fibrosis and tubular atrophy (IFTA) is found in ~25% of 1-year biopsies post-transplant(1, 2). It correlates with decreased graft survival when histological evidence of inflammation is present¬.(3-5) Identifying the etiology of IFTA is important because longterm graft survival has not changed as expected given improved therapies and a dramatically reduced incidence of acute rejection.(6-8) Methods: Gene expression profiles of 234 samples were obtained with matching clinical and outcome data (7 transplant centers). 81 IFTA samples were divided into subphenotypes by the degree of inflammation on histology: IFTA with acute rejection (AR), IFTA with inflammation and IFTA without inflammation. Samples with AR (n=54) and normally functioning transplants (TX; n=99) were used in comparisons. Conclusions: Gene expression profiling of all IFTA phenotypes were strongly enriched for cAR gene dysregulation pathways, 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. We also found that the relative expression of AR-affiliated genes correlated with future graft loss in IFTA samples without inflammation. We conclude that undetected and/or undertreated immune rejection is leading to IFTA and graft failure. RNA was extracted from biopsy samples using the RNEasy kit (Qiagen), biotinylated cRNA prepared using Ambion MessageAmp Biotin II and hybridized to Affymetrix HG U133 Plus PM peg arrays (http://affymetrix.com/index.affx). Probe intensity data were log2–transformed and normalized using a custom-designed frozen Robust Multichip Average (fRMA). Low-variance and low signal probes were filtered according to industry standards, resulting in a filtered gene list with 17,564 transcripts. This dataset is part of the TransQST collection.

Project description:This study examines the effect of interstitial inflammation and interstitial fibrosis and tubular atrophy on renal survival in lupus nephritis.Baseline characteristics, initial (n = 301) and repeat biopsies (n = 94) and clinical outcomes for patients with biopsy-proven lupus nephritis from 1998 to 2014 were retrospectively collected from the medical record. Clinical and morphologic variables were evaluated using a Cox proportional hazards model and multiple imputation to address missing data. Renal survival was defined as the time from initial biopsy to end-stage renal disease [estimated glomerular filtration rate (eGFR) <15?mL/min/1.73 m2], dialysis or transplant.A total of 218 patients had follow-up and Class IV had worse renal survival, especially in patients with active and chronic glomerular lesions {relative to non-IV; Class IV-A: hazard ratio [HR] 0.92 [95% confidence interval (CI) 0.41-2.04], Class IV-AC: HR 5.02 [95% CI 2.70-9.36]}. Interstitial inflammation grade [relative to interstitial inflammation <5%; interstitial inflammation 5-25%: HR 2.36 (95% CI 1.13-4.91), interstitial inflammation 25-50%: HR 3.84 (95% CI 1.53-9.62), interstitial inflammation >50%: HR 7.67 (95% CI 3.75-15.67)] and increased interstitial fibrosis and tubular atrophy (IFTA) category [relative to IFTA <5%; IFTA 5-25%: HR 3.93 (95% CI 1.58-9.75), IFTA 25-50%: HR 4.01 (95% CI 1.37-11.70), IFTA >50%: HR 13.99 (95% CI 4.91-39.83)] predicted worse renal survival among all patients and those with Class IV on initial and repeat biopsy (n = 94) in a dose-dependent manner. Interstitial inflammation grade and IFTA category were significant predictors of renal survival in a multivariable model adjusted for age, gender, race, ethnicity and serum creatinine.Interstitial inflammation and IFTA independently affect renal survival and grading these lesions stratifies risk within the International Society of Nephrology and Renal Pathology Society classification of lupus nephritis.

Dataset Information

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

Publications

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

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