Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms that Correlate with Worse Long-term Outcomes

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.

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