2010 - Transplantomics and Biomarkers in Transplantation
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4.1 - EARLY EVENTS IN THE ALLOGRAFT IDENTIFY MARKERS...
Presenter: Daniel, Maluf, Richmond, USA Authors: Daniel Maluf, Kellie Archer, Mariano Scian, Anne King, Davis Massey, Benjamin Whitehill, Marc Posner
EARLY EVENTS IN THE ALLOGRAFT IDENTIFY MARKERS THAT PREDISPOSE AND INITIATE THE DAMAGE INVOLVED IN THE PROGRESSION TO INTERSTITIAL FIBROSIS (IF) AND TUBULAR ATROPHY (TA)
Daniel Maluf, Kellie Archer, Mariano Scian, Anne King, Davis Massey, Benjamin Whitehill, Marc Posner, Valeria Mas. Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA, USA.
Early gene expression (GE) changes might signal allograft injury post-transplantation (Tx) and identify kidney recipients (KRs) at risk of IF/TA progression. Prospective GE profiling of allograft biopsies (Bx)(N=120) from 30 KRs at pre-implantation (PI), post-reperfusion (PR), 3 and 9 mo post-Tx was evaluated. Time-dependent associations among GE profiling, histological allograft damage and graft stressors were evaluated. GE on PI biopsies with and without glomerusclerosis (GSC) was evaluated. KRs were classified as with (N=12) or without (N=18) IF/TA (Banff score system) at 9 mo post-KTx. The RMA method was used to obtain probe set (Pset) expression summaries. For comparing PI to 3 mo Bx GE profiles, Pset level paired t-tests were performed. For 3 mo GE analysis between the biopsies with and without IF/TA at 9 mo post-KTx a two sample t-test was used. P-values were used in estimating the false discovery rate (FDR) using the q-value method. Allograft Bx from 20 KRs were used as a validation group. Six significant Psets (P<0.001) were identified when analyzing the samples with and without GSC at PI time. 668 probe sets were significant when comparing T0 vs. 3mo post-KTx (FDR<5%). The top molecular and cellular functions associated with these genes were cell death and protein synthesis. Apoptosis signaling was up regulated in the PI biopsies. Growth factors signaling were also up regulated. Cytotoxic T lymphocyte mediated apoptosis of target cells, CD28 signaling in T helper cells and T helper cells differentiation signaling were up regulated in 3mo Bx. GE at 3mo post-KTx (IF/TAvs. no-IF/TA at 9mo post-KTx,) showed 143 significant Psets (p<0.001). HGF and FGF signaling and THBS1 expression were up-regulated in IF/TA Bxs. IL10 signaling were up-regulated in patients without IF/TA at 9 mo post-KTx. GE profiling changes in early protocol graft biopsies was associated with progression to IF/TA.
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