BACKGROUND: Tubulointerstitial damage (TID) is a key feature of chronic allograft injury (CAI) and loss. One proposed mechanism attributing to TID is epithelial-to-mesenchymal transition (EMT); however, it has recently been shown to be unrelated to early TID in adult renal allografts. This has yet to be studied in late TID or in pediatric renal transplantation; both questions were investigated. METHODS: By using 83 unique pediatric renal transplant recipients, 126 protocol, serial, posttransplant renal biopsies were examined by centralized, blinded Banff grading for CAI and transcriptional profiling (AffyU133+2.0) at 3 (n=20), 6 (n=45), 12 (n=19), and 24 months (n=42). Two hundred forty-three EMT-associated genes, identified from the literature, were interrogated for their differential expression in biopsies with and without CAI, using standard bioinformatic algorithms. RESULTS: Early (3-6 months) enrichment of EMT (P≤0.05) related gene expression was noted, correlating with inflammation in the graft (total i scores), with upregulation of hepatocyte growth factor at 24 months, indicating a time-dependent mechanism of action. We observed a strong correlation of EMT-related gene expression with early interstitial fibrosis (r<0.45) for size-mismatched allograft recipients. Throughout 24 months posttransplant, EMT signaling and epithelial-mesenchymal-epithelial cycling were associated with progressive CAI injury, with the greatest risk factors being ischemia, immune burden, and the calcineurin inhibitor toxicity score. CONCLUSIONS: EMT has a role in the evolution of CAI in pediatric transplantation. We postulate that EMT dysregulation plays a dual role in fibrosis/injury repair and healing. The evolution of this chronic injury response stems from size- mismatched transplant ischemia, calcineurin inhibitor nephrotoxicity, and inflammatory response within the allograft.
BACKGROUND: Tubulointerstitial damage (TID) is a key feature of chronic allograft injury (CAI) and loss. One proposed mechanism attributing to TID is epithelial-to-mesenchymal transition (EMT); however, it has recently been shown to be unrelated to early TID in adult renal allografts. This has yet to be studied in late TID or in pediatric renal transplantation; both questions were investigated. METHODS: By using 83 unique pediatric renal transplant recipients, 126 protocol, serial, posttransplant renal biopsies were examined by centralized, blinded Banff grading for CAI and transcriptional profiling (AffyU133+2.0) at 3 (n=20), 6 (n=45), 12 (n=19), and 24 months (n=42). Two hundred forty-three EMT-associated genes, identified from the literature, were interrogated for their differential expression in biopsies with and without CAI, using standard bioinformatic algorithms. RESULTS: Early (3-6 months) enrichment of EMT (P≤0.05) related gene expression was noted, correlating with inflammation in the graft (total i scores), with upregulation of hepatocyte growth factor at 24 months, indicating a time-dependent mechanism of action. We observed a strong correlation of EMT-related gene expression with early interstitial fibrosis (r<0.45) for size-mismatched allograft recipients. Throughout 24 months posttransplant, EMT signaling and epithelial-mesenchymal-epithelial cycling were associated with progressive CAI injury, with the greatest risk factors being ischemia, immune burden, and the calcineurin inhibitortoxicity score. CONCLUSIONS: EMT has a role in the evolution of CAI in pediatric transplantation. We postulate that EMT dysregulation plays a dual role in fibrosis/injury repair and healing. The evolution of this chronic injury response stems from size- mismatched transplant ischemia, calcineurin inhibitornephrotoxicity, and inflammatory response within the allograft.
Authors: Masako Shimamura; Maria C Seleme; Lingling Guo; Ute Saunders; Trenton R Schoeb; James F George; William J Britt Journal: Transplantation Date: 2013-01-15 Impact factor: 4.939
Authors: Thangamani Muthukumar; John R Lee; Darshana M Dadhania; Ruchuang Ding; Vijay K Sharma; Joseph E Schwartz; Manikkam Suthanthiran Journal: Transplant Rev (Orlando) Date: 2014-05-27 Impact factor: 3.943