The Dual Role of Epithelial-to-Mesenchymal Transition in Chronic Allograft Injury in Pediatric Renal Transplantation

Abstract

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. 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. 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. 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.