Format

Send to

Choose Destination
Transplantation. 2011 Oct 15;92(7):787-95. doi: 10.1097/TP.0b013e31822d092c.

The dual role of epithelial-to-mesenchymal transition in chronic allograft injury in pediatric renal transplantation.

Author information

1
Division of Nephrology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.

Abstract

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.

PMID:
21952304
DOI:
10.1097/TP.0b013e31822d092c
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wolters Kluwer
Loading ...
Support Center