Epithelial to Mesenchymal Transition During Late Deterioration of Human Kidney Transplants: The Role of Tubular Cells in Fibrogenesis

• Published in: American journal of transplantation Vol. 5; no. 6; pp. 1367 - 1374
• Main Authors: Vongwiwatana, Attapong, Tasanarong, Adis, Rayner, David C., Melk, Anette, Halloran, Philip F.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Munksgaard International Publishers 01.06.2005; Blackwell
• Subjects: Actins - metabolism; Adult; Atrophy; Biological and medical sciences; Biomarkers; Cadherins - metabolism; Cell Differentiation; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Fibroblasts - pathology; Fibrosis; Graft Rejection - pathology; Heat-Shock Proteins - metabolism; HSP47 Heat-Shock Proteins; Humans; Keratins - metabolism; Kidney Transplantation - pathology; Kidney Tubules - pathology; Male; Medical sciences; Serpins - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; transdifferentiation; Transplantation, Homologous; tubular epithelium; Vimentin - metabolism; Human; Late; Tubular; Mesenchyma; tubular epithelium; Transplantation; Mesenchymal cell; Epithelium; Homotransplantation; Kidney; Renal tubule; Treatment; Urinary system; Surgery; Transdifférentiation; Fibrosis; transdifferentiation; Graft
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2005.00843.x

The hallmark of failing renal transplants is tubular atrophy and interstitial fibrosis (TA/IF). Injury to tubular epithelial cells (TEC) could contribute to fibrogenesis via epithelial–mesenchymal transition (EMT). We examined the features of EMT in renal transplants that developed TA/IF. Biopsies from 10 allograft kidneys with impaired function and TA/IF and 10 biopsies from transplants with stable function were compared to their implantation biopsies. Relative to implantation biopsies, TEC in TA/IF kidneys showed loss of epithelial markers (E‐cadherin, cytokeratin) with altered distribution. Some TEC also showed new cytoplasmic expression of mesenchymal markers vimentin, S100A4, and alpha smooth muscle actin (α‐SMA) and collagen synthesis marker heat shock protein (HSP‐47), both in deteriorating and atrophic tubules. Double immunostaining showed coexpression of cytokeratin and vimentin, S100A4 and HSP‐47, indicating intermediate stages of EMT in TA/IF. These changes were absent or much less in transplants with stable function. EMT features in the TA/IF group correlated with serum creatinine (vimentin, S100A4, HSP‐47), history of T‐cell‐mediated rejection (cytokeratin, S100A4) and proteinuria (cytokeratin). These findings support a model in which the TEC damage induces loss of epithelial features and expression of fibroblast features, as a common pathway of deterioration by either immunologic or nonimmunologic processes.