Received October 31, 2007
Accepted on February 13, 2008

CLINICAL RESEARCH

Early Epithelial Phenotypic Changes Predict Graft Fibrosis

Alexandre Hertig ^*1, Dany Anglicheau ^||, Jérôme Verine ^¶, Nicolas Pallet ^||, Maxime Touzot ^*, Pierre-Yves Ancel ^**, Laurent Mesnard , Nicole Brousse , Edith Baugey , Denis Glotz , Christophe Legendre , Eric Rondeau ^*, and Yi-Chun Xu-Dubois ^***

*Urgences Néphrologiques and Transplantation Rénale and **Département de Santé Publique, Hôpital Tenon, Transplantation Rénale and Anatomo-Pathologie, Hôpital Necker, and ¶Anatomo-Pathologie and Transplantation Rénale, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, INSERM, Unité 702, Hôpital Tenon Université Pierre et Marie Curie-Paris 6, UMR S 702, and ||INSERM, Unité 775, Centre universitaire des Saints-Pères, Paris, France

¹ To whom correspondence should be addressed. E-mail: alexandre.hertig{at}tnn.aphp.fr.

	Abstract

Chronic allograft nephropathy accounts for the loss of approximately 40% of allografts at 10 yr. Currently, no biomarker is available to detect interstitial fibrosis and tubular atrophy in the renal graft at an early stage, when intervention may be beneficial. Because tubular epithelial cells have been shown to exhibit phenotypic changes suggestive of epithelial-to-mesenchymal transition, we studied whether these changes predict the progression of fibrosis in the allograft. Eighty-three kidney transplant recipients who had undergone a protocol graft biopsy at both 3 and 12 mo after transplantation were enrolled. De novo vimentin expression and translocation of -catenin into the cytoplasm of tubular cells were detected on the first biopsy by immunohistochemistry. Patients with expression of these markers in 10% of tubules at 3 mo had a higher interstitial fibrosis score at 1 yr and a greater progression of this score between 3 and 12 mo. The intensity of these phenotypic changes positively and significantly correlated with the progression of fibrosis, and multivariate analysis showed that their presence was an independent risk factor for this progression. In addition, the presence of early phenotypic changes was associated with poorer graft function 18 mo after transplantation. In conclusion, early phenotypic changes indicative of epithelial-to-mesenchymal transition predict the progression toward interstitial fibrosis in human renal allografts.