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Previous Volume 348:403-413 January 30, 2003 Number 5 Next

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ABSTRACT

Background During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated.

Methods Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens.

Results Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of ₂ integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells.

Conclusions Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients.

Source Information

From the Servicio de Inmunología (M.Y.-M., M.R.-H., C.D.-J., F.S.-M.), Biología Molecular (E.L.-P., C.G., M.L.-C.), and Nefrología (R.S., A.A., J.A.S.-T., V.A., A.C.), Hospital Universitario de la Princesa, Universidad Autónoma de Madrid; the Servicio de Nefrología, Hospital Universitario La Paz (M.A.B., M.A.C., G.P.); and the Instituto Reina Sofía de Investigaciones Nefrológicas (M.Y.-M., E.L.-P., R.S., M.R.-H., C.D.-J., J.A.J.-H., A.A., J.A.S.-T., M.A.B., V.A., M.A.C., G.P., A.C., C.G., F.S.-M., M.L.-C.) — all in Madrid; the Servicio de Anatomía Patológica, Hospital Universitario de Guadalajara, Guadalajara, Spain (J.A.J.-H.).

Drs. Yáñez-Mó and Lara-Pezzi contributed equally to the article.

Address reprint requests to Dr. López-Cabrera at the Departamento de Biología Molecular, Hospital Universitario de la Princesa, C/Diego de León no. 62, 28006 Madrid, Spain, or at mlopez{at}hlpr.insalud.es.

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Related Letters:

Peritoneal Dialysis and Epithelial-to-Mesenchymal Transition
Stein J. A., Mannello F., Rampino T., Dal Canton A., Yáñez-Mó M., Lara-Pezzi E., López-Cabrera M.
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N Engl J Med 2003; 348:2037-2039, May 15, 2003. Correspondence

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