Mesothelial-to-mesenchymal transition (MMT) is an autoregulated physiological process of tissue repair that in uncontrolled conditions, such as peritoneal dialysis (PD), can lead to peritoneal fibrosis. The maximum expression of sclerotic peritoneal syndromes (SPS) is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. The SPS includes a wide range of peritoneal fibrosis that appears progressively and is considered as a reversible process, while EPS does not. EPS is a serious complication of PD characterized by a progressive intra-abdominal inflammatory process that results in bridles and severe fibrous tissue formation which cover and constrict the viscera. Recent studies show that transdifferentiated mesothelial cells isolated from the PD effluent correlate very well with the clinical events such as the number of hemoperitoneum and peritonitis, as well as with PD function (lower ultrafiltration and high Cr-MTC). In addition, in peritoneal biopsies from PD patients, the MMT correlates very well with anatomical changes (fibrosis and angiogenesis). However, the pathway to reach EPS from SPS has not been fully and completely established. Herein, we present important evidence pointing to the MMT that is present in the initial peritoneal fibrosis stages and it is perpetual over time, with at least theoretical possibility that MMT initiated the fibrosing process to reach EPS. 1. Introduction Peritoneal dialysis (PD) is a form of renal replacement therapy that uses the peritoneal membrane (PM) as semipermeable barrier for the exchange of toxic substances and water. This technique has increased during the last years, in parallel to its complications. Currently, prolonged survival on PD has been reached due to technological advances, prevention, and early diagnosis of uremic complications. The basic objective of DP is the long-term preservation of the PM function. The PM is lined by a monolayer of MCs that have characteristics of epithelial cells and act as a permeability barrier across which ultrafiltration and diffusion take place. The long-term exposure to hyperosmotic, hyperglycaemic, and low pH of dialysis solutions and repeated episodes of peritonitis or hemoperitoneum cause injury of the peritoneum, which progressively becomes denuded of MCs and undergoes fibrosis and neovascularization [1]. Such structural alterations are considered the major cause of ultrafiltration failure [1, 2]. In this context, it has been proposed that local production of vascular endothelial growth factor (VEGF), a potent proangiogenic cytokine,
References
[1]
R. Selgas, M. A. Bajo, G. Del Peso, and C. Jimenez, “Preserving the peritoneal dialysis membrane in long-term peritoneal dialysis patients,” Seminars in Dialysis, vol. 8, pp. 326–332, 1995.
[2]
J. D. Williams, K. J. Craig, N. Topley et al., “Morphologic changes in the peritoneal membrane of patients with renal disease,” Journal of the American Society of Nephrology, vol. 13, no. 2, pp. 470–479, 2002.
[3]
R. T. Krediet, B. Lindholm, and B. Rippe, “Pathophysiology of peritoneal membrane failure,” Peritoneal Dialysis International, vol. 20, supplement 4, pp. S22–S42, 2000.
[4]
R. Pecoits-Filho, M. R. T. Araújo, B. Lindholm et al., “Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate,” Nephrology Dialysis Transplantation, vol. 17, no. 8, pp. 1480–1486, 2002.
[5]
M. M. Zweers, D. G. Struijk, W. Smit, and R. T. Krediet, “Vascular endothelial growth factor in peritoneal dialysis: a longitudinal follow-up,” Journal of Laboratory and Clinical Medicine, vol. 137, no. 2, pp. 125–132, 2001.
[6]
M. M. Zweers, D. R. de Waart, W. Smit, D. G. Struijk, and R. T. Krediet, “Growth factors VEGF and TGF-β1 in peritoneal dialysis,” Journal of Laboratory and Clinical Medicine, vol. 134, no. 2, pp. 124–132, 1999.
[7]
W. A. Border and N. A. Noble, “Transforming growth factor β in tissue fibrosis,” The New England Journal of Medicine, vol. 331, no. 19, pp. 1286–1292, 1994.
[8]
N. Di Paolo and G. Garosi, “Peritoneal sclerosis,” Journal of Nephrology, vol. 12, no. 6, pp. 347–361, 1999.
[9]
Y. Nomoto, Y. Kawaguchi, H. Kubo, H. Hirano, S. Sakai, and K. Kurokawa, “Sclerosing encapsulating peritonitis in patients undergoing continuous ambulatory peritoneal dialysis: a report of the Japanese sclerosing encapsulating peritonitis study group,” American Journal of Kidney Diseases, vol. 28, no. 3, pp. 420–427, 1996.
[10]
M. Yá？ez-Mo, E. Lara-Pezzi, R. Selgas et al., “Peritoneal dialysis induces an epithelial-mesenchymal transition of mesothelia cells,” The New England Journal of Medicine, vol. 348, pp. 403–413, 2003.
[11]
G. del Peso, J. A. Jiménez-Heffernan, M. A. Bajo et al., “Epithelial-to-mesenchymal transition of mesothelial cells is an early event during peritoneal dialysis and is associated with high peritoneal transport,” Kidney International, vol. 73, supplement 108, pp. S26–S33, 2008.
[12]
L. S. Aroeira, A. Aguilera, J. A. Sánchez-Tomero et al., “Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions,” Journal of the American Society of Nephrology, vol. 18, no. 7, pp. 2004–2013, 2007.
[13]
J. Loureiro, M. Schilte, A. Aguilera et al., “BMP-7 blocks mesenchymal conversion of mesothelial cells and prevents peritoneal damage induced by dialysis fluid exposure,” Nephrology Dialysis Transplantation, vol. 25, no. 4, pp. 1098–1108, 2010.
[14]
J. Loureiro, A. Aguilera, R. Selgas et al., “Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage,” Journal of the American Society of Nephrology, vol. 22, pp. 1682–1695, 2011.
[15]
F. Schneble, K. E. Bonzel, R. Waldherr, S. Bachmann, H. Roth, and K. Scharer, “Peritoneal morphology in children treated by continuous ambulatory peritoneal dialysis,” Pediatric Nephrology, vol. 6, no. 6, pp. 542–546, 1992.
[16]
J. Rubin, G. A. Herrera, and D. Collins, “An autopsy study of the peritoneal cavity from patients on continuous ambulatory peritoneal dialysis,” American Journal of Kidney Diseases, vol. 18, no. 1, pp. 97–102, 1991.
[17]
P. Holland, “Sclerosing encapsulating peritonitis in chronic ambulatory peritoneal dialysis,” Clinical Radiology, vol. 41, no. 1, pp. 19–23, 1990.
[18]
T. S. Ing, J. T. Daugirdas, and V. C. Gandhi, “Peritoneal sclerosis in peritoneal dialysis patients,” American Journal of Nephrology, vol. 4, no. 3, pp. 173–176, 1984.
[19]
F. Carbonnel, F. Barrie, L. Beaugerie et al., “Sclerosing peritonitis: a report of 10 cases,” Gastroenterologie Clinique et Biologique, vol. 19, no. 11, pp. 876–882, 1995.
[20]
J. P. Thiery, “Epithelial-mesenchymal transitions in development and pathologies,” Current Opinion in Cell Biology, vol. 15, no. 6, pp. 740–746, 2003.
[21]
S. Schultz-Cherry, J. Lawler, and J. E. Murphy-Ullrich, “The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-β,” The Journal of Biological Chemistry, vol. 269, no. 43, pp. 26783–26788, 1994.
[22]
K. N. Lai, K. B. Lai, C. W. K. Lam, T. M. Chan, F. K. Li, and J. C. K. Leung, “Changes of cytokine profiles during peritonitis in patients on continuous ambulatory peritoneal dialysis,” American Journal of Kidney Diseases, vol. 35, no. 4, pp. 644–652, 2000.
[23]
A. S. Gangji, K. S. Brimble, and P. J. Margetts, “Association between markers of inflammation, fibrosis and hypervolemia in peritoneal dialysis patients,” Blood Purification, vol. 28, no. 4, pp. 354–358, 2009.
[24]
Q. Yao, K. Pawlaczyk, E. R. Ayala et al., “The role of the TGF/Smad signaling pathway in peritoneal fibrosis induced by peritoneal dialysis solutions,” Nephron, vol. 109, no. 2, pp. e71–e78, 2008.
[25]
F. A. Offner, H. Feichtinger, S. Stadlmann et al., “Transforming growth factor-β synthesis by human peritoneal mesothelial cells: induction by interleukin-1,” The American Journal of Pathology, vol. 148, no. 5, pp. 1679–1688, 1996.
[26]
A. Desmouliere, A. Geinoz, F. Gabbiani, and G. Gabbiani, “Transforming growth factor-β1 induces α-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts,” Journal of Cell Biology, vol. 122, no. 1, pp. 103–111, 1993.
[27]
C. Viedt, A. Burger, and G. M. Hansch, “Fibronectin synthesis in tubular epithelial cells: up-regulation of the EDA splice variant by transforming growth factor β,” Kidney International, vol. 48, no. 6, pp. 1810–1817, 1995.
[28]
M. Gharaee-Kermani, R. Wiggins, F. Wolber, M. Goyal, and S. H. Phan, “Fibronectin is the major fibroblast chemoattractant in rabbit anti-glomerular basement membrane disease,” The American Journal of Pathology, vol. 148, no. 3, pp. 961–967, 1996.
[29]
K. H. Zarrinkalam, J. M. Stanley, J. Gray, N. Oliver, and R. J. Faull, “Connective tissue growth factor and its regulation in the peritoneal cavity of peritoneal dialysis patients,” Kidney International, vol. 64, no. 1, pp. 331–338, 2003.
[30]
A. A. Eddy, “Expression of genes that promote renal interstitial fibrosis in rats with proteinuria,” Kidney International, vol. 49, pp. S49–S54, 1996.
[31]
J. W. Dobbie, “Role of imbalance of intracavity fibrin formation and removal in the pathogenesis of peritoneal lesions in CAPD,” Peritoneal Dialysis International, vol. 17, no. 2, pp. 121–124, 1997.
[32]
C. J. Holmes, “Biocompatibility of peritoneal dialysis solutions,” Peritoneal Dialysis International, vol. 13, no. 2, pp. 88–94, 1993.
[33]
D. Fraser, L. Wakefield, and A. Phillips, “Independent regulation of transforming growth factor-β1 transcription and translation by glucose and platelet-derived growth factor,” The American Journal of Pathology, vol. 161, no. 3, pp. 1039–1049, 2002.
[34]
S. Teshima-Kondo, K. Kondo, L. Prado-Lourenco et al., “Hyperglycemia upregulates translation of the fibroblast growth factor 2 mRNA in mouse aorta via internal ribosome entry site,” The FASEB Journal, vol. 18, no. 13, pp. 1583–1585, 2004.
[35]
S. Ogata, N. Yorioka, K. Kiribayashi, T. Naito, M. Kuratsune, and Y. Nishida, “Viability of, and basic fibroblast growth factor secretion by, human peritoneal mesothelial cells cultured with various components of peritoneal dialysis fluid.,” Advances in Peritoneal Dialysis, vol. 19, pp. 2–5, 2003.
[36]
A. Breborowicz and D. G. Oreopoulos, “Biocompatibility of peritoneal dialysis solutions,” American Journal of Kidney Diseases, vol. 27, no. 5, pp. 738–743, 1996.
[37]
T. Liberek, N. Topley, A. Jorres et al., “Peritoneal dialysis fluid inhibition of polymorphonuclear leukocyte respiratory burst activation is related to the lowering of intracellular pH,” Nephron, vol. 65, no. 2, pp. 260–265, 1993.
[38]
A. P. Wieslander, M. K. Nordin, E. Martinson, P. T. T. Kjellstrand, and U. C. Boberg, “Heat sterilized PD-fluids impair growth and inflammatory responses of cultured cell lines and human leukocytes,” Clinical Nephrology, vol. 39, no. 6, pp. 343–348, 1993.
[39]
W. K. Lo, K. T. Chan, A. C. T. Leung, S. W. Pang, and C. Y. Tse, “Sclerosing peritonitis complicating prolonged use of chlorhexidine in alcohol in the connection procedure for continuous ambulatory peritoneal dialysis,” Peritoneal Dialysis International, vol. 11, no. 2, pp. 166–172, 1991.
[40]
J. P. Keating, M. Neill, and G. L. Hill, “Sclerosing encapsulating peritonitis after intraperitoneal use of povidone iodine,” Australian and New Zealand Journal of Surgery, vol. 67, no. 10, pp. 743–744, 1997.
[41]
Y. Tomino, “Mechanisms and interventions in peritoneal fibrosis,” Clinical and Experimental Nephrology, vol. 16, pp. 109–114, 2012.
[42]
K. Honda and H. Oda, “Pathology of encapsulating peritoneal sclerosis,” Peritoneal Dialysis International, vol. 25, supplement 4, pp. S19–S29, 2005.
[43]
G. Gillerot, E. Goffin, C. Michel et al., “Genetic and clinical factors influence the baseline permeability of the peritoneal membrane,” Kidney International, vol. 67, no. 6, pp. 2477–2487, 2005.
[44]
M. Numata, M. Nakayama, T. Hosoya et al., “Possible pathologic involvement of receptor for advanced glycation end products (RAGE) for development of encapsulating peritoneal sclerosis in Japanese CAPD patients,” Clinical Nephrology, vol. 62, no. 6, pp. 455–460, 2004.
[45]
P. J. Margetts, P. Bonniaud, L. Liu et al., “Transient overexpression of TGF-β1 induces epithelial mesenchymal transition in the rodent peritoneum,” Journal of the American Society of Nephrology, vol. 16, no. 2, pp. 425–436, 2005.
[46]
J. Y. Do, Y. L. Kim, J. W. Park et al., “The association between the vascular endothelial growth factor-to-cancer antigen 125 ratio in peritoneal dialysis effluent and the epithelial-to-mesenchymal transition in continuous ambulatory peritoneal dialysis,” Peritoneal Dialysis International, vol. 28, supplement 3, pp. S101–S106, 2008.
[47]
M. A. Yu, K. S. Shin, J. H. Kim et al., “HGF and BMP-7 ameliorate high glucose-induced epithelial-to-mesenchymal transition of peritoneal mesothelium,” Journal of the American Society of Nephrology, vol. 20, no. 3, pp. 567–581, 2009.
[48]
L. S. Aroeira, E. Lara-Pezzi, J. Loureiro et al., “Cyclooxygenase-2 mediates dialysate-induced alterations of the peritoneal membrane,” Journal of the American Society of Nephrology, vol. 20, pp. 582–592, 2009.
[49]
P. Sandoval, J. Loureiro, G. González-Mateo et al., “PPAR-γ agonist rosiglitazone protects peritoneal membrane from dialysis fluid-induced damage,” Laboratory Investigation, vol. 90, pp. 1517–1532, 2010.
[50]
G. Barini, A. Schuinski, T. P. Moraes, F. Meyer, and R. Pecoits-Filho, “Inflammation and the peritoneal membrane: causes and impact on structure and function during peritoneal dialysis,” Mediators of Inflammation, vol. 2012, Article ID 912595, 4 pages, 2012.
[51]
F. de Alvaro, M. J. Castro, F. Dapena et al., “Peritoneal resting is beneficial in peritoneal hyperpermeability and ultrafiltration failure,” Advances in Peritoneal Dialysis, vol. 9, pp. 56–61, 1993.
[52]
R. J. Rigby and C. M. Hawley, “Sclerosing peritonitis: the experience in Australia,” Nephrology Dialysis Transplantation, vol. 13, no. 1, pp. 154–159, 1998.
[53]
H. Kawanishi and M. Moriishi, “Epidemiology of encapsulating peritoneal sclerosis in Japan,” Peritoneal Dialysis International, vol. 25, supplement 4, pp. S14–S18, 2005.
[54]
L. S. Aroeira, A. Aguilera, R. Selgas et al., “Mesenchymal conversion of mesothelial cells as a mechanism responsible for high solute transport rate in peritoneal dialysis: role of vascular endothelial growth factor,” American Journal of Kidney Diseases, vol. 46, no. 5, pp. 938–948, 2005.
[55]
Y. Kawaguchi, T. Hasegawa, H. Kubo, H. Yamamoto, M. Nakayama, and T. Shigematsu, “Current issues of continuous ambulatory peritoneal dialysis,” Artificial Organs, vol. 19, no. 12, pp. 1204–1209, 1995.
[56]
I. E. Afthentopoulos, P. Passadakis, D. G. Oreopoulos, and J. Bargman, “Erratum: sclerosing peritonitis in continuous ambulatory peritoneal dialysis patients: one center's experience and review of the literature, Advances in Renal Replacement Therapy, 5, article 353, 1998,” Advances in Renal Replacement Therapy, vol. 5, no. 3, pp. 157–167, 1998.
[57]
A. Slingeneyer, “Preliminary report on a cooperative international study on sclerosing encapsulating peritonitis,” Nephrology Dialysis Transplantation, vol. 3, pp. 66–69, 1988.
[58]
P. G. Bentley and D. R. Higgs, “Peritoneal tuberculosis with ureteric obstruction, mimicking retroperitoneal fibrosis,” British Journal of Urology, vol. 48, no. 3, article 170, 1976.
