Preventing peritoneal membrane fibrosis in peritoneal dialysis patients

Long-term peritoneal dialysis causes morphologic and functional changes in the peritoneal membrane. Although mesothelial-mesenchymal transition of peritoneal mesothelial cells is a key process leading to peritoneal fibrosis, and bioincompatible peritoneal dialysis solutions (glucose, glucose degradation products, and advanced glycation end products or a combination) are responsible for altering mesothelial cell function and proliferation, mechanisms underlying these processes remain largely unclear. Peritoneal fibrosis has 2 cooperative parts, the fibrosis process itself and the inflammation. The link between these 2 processes is frequently bidirectional, with each one inducing the other. This review outlines our current understanding about the definition and pathophysiology of peritoneal fibrosis, recent studies on key fibrogenic molecular machinery in peritoneal fibrosis, such as the role of transforming growth factor-β/Smads, transforming growth factor-β β/Smad independent pathways, and noncoding RNAs. The diagnosis of peritoneal fibrosis, including effluent biomarkers and the histopathology of a peritoneal biopsy, which is the gold standard for demonstrating peritoneal fibrosis, is introduced in detail. Several interventions for peritoneal fibrosis based on biomarkers, cytology, histology, functional studies, and antagonists are presented in this review. Recent experimental trials in animal models, including pharmacology and gene therapy, which could offer novel insights into the treatment of peritoneal fibrosis in the near future, are also discussed in depth. Long-term peritoneal dialysis causes morphologic and functional changes in the peritoneal membrane. Although mesothelial-mesenchymal transition of peritoneal mesothelial cells is a key process leading to peritoneal fibrosis, and bioincompatible peritoneal dialysis solutions (glucose, glucose degradation products, and advanced glycation end products or a combination) are responsible for altering mesothelial cell function and proliferation, mechanisms underlying these processes remain largely unclear. Peritoneal fibrosis has 2 cooperative parts, the fibrosis process itself and the inflammation. The link between these 2 processes is frequently bidirectional, with each one inducing the other. This review outlines our current understanding about the definition and pathophysiology of peritoneal fibrosis, recent studies on key fibrogenic molecular machinery in peritoneal fibrosis, such as the role of transforming growth factor-β/Smads, transforming growth factor-β β/Smad independent pathways, and noncoding RNAs. The diagnosis of peritoneal fibrosis, including effluent biomarkers and the histopathology of a peritoneal biopsy, which is the gold standard for demonstrating peritoneal fibrosis, is introduced in detail. Several interventions for peritoneal fibrosis based on biomarkers, cytology, histology, functional studies, and antagonists are presented in this review. Recent experimental trials in animal models, including pharmacology and gene therapy, which could offer novel insights into the treatment of peritoneal fibrosis in the near future, are also discussed in depth. In 1994, Chaimovitz1Chaimovitz C. Peritoneal dialysis.Kidney Int. 1994; 45: 1226-1240Abstract Full Text PDF PubMed Google Scholar described peritoneal fibrosis in a peritoneal dialysis (PD) patient at a nephrology forum. The most important feature that he noted was the universal absence of a mesothelial layer in the context of submesothelial thickening, representing tissue fibrosis, which had been previously described by Dobbie et al.2Dobbie J.W. Zaki M. Wilson L. Ultrastructural studies on the peritoneum with special reference to chronic ambulatory peritoneal dialysis.Scott Med J. 1981; 26: 213-223Crossref PubMed Google Scholar, 3Dobbie J.W. Lloyd J.K. Gall C.A. Categorization of ultrastructural changes in peritoneal mesothelium, stroma and blood vessels in uremia and CAPD patients.Adv Perit Dial. 1990; 6: 3-10PubMed Google Scholar The definition of peritoneal fibrosis has been difficult because terms such as fibrosis, sclerosis, and encapsulation have not been clearly differentiated. Garosi et al.4Garosi G. Cappelletti F. Di Paolo N. Fibrosis and sclerosis: different disorders or different stages?.Contrib Nephrol. 2006; 150: 62-69Crossref PubMed Scopus (9) Google Scholar stated that peritoneal sclerosis varied from clinically mild, silent sclerosis, which was almost always present, to the rare and fatal cases of encapsulating peritoneal sclerosis (EPS), a single disorder with variable manifestations and stages.5Loureiro J. Gónzalez-Mateo G. Jimenez-Heffernan J. et al.Are the mesothelial-to-mesenchymal transition, sclerotic peritonitis syndromes, and encapsulating peritoneal sclerosis part of the same process?.Int J Nephrol. 2013; 2013: 263285Crossref PubMed Scopus (7) Google Scholar According to data from peritoneal biopsies performed during PD with bioincompatible solutions, the prevalence of peritoneal fibrosis is almost universal at midterm. In this review, we show a decrease in this prevalence using less bioincompatible solutions. Peritoneal fibrosis has 2 cooperative parts, the fibrosis process itself and the inflammation promoted by the nonphysiologic content of solutions and infections.6Williams J.D. Craig K.J. Topley N. et al.Peritoneal Biopsy Study GroupMorphologic changes in the peritoneal membrane of patients with renal disease.J Am Soc Nephrol. 2002; 13: 470-479PubMed Google Scholar, 7Aguilera A. Yáñez-Mo M. Selgas R. et al.Epithelial to mesenchymal transition as a triggering factor of peritoneal membrane fibrosis and angiogenesis in peritoneal dialysis patients.Curr Opin Investig Drugs. 2005; 6: 262-268PubMed Google Scholar, 8Hung K.Y. Huang J.W. Tsai T.J. et al.Peritoneal fibrosing syndrome: pathogenetic mechanism and current therapeutic strategies.J Chin Med Assoc. 2005; 68: 401-405Abstract Full Text PDF PubMed Google Scholar, 9Aroeira L.S. Aguilera A. 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Transformed MCs are able to produce extracellular matrix and cause fibrosis, which is observed in submesothelial areas, demonstrating invasive capacity.12Yanez-Mo M. Lara-Pezzi E. Selgas R. et al.Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.N Engl J Med. 2003; 348: 403-413Crossref PubMed Scopus (402) Google Scholar The system involved in this transition is transforming growth factor-β (TGF-β), being the high production of vascular endothelial growth factor (VEGF), an outstanding consequence. VEGF receptors and coreceptors have recently been characterized in human MCs and animal models.13Pérez-Lozano M.L. Sandoval P. 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Liu H. et al.Transition of mesothelial cell to fibroblast in peritoneal dialysis: EMT, Stem cell or bystander?.Perit Dial Int. 2015; 35: 14-25Crossref PubMed Google Scholar and lineage tracing analyses in animal models question the transformation of MCs, suggesting distinctive fates for MCs and submesothelial fibroblasts during injury.16Chen Y.T. Chang Y.T. Pan S.Y. et al.Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury.J Am Soc Nephrol. 2014; 25: 2847-2858Crossref PubMed Scopus (21) Google Scholar This aggressive model, however, does not represent PD in humans. Liu et al.15Liu Y. Dong Z. Liu H. et al.Transition of mesothelial cell to fibroblast in peritoneal dialysis: EMT, Stem cell or bystander?.Perit Dial Int. 2015; 35: 14-25Crossref PubMed Google Scholar conceded the possibility that both adult MCs and precursors can be the origin of transitional cells. The most important agents in PD solutions responsible for altering MC function and proliferation are glucose and glucose-degradation products, which stimulate TGF-β and VEGF production by MCs and others.17Loureiro J. Aguilera A. Selgas R. et al.Blocking TGF-beta1 protects the peritoneal membrane from dialysate-induced damage.J Am Soc Nephrol. 2011; 22: 1682-1695Crossref PubMed Scopus (51) Google Scholar, 18Selgas R. Bajo A. Jiménez-Heffernan J.A. et al.Epithelial-to-mesenchymal transition of the mesothelial cell–its role in the response of the peritoneum to dialysis.Nephrol Dial Transplant. 2006; 21: ii2-ii7Crossref PubMed Scopus (49) Google Scholar, 19Tomino Y. Mechanisms and interventions in peritoneal fibrosis.Clin Exp Nephrol. 2012; 16: 109-114Crossref PubMed Scopus (14) Google Scholar, 20Witowski J. Wisniewska J. 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Wong P.N. Mak S.K. et al.Persistent sterile peritoneal inflammation after catheter removal for refractory bacterial peritonitis predicts full-blown encapsulating peritoneal sclerosis.Perit Dial Int. 2013; 33: 507-514Crossref PubMed Scopus (5) Google Scholar Detrimental changes are correlated with the number, severity, and timing of episodes.24del Peso G. Fernández-Reyes M.J. Hevia C. et al.Factors influencing peritoneal transport parameters during the first year on peritoneal dialysis: peritonitis is the main factor.Nephrol Dial Transplant. 2005; 20: 1201-1206Crossref PubMed Scopus (32) Google Scholar, 25Selgas R. Paiva A. Bajo M.A. et al.Consequences of peritonitis episodes appearing late during peritoneal dialysis (PD) in patients able to continue PD.Adv Perit Dial. 1998; 14: 168-172PubMed Google Scholar, 26Selgas R. Fernandez-Reyes M.J. Bosque E. et al.Functional longevity of the human peritoneum: how long is continuous peritoneal dialysis possible? 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