**The Mesothelial to Mesenchymal Transition a Pathogenic and Therapeutic Key for Peritoneal Membrane Failure**

Abelardo Aguilera, Jesús Loureiro, Guadalupe Gónzalez-Mateo, Rafael Selgas and Manuel López-Cabrera

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56598

**1. Introduction**

Peritoneal dialysis (PD) is a form of renal replacement therapy that is growing progressively, possibly because of the freedom it offers to the patients and the undoubted improvement in the PD technique. Parallel the PD-related complications have also increased. In PD, the peritoneal membrane (PM) is exposed to bio-incompatible dialysis solutions, rich in glucose, which can cause peritoneal injury when associated with peritoneal incidents like repeated episodes of peritonitis or hemoperitoneum [1]. Progressive fibrosis, angiogenesis and ulti‐ mately, ultrafiltration failure, are some characteristics of the so-called sclerotic peritonitis syndromes (SPS) [2].

Several pathologic factors, such as inflammatory mediators, high glucose content, the presence of glucose degradation products, and low pH can induce peritoneal mesothelial cells (MCs) to lose certain epithelial characteristics, and they progressively acquire a fibroblast-like phenotype soon after initiation of PD [3]. This so-called mesothelial-to-mesenchymal transition (MMT) serves as a trigger for peritoneal fibrosis and angiogenesis, via up-regulation of transforming growth factor-β (TGF-β1 and vascular endothelial growth factor (VEGF), respectively. As such, MMT is considered an important potential therapeutic target in sclerotic peritonitis syndromes [4]. Encapsulating peritoneal sclerosis (EPS) is a severe form of perito‐ neal fibrosis characterized by intestinal encapsulation through the formation of excessive matrix components that subsequently may lead to obstruction of the intestinal tract [5]. Although rare, EPS is a serious complication of PD for which no specific and definitive

© 2013 Aguilera et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

treatment exists [6]. However, peritoneal resting, steroids, immunosuppressive agents and Tamoxifen have been used previously as therapeutic approaches with divergent results [4]. Herein, we review in detail the effect of PD liquids and other peritoneal accidents like peritonitis and hemoperitoneum on the MCs physiology, the trandifferentiation in fibroblastlike cells (MMT), its clinical correlation with data from peritoneal and morphologic function (peritoneal biopsies), the initiation and perpetuation of peritoneal fibrosis (SPS) and his eventual rise to EPS. We also purpose therapeutic alternatives, ranging from the improvement in the biocompatibility of the liquids of DP, the use of drugs available on the market today, or even the use of molecular strategies, as blockades or stimulation of genes involved in the peritoneal damage.

#### **2. Morphologic and phenotypic MCs characterization**

The mesothelium is a continuous superficial layer of MCs formed by flattened, polygonal, mononuclear, squamous epithelial cells. This monolayer shows remarkable fibrinolytic properties and is thought to be involved in the prevention of fibrous adhesion formation in the peritoneum. MCs cells have vast biosynthetic capacity and secrete phospholipids and phosphotidylcholine in the form of lamellar bodies that provide a lubricating surface for the movement of abdominal viscera [7]. Besides this function, the mesothelium also modulates peritoneal microcirculation by secreting vasodilators (eg, prostaglandin E2 and nitric oxide), as well as vasoconstrictors (eg, endothelin) [8]. The luminal aspect of MCs plasmalemma has numerous cytoplasmic extensions called "microvilli" which play a significant role in the transperitoneal transfer of anionic macromolecules such as proteins. Microvilli are extremely sensitive and easily lost due to injury [9].

**Figure 1. Morphology and gene expression of MCs**. Panel "A" shows a culture of MCs isolated from omentum do‐ nor. Cells show the typical cobblestone phenotype. Panel "B" shows MCs isolated from PD effluent with transitional phenotype, and panel "C" shows a fibroblastoid phenotype these cells were isolated and cultured from the PD efflu‐

MMT and Peritoneal Membrane Failure http://dx.doi.org/10.5772/56598 23

The morphological changes and down-regulation of cytokeratin and E-Cadherin in effluentderived MC are indicative of an MMT. MMT is a complex and generally reversible process that starts with the disruption of intercellular junctions and loss of apical–basolateral polarity, typical of epithelial cells, which are then transformed into fibroblast-like cells with increased migratory, invasive and fibrogenic features. The objective of this process is to repair tissue wounds by promoting the recovery of ancestor capabilities of epithelial cells. Cell migration, production of extracellular matrix and induction of neoangiogenesis are the main activities [11, 12]. This process is conducted by the transforming growth factor-β (TGF-β) and the representative cell form is the myofibroblast (Figure 2). TGF-β synthesis may be stimulated by glucose, and infections, via peritoneal leucocyte-derived factors. TGF-β has been found to be up-regulated in peritoneal inflammatory processes and its over-expression has been correlated to worse PD outcomes [13]. Moreover, the injection of an adenovirus vector that transferred active TGF-β1 in rat and mice peritoneum induces myofibroblastic conversion of MC. [14, 15]. TGF-β is a growth factor that has been implicated as the causal agent in fibrosis of different

ent. The genetic pattern of each phenotype is described below.

tissues and organs [16].

MCs can be isolated from healthy omentum donors of elective abdominal surgeries and the effluent from patients with PD. The analysis of the effluent drained peritoneal MCs has allowed us to assess the health status of peritoneal. The purity of effluent and omentum-derived MC cultures are determined by the expression of standard mesothelial markers: ICAM-1, cytoker‐ atins, and calretinine. MCs cultures remain stable, without any evident sign of senescence, for at least two to three passages [10, 11].

The analysis of cytokeratins and E-cadherin expression, that are typical epithelial markers and highly expressed in MC, is important to determine more precisely the nature of effluentderived cells. High expression of cytokeratins and E-cadherin is only observed in omentumderived MC, whereas effluent-derived cells show a progressive reduction in the expression of these molecules, although even fibroblast-like MC may maintain a small population of positive cells (Figure 1). In mixed populations the expression of cytokeratins and E-Cadherin is normally bimodal. Fibroblasts are completely negative for these two markers. Previous studies had characterized the cobblestone-like MC from effluents as indistinguishable from omentumderived MC. However, already in this early stage a loss of apico-basolateral polarity as well as down-regulation of cytokeratins and E-Cadherin is observed *ex vivo*, even though cells still show a morphologically epithelioid appearance [10-12].


treatment exists [6]. However, peritoneal resting, steroids, immunosuppressive agents and Tamoxifen have been used previously as therapeutic approaches with divergent results [4]. Herein, we review in detail the effect of PD liquids and other peritoneal accidents like peritonitis and hemoperitoneum on the MCs physiology, the trandifferentiation in fibroblastlike cells (MMT), its clinical correlation with data from peritoneal and morphologic function (peritoneal biopsies), the initiation and perpetuation of peritoneal fibrosis (SPS) and his eventual rise to EPS. We also purpose therapeutic alternatives, ranging from the improvement in the biocompatibility of the liquids of DP, the use of drugs available on the market today, or even the use of molecular strategies, as blockades or stimulation of genes involved in the

The mesothelium is a continuous superficial layer of MCs formed by flattened, polygonal, mononuclear, squamous epithelial cells. This monolayer shows remarkable fibrinolytic properties and is thought to be involved in the prevention of fibrous adhesion formation in the peritoneum. MCs cells have vast biosynthetic capacity and secrete phospholipids and phosphotidylcholine in the form of lamellar bodies that provide a lubricating surface for the movement of abdominal viscera [7]. Besides this function, the mesothelium also modulates peritoneal microcirculation by secreting vasodilators (eg, prostaglandin E2 and nitric oxide), as well as vasoconstrictors (eg, endothelin) [8]. The luminal aspect of MCs plasmalemma has numerous cytoplasmic extensions called "microvilli" which play a significant role in the transperitoneal transfer of anionic macromolecules such as proteins. Microvilli are extremely

MCs can be isolated from healthy omentum donors of elective abdominal surgeries and the effluent from patients with PD. The analysis of the effluent drained peritoneal MCs has allowed us to assess the health status of peritoneal. The purity of effluent and omentum-derived MC cultures are determined by the expression of standard mesothelial markers: ICAM-1, cytoker‐ atins, and calretinine. MCs cultures remain stable, without any evident sign of senescence, for

The analysis of cytokeratins and E-cadherin expression, that are typical epithelial markers and highly expressed in MC, is important to determine more precisely the nature of effluentderived cells. High expression of cytokeratins and E-cadherin is only observed in omentumderived MC, whereas effluent-derived cells show a progressive reduction in the expression of these molecules, although even fibroblast-like MC may maintain a small population of positive cells (Figure 1). In mixed populations the expression of cytokeratins and E-Cadherin is normally bimodal. Fibroblasts are completely negative for these two markers. Previous studies had characterized the cobblestone-like MC from effluents as indistinguishable from omentumderived MC. However, already in this early stage a loss of apico-basolateral polarity as well as down-regulation of cytokeratins and E-Cadherin is observed *ex vivo*, even though cells still

**2. Morphologic and phenotypic MCs characterization**

peritoneal damage.

22 The Latest in Peritoneal Dialysis

sensitive and easily lost due to injury [9].

at least two to three passages [10, 11].

show a morphologically epithelioid appearance [10-12].

**Figure 1. Morphology and gene expression of MCs**. Panel "A" shows a culture of MCs isolated from omentum do‐ nor. Cells show the typical cobblestone phenotype. Panel "B" shows MCs isolated from PD effluent with transitional phenotype, and panel "C" shows a fibroblastoid phenotype these cells were isolated and cultured from the PD efflu‐ ent. The genetic pattern of each phenotype is described below.

The morphological changes and down-regulation of cytokeratin and E-Cadherin in effluentderived MC are indicative of an MMT. MMT is a complex and generally reversible process that starts with the disruption of intercellular junctions and loss of apical–basolateral polarity, typical of epithelial cells, which are then transformed into fibroblast-like cells with increased migratory, invasive and fibrogenic features. The objective of this process is to repair tissue wounds by promoting the recovery of ancestor capabilities of epithelial cells. Cell migration, production of extracellular matrix and induction of neoangiogenesis are the main activities [11, 12]. This process is conducted by the transforming growth factor-β (TGF-β) and the representative cell form is the myofibroblast (Figure 2). TGF-β synthesis may be stimulated by glucose, and infections, via peritoneal leucocyte-derived factors. TGF-β has been found to be up-regulated in peritoneal inflammatory processes and its over-expression has been correlated to worse PD outcomes [13]. Moreover, the injection of an adenovirus vector that transferred active TGF-β1 in rat and mice peritoneum induces myofibroblastic conversion of MC. [14, 15]. TGF-β is a growth factor that has been implicated as the causal agent in fibrosis of different tissues and organs [16].

**Figure 2. From a normal peritoneum to a PD peritoneum suffering MMT**. Panel "A" shows a normal peritoneun without fibrosis, angiogenesis or MMT (3D image). Panel "B" shows a PD paritoneum with MCs exposed to PD fluids. MCs lose their microvilli, suffer MMT and invade submesothelial area, where synthesize VEGF, angiogenesis, prolifera‐ tion, migration and EMC production. Both glucose (GDPs and AGEs) from PD fluids and inflammatory molecules stim‐ ulate TGF-β production which trigger MMT.

#### **3. MMT signalling**

Figure 3 shows the signaling cascade of MMT which begins with the activation of TGF-β which is considered the master molecule in peritoneal injury during PD. Activation of TGF-β receptors triggers smads-dependent and smads-independent signaling. Smads depending pathway include integrin-linked kinase, GSK-3, β-catenin, Lef-1/Tcf and AP gene cascade. Smads independing include RhoAp160ROCK and H-Ras/Raf/ ERK pathways [17-32].

#### **4. Clinical implication of MMT in PM failure**

We have described three major morphologies of MCs cultures from PD effluents: cobblestonelike, similar to omentum-derived MC, transitional and fibroblast-like MC which remained stable for at least two to three cell passages. After analyzing more than two hundred MC cultures with growth capacity, from more than 100 PD patients, we determined that the frequencies of the different effluent-derived MC cultures are approximately 53 percent for cobblestone-like, 24 percent for transitional, and 17 percent for fibroblast-like MC. The prevalence of non-epitheliod MC cultures (transitional or fibroblast-like) is associated with the time the patients have been subjected to PD and with the episodes of acute or recurrent peritonitis or hemoperitoneum [3, 10, 11]. We have also described a less frequent (less than 6 percent) cell culture with mixed morphologies [3, 10]. Effluent mesothelial cells were isolated from 37 PD patients and analyzed for mesenchymal conversion. Mass transfer coefficient for creatinine (Cr-MTC) was used to evaluate peritoneal function. VEGF concentration was

pression and MMT.

**Figure 3. TGF-β signaling.** Glucose, low pH from PD fluids, advanced glycation end products (AGEs), glucose degrada‐ tion products (GDPs), peritonitis and haemoperitoneum stimulate TGF-β synthesis, and possibly FGF which in turn trig‐ gers the healing processes that ultimately lead to tissue fibrosis and angiogenesis. The increase in total VEGF production might increase the VEGF-C levels, which are directly implicated in lymphogenesis. TGF-β receptor I phos‐ phorylates Smad 2 and 3 inducing their association with the common partner Smad 4, and then they translocate into the nucleus, where they control the expression of TGF-β-responsive genes, such as that encoding integrin-linked kin‐ ase (ILK). The activation of up-regulated ILK by β1 integrins results in strong phosphorylation of Akt and glycogen syn‐ thase kinase-3 (GSK-3). Phosphorylated-Akt triggers NF-kB activation, which in turn induces the expression of Smad 7, an inhibitory Smad molecule that interferes with the phosporylation of Smad 2 and 3, and of snail, a key regulator of MMT. The transcription factor snail regulates MMT by inhibiting the expression of E-cadherin, and by inducing growth arrest and survival, which confer selective advantage to migrating trans-differentiated cells. The phosphorylation of GSK-3 by ILK results in its inhibition and subsequent stabilization of β-catenin, released from the adherens junction, and of AP-1. Stabilized b-catenin, in conjunction with Lef-1/Tcf, may per se induce MMT, and AP-1 activates MMP-9 expression inducing the invasion of ECM. One of the main Smad-independent signalling cascades triggered by TGF-β receptor I ligation, includes the RhoAp160ROCK pathway that regulates cytoskeleton remodelling and cellular migra‐ tion/ invasion. In addition, RhoA induces the expression of α-SMA in a ROCK-independent manner. Another signal transduction stimulated by TGF-β is the H-Ras/Raf/ ERK pathway, which is also necessary for the induction of snail ex‐

MMT and Peritoneal Membrane Failure http://dx.doi.org/10.5772/56598 25

**Figure 3. TGF-β signaling.** Glucose, low pH from PD fluids, advanced glycation end products (AGEs), glucose degrada‐ tion products (GDPs), peritonitis and haemoperitoneum stimulate TGF-β synthesis, and possibly FGF which in turn trig‐ gers the healing processes that ultimately lead to tissue fibrosis and angiogenesis. The increase in total VEGF production might increase the VEGF-C levels, which are directly implicated in lymphogenesis. TGF-β receptor I phos‐ phorylates Smad 2 and 3 inducing their association with the common partner Smad 4, and then they translocate into the nucleus, where they control the expression of TGF-β-responsive genes, such as that encoding integrin-linked kin‐ ase (ILK). The activation of up-regulated ILK by β1 integrins results in strong phosphorylation of Akt and glycogen syn‐ thase kinase-3 (GSK-3). Phosphorylated-Akt triggers NF-kB activation, which in turn induces the expression of Smad 7, an inhibitory Smad molecule that interferes with the phosporylation of Smad 2 and 3, and of snail, a key regulator of MMT. The transcription factor snail regulates MMT by inhibiting the expression of E-cadherin, and by inducing growth arrest and survival, which confer selective advantage to migrating trans-differentiated cells. The phosphorylation of GSK-3 by ILK results in its inhibition and subsequent stabilization of β-catenin, released from the adherens junction, and of AP-1. Stabilized b-catenin, in conjunction with Lef-1/Tcf, may per se induce MMT, and AP-1 activates MMP-9 expression inducing the invasion of ECM. One of the main Smad-independent signalling cascades triggered by TGF-β receptor I ligation, includes the RhoAp160ROCK pathway that regulates cytoskeleton remodelling and cellular migra‐ tion/ invasion. In addition, RhoA induces the expression of α-SMA in a ROCK-independent manner. Another signal transduction stimulated by TGF-β is the H-Ras/Raf/ ERK pathway, which is also necessary for the induction of snail ex‐ pression and MMT.

**Figure 2. From a normal peritoneum to a PD peritoneum suffering MMT**. Panel "A" shows a normal peritoneun without fibrosis, angiogenesis or MMT (3D image). Panel "B" shows a PD paritoneum with MCs exposed to PD fluids. MCs lose their microvilli, suffer MMT and invade submesothelial area, where synthesize VEGF, angiogenesis, prolifera‐ tion, migration and EMC production. Both glucose (GDPs and AGEs) from PD fluids and inflammatory molecules stim‐

Figure 3 shows the signaling cascade of MMT which begins with the activation of TGF-β which is considered the master molecule in peritoneal injury during PD. Activation of TGF-β receptors triggers smads-dependent and smads-independent signaling. Smads depending pathway include integrin-linked kinase, GSK-3, β-catenin, Lef-1/Tcf and AP gene cascade. Smads independing include RhoAp160ROCK and H-Ras/Raf/ ERK pathways [17-32].

We have described three major morphologies of MCs cultures from PD effluents: cobblestonelike, similar to omentum-derived MC, transitional and fibroblast-like MC which remained stable for at least two to three cell passages. After analyzing more than two hundred MC cultures with growth capacity, from more than 100 PD patients, we determined that the frequencies of the different effluent-derived MC cultures are approximately 53 percent for

ulate TGF-β production which trigger MMT.

**4. Clinical implication of MMT in PM failure**

**3. MMT signalling**

24 The Latest in Peritoneal Dialysis

cobblestone-like, 24 percent for transitional, and 17 percent for fibroblast-like MC. The prevalence of non-epitheliod MC cultures (transitional or fibroblast-like) is associated with the time the patients have been subjected to PD and with the episodes of acute or recurrent peritonitis or hemoperitoneum [3, 10, 11]. We have also described a less frequent (less than 6 percent) cell culture with mixed morphologies [3, 10]. Effluent mesothelial cells were isolated from 37 PD patients and analyzed for mesenchymal conversion. Mass transfer coefficient for creatinine (Cr-MTC) was used to evaluate peritoneal function. VEGF concentration was measured by using standard procedures. Patients whose drainage contained nonepithelioid mesothelial cells had greater serum VEGF levels than those with epithelial-like mesothelial cells in their effluent. VEGF production ex vivo by effluent mesothelial cells correlated with serum VEGF level. In addition, Cr-MTC correlated with VEGF levels in culture and serum. Cr-MTC also was associated with mesothelial cell phenotype. VEGF expression in stromal cells, retaining mesothelial markers, was observed in peritoneal biopsy specimens from hightransporter patients. These results suggest that mesothelial cells that have undergone epithe‐ lial-to-mesenchymal transition are the main source of VEGF in PD patients and therefore may be responsible for a high peritoneal transport rate [3].

**5. Are MMT, SPS and EPS part of the same process?**

pathological criterion for differential diagnosis [6, 35, 36].

attenuated PM failure induced by PD fluids.

From MMT to SPS. Peritoneal fibrosis (or sclerosis) is a term that comprises a wide spectrum of peritoneal structural alterations, ranging from mild inflammation to severe sclerosing peritonitis and its most complicated manifestation, encapsulating peritonitis sclerosis (EPS) [6, 35, 36]. Simple sclerosis (SS), an intermediate stage of peritoneal fibrosis, is the most common peritoneal lesion found in the patients after few months on PD, and could represent the initial phase of sclerosing peritonitis syndrome (SPS). Rubin et al [5] described a normal thickness of the peritoneum of 20 μm, but after a few months on PD could reach up to 40 μm (SS). The SP is a progressive sclerosis that is characterized by a dramatic thickening of the peritoneum (up to 4000 μm) and is accompanied by inflammatory infiltrates, calcification, neo-vascularization and dilatation of blood and lymphatic vessels, being the thickening the most commonly used

MMT and Peritoneal Membrane Failure http://dx.doi.org/10.5772/56598 27

The importance of establishing a connection between MMT, SPS and EPS is the potential therapeutic and preventive effect of blocking this axis. Also emerging evidence suggests that partial or total blockage of the MMT prevents early stages of PM fibrosis and angiogenesis and preserves the PM function. Moreover, current studies show TGF-β is probably the most important molecule in the PM failure development, so act on a single molecule, the TGF-β, facilitates therapeutic approach. In fact we have shown that blockade of TGF-β significantly

One of the biggest problems to establish the definitive connection between SPS and EPS is that the EPS animal model has not been fully and properly developed. While in our mice PD model in 4 or more weeks reaches the typical changes induced by PD fluids on humans, the peritoneal fibrosis model with chlorhexidine results artificial and extremely aggressive. The experimental development of an appropriate EPS model is mandatory. Possibly the most appropriate EPS mice model would be to maintain long-term (months) in PD according to our model of SPS. Once accepted this limitation, the current data suggest that MMT and SPS are part of the process. We have analyzed serially PM pieces of mice in PD at baseline, 15 and 30 days and we found a linear correlation between time on PD, the thickness of the PM and the number of MCs cytokeratin (+) and FSP-1 (+) in the area submesothelial. This phenomenon was accom‐ panied by progressive loss of the mesothelial monolayer which indicates an important participation of the MMT in the development of peritoneal fibrosis (our unpublished results). Using a TGF-β adenovirus model, we found early MMT at 4 day after stimuli intraperitoneal injection that was correlated with PM fibrosis [14]. Similar finding was found by others [15]. Clinically, in MCs serially isolated and cultured from PD effluents, the MMT was present progressively over time in PD and is associated with solute transport disorders and ultrafil‐ tration failure [37]. In PM biopsies from 35 PD stable patients performed during the first 2 years on PD, we demonstrated that the first morphological change in peritoneum that appears as a consequence of PD is submesothelial thickening partially caused by the MMT. This phenotype change is associated with an increase in peritoneal solute transport independent of the number of capillaries present in the tissue [1, 3]. Reaching this point, the following questions arise, as follows: could have peritoneal fibrosis without MMT?, or more specifically,

In a clinical study performed by our group, we studied the peritoneal anatomical changes during the first months on PD, and to correlate them with peritoneal functional parameters. We studied 35 stable PD patients for up to 2 years on PD, with a mean age of 45.37 years. Seventy-four percent of patients presented loss of the mesothelial layer, 46% fibrosis and 17% in situ evidence of MMT (submesothelial cytokeratin staining), which increased over time. All patients with MMT showed myofibroblasts, while only 36% of patients without MMT had myofibroblasts. The myofibroblasts represent a dynamic population of cells showing func‐ tional and phenotypic diversity. During the last years, numerous different molecules have been reported to be expressed by tissue fibroblasts including peritoneal ones [10]. The origin of tissue fibroblasts has been largely overlooked, so that their lineage is not fully elucidated. There is now evidence supporting that fibro-myofibroblasts might originate from different sources. Firstly, they may differentiate from resident tissue stem cells or fibroblasts. Secondly, they can originate from nearby epithelial cells through a process known as MMT. Finally, the bone marrow and circulating cells may be responsible for the production of fibro-myofibro‐ blasts circulating in the blood stream to their final tissue destination [33].

In PD, emergent evidence points that fibroblasts may arise from local conversion of epithelial cells by MMT or from CD34 + cells (fibrocytes) of the bloodstream after being recruited from bone marrow. In the case of renal fibrosis models, it has been shown that 36% of new fibroblasts derive from MMT, 15% from bone marrow and the rest comes from local proliferation of resident fibroblasts. In PD-related fibrosis, we have demonstrated the expression of mesothe‐ lial markers in stromal spindle-like cells, suggesting that they stemmed from local conversion of MC. In contrast, we did not observe a significant contribution of CD34+ cells from bone marrow to the submesothelial fibroblast population in the fibrotic peritoneal tissue [33].

In regard to angiogenesis, the number of peritoneal vessels did not vary when we compared different times on PD. Vasculopathy was present in 17% of the samples. Functional studies were used to define the peritoneal transport status. Patients in the highest quartile of mass transfer area coefficient of creatinine (Cr-MTAC) showed significantly higher MMT prevalence but similar number of peritoneal vessels. In the multivariate analysis, the highest quartile of Cr-MTAC remained as an independent factor predicting the presence of MMT after adjusting for fibrosis [34]. These findings indicate that MMT is a frequent morphological change in the peritoneal membrane. These myofibroblastic cells with submesothelial localization may arise from local conversion of MC during the repair responses and the high solute transport status is associated with MMT.

#### **5. Are MMT, SPS and EPS part of the same process?**

measured by using standard procedures. Patients whose drainage contained nonepithelioid mesothelial cells had greater serum VEGF levels than those with epithelial-like mesothelial cells in their effluent. VEGF production ex vivo by effluent mesothelial cells correlated with serum VEGF level. In addition, Cr-MTC correlated with VEGF levels in culture and serum. Cr-MTC also was associated with mesothelial cell phenotype. VEGF expression in stromal cells, retaining mesothelial markers, was observed in peritoneal biopsy specimens from hightransporter patients. These results suggest that mesothelial cells that have undergone epithe‐ lial-to-mesenchymal transition are the main source of VEGF in PD patients and therefore may

In a clinical study performed by our group, we studied the peritoneal anatomical changes during the first months on PD, and to correlate them with peritoneal functional parameters. We studied 35 stable PD patients for up to 2 years on PD, with a mean age of 45.37 years. Seventy-four percent of patients presented loss of the mesothelial layer, 46% fibrosis and 17% in situ evidence of MMT (submesothelial cytokeratin staining), which increased over time. All patients with MMT showed myofibroblasts, while only 36% of patients without MMT had myofibroblasts. The myofibroblasts represent a dynamic population of cells showing func‐ tional and phenotypic diversity. During the last years, numerous different molecules have been reported to be expressed by tissue fibroblasts including peritoneal ones [10]. The origin of tissue fibroblasts has been largely overlooked, so that their lineage is not fully elucidated. There is now evidence supporting that fibro-myofibroblasts might originate from different sources. Firstly, they may differentiate from resident tissue stem cells or fibroblasts. Secondly, they can originate from nearby epithelial cells through a process known as MMT. Finally, the bone marrow and circulating cells may be responsible for the production of fibro-myofibro‐

In PD, emergent evidence points that fibroblasts may arise from local conversion of epithelial cells by MMT or from CD34 + cells (fibrocytes) of the bloodstream after being recruited from bone marrow. In the case of renal fibrosis models, it has been shown that 36% of new fibroblasts derive from MMT, 15% from bone marrow and the rest comes from local proliferation of resident fibroblasts. In PD-related fibrosis, we have demonstrated the expression of mesothe‐ lial markers in stromal spindle-like cells, suggesting that they stemmed from local conversion of MC. In contrast, we did not observe a significant contribution of CD34+ cells from bone marrow to the submesothelial fibroblast population in the fibrotic peritoneal tissue [33].

In regard to angiogenesis, the number of peritoneal vessels did not vary when we compared different times on PD. Vasculopathy was present in 17% of the samples. Functional studies were used to define the peritoneal transport status. Patients in the highest quartile of mass transfer area coefficient of creatinine (Cr-MTAC) showed significantly higher MMT prevalence but similar number of peritoneal vessels. In the multivariate analysis, the highest quartile of Cr-MTAC remained as an independent factor predicting the presence of MMT after adjusting for fibrosis [34]. These findings indicate that MMT is a frequent morphological change in the peritoneal membrane. These myofibroblastic cells with submesothelial localization may arise from local conversion of MC during the repair responses and the high solute transport status

blasts circulating in the blood stream to their final tissue destination [33].

be responsible for a high peritoneal transport rate [3].

26 The Latest in Peritoneal Dialysis

is associated with MMT.

From MMT to SPS. Peritoneal fibrosis (or sclerosis) is a term that comprises a wide spectrum of peritoneal structural alterations, ranging from mild inflammation to severe sclerosing peritonitis and its most complicated manifestation, encapsulating peritonitis sclerosis (EPS) [6, 35, 36]. Simple sclerosis (SS), an intermediate stage of peritoneal fibrosis, is the most common peritoneal lesion found in the patients after few months on PD, and could represent the initial phase of sclerosing peritonitis syndrome (SPS). Rubin et al [5] described a normal thickness of the peritoneum of 20 μm, but after a few months on PD could reach up to 40 μm (SS). The SP is a progressive sclerosis that is characterized by a dramatic thickening of the peritoneum (up to 4000 μm) and is accompanied by inflammatory infiltrates, calcification, neo-vascularization and dilatation of blood and lymphatic vessels, being the thickening the most commonly used pathological criterion for differential diagnosis [6, 35, 36].

The importance of establishing a connection between MMT, SPS and EPS is the potential therapeutic and preventive effect of blocking this axis. Also emerging evidence suggests that partial or total blockage of the MMT prevents early stages of PM fibrosis and angiogenesis and preserves the PM function. Moreover, current studies show TGF-β is probably the most important molecule in the PM failure development, so act on a single molecule, the TGF-β, facilitates therapeutic approach. In fact we have shown that blockade of TGF-β significantly attenuated PM failure induced by PD fluids.

One of the biggest problems to establish the definitive connection between SPS and EPS is that the EPS animal model has not been fully and properly developed. While in our mice PD model in 4 or more weeks reaches the typical changes induced by PD fluids on humans, the peritoneal fibrosis model with chlorhexidine results artificial and extremely aggressive. The experimental development of an appropriate EPS model is mandatory. Possibly the most appropriate EPS mice model would be to maintain long-term (months) in PD according to our model of SPS. Once accepted this limitation, the current data suggest that MMT and SPS are part of the process. We have analyzed serially PM pieces of mice in PD at baseline, 15 and 30 days and we found a linear correlation between time on PD, the thickness of the PM and the number of MCs cytokeratin (+) and FSP-1 (+) in the area submesothelial. This phenomenon was accom‐ panied by progressive loss of the mesothelial monolayer which indicates an important participation of the MMT in the development of peritoneal fibrosis (our unpublished results). Using a TGF-β adenovirus model, we found early MMT at 4 day after stimuli intraperitoneal injection that was correlated with PM fibrosis [14]. Similar finding was found by others [15]. Clinically, in MCs serially isolated and cultured from PD effluents, the MMT was present progressively over time in PD and is associated with solute transport disorders and ultrafil‐ tration failure [37]. In PM biopsies from 35 PD stable patients performed during the first 2 years on PD, we demonstrated that the first morphological change in peritoneum that appears as a consequence of PD is submesothelial thickening partially caused by the MMT. This phenotype change is associated with an increase in peritoneal solute transport independent of the number of capillaries present in the tissue [1, 3]. Reaching this point, the following questions arise, as follows: could have peritoneal fibrosis without MMT?, or more specifically, could have MMT without the participation of TGF-β?. Experimental data by us [14] and others [15] indicate that blocking MMT in different degrees result in a significantly attenuation of structural and functional changes of PM. Using the adenovirus (TGF-β) and our PD mice model, the double submesothelial staining for cytokeratin (+) and FSP1 (+) was positive in approximately 37% of activated fibroblasts, indicating its epithelial origin [14]. However, the peritoneal fibrosis is inhibited in more than 50% indicating that direct inhibition of TGF-β with anti-TGF-β peptides inhibited other effects of this molecule as the activation of regional fibroblasts. Promising results have also obtained acting on immune system [38], on AGEs accumulation [39] or on renin-angiotensin system (ACE, AR-II, Paricalcitol) and BMP-7 which also modulate directly or indirectly the TGF-β [40]. These arguments lead us to conclude that TGF-β is a key in the initiation and possibly perpetuation of an uncontrolled MMT, which leads to fibrosis and SPS.

may be an initial phenomenon and few signs of it are in severe stages of fibrosis. However, in bridles and postsurgical adhesions, we have found MMT signs (unpublished data by us), and Bowel adherences may represent an intermediate degree between the SPS and EPS (our unpublished data by us), which encourages to conduct studies aimed to find MMT peritoneum

MMT and Peritoneal Membrane Failure http://dx.doi.org/10.5772/56598 29

These findings represent important evidence linking both processes, but indirect evidence may also be marked. In human studies [3, 11] and in experimental animals [47], our studies demonstrated a direct relationship between MMT and time on PD. Similarly, the several studies showed a parallel between EPS and time on PD [2, 48]. Another important fact is that peritoneal function studies also show a parallel between high frequency ofMMT ofMCs, high Cr-MTC, and low ultrafiltration. Indeed we observed a higher frequency of mesothelial fibroblastoid phenotype in patients with type Cr-MTC >11 mL/min [3]. Furthermore, as is well known, patients with EPS even displayed these with SPS showed similar functional PM deterioration [35, 49, 50]. Another indirect association between these two events is peritonitis. Yañez-Mo and coworkers [11] found that the frequency of nonepithelioidMCwas associated with episodes of peritonitis, thismeans that peritonitis leads to theMMT. In the case of theEPS, there are some studies in the literature that correlate it with peritonitis events. Previous studies suggest that peritonitis may predispose to EPS, especially if this is caused by *Staphylococcus aureus*, fungi, and/or *Pseudomonas* [9, 51]. There is also an association between persistent infections such as tuberculosis peritonitis and EPS [52]. Although peritonitis and EPS are highly associated in several studies it is also known that, especially in a long-term case, EPS may occur without peritonitis. Moreover, patients that have suffered from more events of peritonitis have a higher incidence of MMT and EPS, which suggest again that these processes are related. Finally, we have analyzed more than 10 peritoneal biopsies from patients with EPS where we had found a significant amount of mesothelial cells (CK +) in the peritoneal subme‐ sothelial area, which indicates that despite the significant denudation of the peritoneal MCs

Based on the concept, that MMT, fibrosis and angiogenesis may be part of the same process of peritoneal membrane failure, therapeutic approaches may be addressed to prevent either MMT of the MC or its deleterious effects such as ECM synthesis and/or VEGF production. In this context, *in vitro* and *ex vivo* cultures of MC may be useful for testing pharmacological agents with potential effects on MMT of the MC. Two molecules with expected preventive effect on the MMT of MC are hepatocyte growth factor (HGF) and bone morphogenic protein-7 (BMP-7). It has been demonstrated that these molecules are able to inhibit and reverse MMT and renal fibrosis in animal models. [53-54]. Other strategies that would open new avenues of therapeutic intervention to prevent or reverse MMT of MC may include the inhibition of ILK, RhoA-ROCK or Akt-mediated signaling cascades [25-33, 55]. In this context, the administration of the ROCK inhibitor Y-27632 resulted in suppression of α-SMA expression and renal interstitial fibrosis

with EPS.

monolayer.

**6. The MMT as therapeutic target**

in a mouse model of ureteral obstruction. [55]

**From SPS to EPS***.* The next question is as follows: at which point the SPS becomes an irrever‐ sible process to become EPS? The "two-hit" hypothesis explains the EPS as the result of the PD injury. Two factors are required for the onset of EPS: a predisposing factor, such as peritoneal deterioration from persistent injury caused by peritoneal dialysis (the first "hit"), and an initiating factor, such as inflammatory stimuli superimposed on the chronically injured peritoneum (the second "hit"). Peritoneal deterioration (consisting of mesothelial denudation, interstitial fibrosis, vasculopathy, and angiogenesis) leads to an increased tendency toward plasma exudations that contain fibrin and coagulation factors. The fibrins in the exudates contribute to the intestinal adhesions and formation of fibrin capsule. Inflammatory stimuli caused by infectious peritonitis are superimposed on the damaged peritoneum and act as an initiating factor to trigger the onset of EPS. Inflammatory cytokines also induce activation and proliferation of the peritoneal fibroblasts, promoting peritoneal fibrosis and intestinal adhe‐ sions. The relationship between the extent of the first and second "hits" can be demonstrated. The extent of peritoneal damage (the first "hit") increases with the duration of peritoneal dialysis [41, 42].

The onset of EPS depends on the total intensity of both lesions: peritoneal damage and inflammatory stimuli. For the onset of EPS, the total intensity must be greater than a given threshold. The extent of the inflammatory stimuli (the second "hit") are required for the onset of EPS [41, 42].

In both cases (acute and chronic peritoneal injury), the TGF-β is activated with subsequent initiation and perpetuation of MMT and its deleterious effects (fibrosis, angiogenesis, etc.). However, it is very difficult to establish the point of no return in peritoneal lesions clinically because patients with type-I PM failure usually recover functionality and possibly tissue damage with rest peritoneal [43]. In experimental animals, data about fibrosis reversibility are not available. Unfortunately, the initial degree of PM fibrosis has been determined in very few cases (peritoneal biopsies not available). Finally a genetic component cannot be ruled [44, 45].

**From MMT to EPS.** In both, experimental animals [14, 46] and human peritoneal biopsies from patients within 2 years in PD [34], it seems clear that MMT is an early phenomenon able to determine the degree of peritoneal fibrosis and the future of the PM. But no information about MMT in patients with long term in PD or diagnosis of EPS is available. It is possible that MMT may be an initial phenomenon and few signs of it are in severe stages of fibrosis. However, in bridles and postsurgical adhesions, we have found MMT signs (unpublished data by us), and Bowel adherences may represent an intermediate degree between the SPS and EPS (our unpublished data by us), which encourages to conduct studies aimed to find MMT peritoneum with EPS.

These findings represent important evidence linking both processes, but indirect evidence may also be marked. In human studies [3, 11] and in experimental animals [47], our studies demonstrated a direct relationship between MMT and time on PD. Similarly, the several studies showed a parallel between EPS and time on PD [2, 48]. Another important fact is that peritoneal function studies also show a parallel between high frequency ofMMT ofMCs, high Cr-MTC, and low ultrafiltration. Indeed we observed a higher frequency of mesothelial fibroblastoid phenotype in patients with type Cr-MTC >11 mL/min [3]. Furthermore, as is well known, patients with EPS even displayed these with SPS showed similar functional PM deterioration [35, 49, 50]. Another indirect association between these two events is peritonitis. Yañez-Mo and coworkers [11] found that the frequency of nonepithelioidMCwas associated with episodes of peritonitis, thismeans that peritonitis leads to theMMT. In the case of theEPS, there are some studies in the literature that correlate it with peritonitis events. Previous studies suggest that peritonitis may predispose to EPS, especially if this is caused by *Staphylococcus aureus*, fungi, and/or *Pseudomonas* [9, 51]. There is also an association between persistent infections such as tuberculosis peritonitis and EPS [52]. Although peritonitis and EPS are highly associated in several studies it is also known that, especially in a long-term case, EPS may occur without peritonitis. Moreover, patients that have suffered from more events of peritonitis have a higher incidence of MMT and EPS, which suggest again that these processes are related. Finally, we have analyzed more than 10 peritoneal biopsies from patients with EPS where we had found a significant amount of mesothelial cells (CK +) in the peritoneal subme‐ sothelial area, which indicates that despite the significant denudation of the peritoneal MCs monolayer.

#### **6. The MMT as therapeutic target**

could have MMT without the participation of TGF-β?. Experimental data by us [14] and others [15] indicate that blocking MMT in different degrees result in a significantly attenuation of structural and functional changes of PM. Using the adenovirus (TGF-β) and our PD mice model, the double submesothelial staining for cytokeratin (+) and FSP1 (+) was positive in approximately 37% of activated fibroblasts, indicating its epithelial origin [14]. However, the peritoneal fibrosis is inhibited in more than 50% indicating that direct inhibition of TGF-β with anti-TGF-β peptides inhibited other effects of this molecule as the activation of regional fibroblasts. Promising results have also obtained acting on immune system [38], on AGEs accumulation [39] or on renin-angiotensin system (ACE, AR-II, Paricalcitol) and BMP-7 which also modulate directly or indirectly the TGF-β [40]. These arguments lead us to conclude that TGF-β is a key in the initiation and possibly perpetuation of an uncontrolled MMT, which

**From SPS to EPS***.* The next question is as follows: at which point the SPS becomes an irrever‐ sible process to become EPS? The "two-hit" hypothesis explains the EPS as the result of the PD injury. Two factors are required for the onset of EPS: a predisposing factor, such as peritoneal deterioration from persistent injury caused by peritoneal dialysis (the first "hit"), and an initiating factor, such as inflammatory stimuli superimposed on the chronically injured peritoneum (the second "hit"). Peritoneal deterioration (consisting of mesothelial denudation, interstitial fibrosis, vasculopathy, and angiogenesis) leads to an increased tendency toward plasma exudations that contain fibrin and coagulation factors. The fibrins in the exudates contribute to the intestinal adhesions and formation of fibrin capsule. Inflammatory stimuli caused by infectious peritonitis are superimposed on the damaged peritoneum and act as an initiating factor to trigger the onset of EPS. Inflammatory cytokines also induce activation and proliferation of the peritoneal fibroblasts, promoting peritoneal fibrosis and intestinal adhe‐ sions. The relationship between the extent of the first and second "hits" can be demonstrated. The extent of peritoneal damage (the first "hit") increases with the duration of peritoneal

The onset of EPS depends on the total intensity of both lesions: peritoneal damage and inflammatory stimuli. For the onset of EPS, the total intensity must be greater than a given threshold. The extent of the inflammatory stimuli (the second "hit") are required for the onset

In both cases (acute and chronic peritoneal injury), the TGF-β is activated with subsequent initiation and perpetuation of MMT and its deleterious effects (fibrosis, angiogenesis, etc.). However, it is very difficult to establish the point of no return in peritoneal lesions clinically because patients with type-I PM failure usually recover functionality and possibly tissue damage with rest peritoneal [43]. In experimental animals, data about fibrosis reversibility are not available. Unfortunately, the initial degree of PM fibrosis has been determined in very few cases (peritoneal biopsies not available). Finally a genetic component cannot be ruled [44, 45]. **From MMT to EPS.** In both, experimental animals [14, 46] and human peritoneal biopsies from patients within 2 years in PD [34], it seems clear that MMT is an early phenomenon able to determine the degree of peritoneal fibrosis and the future of the PM. But no information about MMT in patients with long term in PD or diagnosis of EPS is available. It is possible that MMT

leads to fibrosis and SPS.

28 The Latest in Peritoneal Dialysis

dialysis [41, 42].

of EPS [41, 42].

Based on the concept, that MMT, fibrosis and angiogenesis may be part of the same process of peritoneal membrane failure, therapeutic approaches may be addressed to prevent either MMT of the MC or its deleterious effects such as ECM synthesis and/or VEGF production. In this context, *in vitro* and *ex vivo* cultures of MC may be useful for testing pharmacological agents with potential effects on MMT of the MC. Two molecules with expected preventive effect on the MMT of MC are hepatocyte growth factor (HGF) and bone morphogenic protein-7 (BMP-7). It has been demonstrated that these molecules are able to inhibit and reverse MMT and renal fibrosis in animal models. [53-54]. Other strategies that would open new avenues of therapeutic intervention to prevent or reverse MMT of MC may include the inhibition of ILK, RhoA-ROCK or Akt-mediated signaling cascades [25-33, 55]. In this context, the administration of the ROCK inhibitor Y-27632 resulted in suppression of α-SMA expression and renal interstitial fibrosis in a mouse model of ureteral obstruction. [55]

smads cascade inhibiting the MMT (our unpublished results). Finally, we were able to inhibit specifically TGF-β with anti-TGF-β specific peptides demonstrating the role of TGF-β in the initiation and perpetuation of MMT [14]. In this context, other promising substances are pentoxifylline, dipyridamole, and emodin [59-61]. Figure 4 summarizes the sites where we may act by blocking the MMT or adverse effects. Some of these drugs and / or therapeutic

Recent findings suggest that in the peritoneum new fibroblast-like cells arise from local conversion of MMT during the repair responses that take place in long-term PD. These transdifferentiated MC may invade the submesothelial tissue and may contribute to peritoneal fibrosis and angiogenesis, which ultimately lead to peritoneal membrane failure. MMT appears as the central point in the pathogenesis of peritoneal damage associated to PD. Current data support a connection between MMT and SPS. However, the jump from SPS to EPS and the connection between MMT and EPS have not been fully established. MMT can be a therapeutic target the blockade of which could benefit especially in initial stages of the process.

This work was supported by grant SAF2010-21249 from the "Ministerio de Economia y Competitividad" to M.L.-C. and by grant S2010/BMD-2321 from "Comunidad Autónoma de Madrid" to M.L.-C. and R.S. This work was also partially supported by grants PI 09/0776 from "Fondo de Investigaciones Sanitarias" to A.A. RETICS 06/0016 (REDinREN, Fondos FEDER,

, Guadalupe Gónzalez-Mateo2

\*Address all correspondence to: abelardo.aguilera@salud.madrid.org aguileraa@terra.es

1 Unidad de Biología Molecular and Servicio de Nefrología. Hospital Universitario de la

2 Hospital Universitario La Paz, Instituto de Investigación Sanitaria la Paz (IdiPAZ), Ma‐

3 Centro de Biología Molecular-Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain

, Rafael Selgas2

MMT and Peritoneal Membrane Failure http://dx.doi.org/10.5772/56598 31

and

EU) to R.S and Baxter Grand nº 10CECEU1008 2010 to AA and ML-C.

Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

strategies have been described by our group.

**7. Conclusion**

**Acknowledgements**

**Author details**

drid, Spain

Manuel López-Cabrera3

Abelardo Aguilera1\*, Jesús Loureiro1

**Figure 4. Therapeutic approach to MMT.** MMT *in vivo* results from integrated signals that are induced by multiple stimuli. These include elevated glucose and glucose degradation products (GDP) and concentration of PD fluids, which through the formation of advanced glycation-end products (AGE) stimulate the transdifferentiation of MC. The forma‐ tion of AGE may also be due to the uremic status of the PD patients. The low pH of the dialysates and the mechanical injury during PD fluid exchanges may cause tissue irritation and contribute to chronic inflammation of the perito‐ neum, which promote MMT. Episodes of bacterial or fungal infections or hemoperitoneum cause acute inflammation and upregulation of cytokines and growth factors such as TGF-β, IL-1, fibroblast growth factor-2 (FGF-2), TNF-α, and angiotensin-II, among others, which are strong inducers of MMT. The therapeutic strategies may be designed either to prevent or to reverse the MMT itself or to treat its effects such as cellular invasion, fibrosis, or angiogenesis. The dia‐ gram illustrates six steps related to the MMT process of the MC that can be clinically managed, alone or in combina‐ tion, to prevent peritoneal membrane failure. The numbers represent the steps where different drugs or molecules can act. 1: Tamoxifen, AGEs accumulation inhibitors (Rosiglitazone), BMP7 and HGF; 2: BMP7 and HGF; 3: Invasion In‐ hibitors (MMPs blocked); 4: Antifibrotic i, e: rapamycin; 5: Tamoxifen and heparin; 6: Angiogenesis inhibitors (rapamy‐ cin, inhinitors CO2, etc.)

We performed our studies using testing different drugs or anti-MMT strategies. We have developed a PD mouse model, this consist in the intra-abdominal catheter implantation with a subcutaneous chamber localized in the top of mouse back. After, we injected a daily intraperitoneal injection of PD solution (1.5-2 mL) at least for 4 weeks. In-vitro we used MCs isolated from omentum and from PD peritoneal effluent. We managed to inhibit the MMT and its adverse effects from using rBMP7 [40]. With Rapamycin got a specific inhibition of fibrosis and the vessels formation specifically lymphatic vessels (56, 57, our unpublished results). Rosiglitazone showed an inhibitory effect on the accumulation of submesothelial AGEs, also anti-inflammatory action mediated by T-cells was observed [39]. Similarly, celecocib inhibited the peritoneal fibrosis by an anti-cox2 effect [38]. MMT also was prevented by tamoxifen. This drug inhibited the peritoneal fibrosis and increased MCs fibrinolytic capacity [47]. Clinically, tamoxifen also improved survival in patients diagnosed of EPS [58]. Paricalcitol acted on smads cascade inhibiting the MMT (our unpublished results). Finally, we were able to inhibit specifically TGF-β with anti-TGF-β specific peptides demonstrating the role of TGF-β in the initiation and perpetuation of MMT [14]. In this context, other promising substances are pentoxifylline, dipyridamole, and emodin [59-61]. Figure 4 summarizes the sites where we may act by blocking the MMT or adverse effects. Some of these drugs and / or therapeutic strategies have been described by our group.

#### **7. Conclusion**

Recent findings suggest that in the peritoneum new fibroblast-like cells arise from local conversion of MMT during the repair responses that take place in long-term PD. These transdifferentiated MC may invade the submesothelial tissue and may contribute to peritoneal fibrosis and angiogenesis, which ultimately lead to peritoneal membrane failure. MMT appears as the central point in the pathogenesis of peritoneal damage associated to PD. Current data support a connection between MMT and SPS. However, the jump from SPS to EPS and the connection between MMT and EPS have not been fully established. MMT can be a therapeutic target the blockade of which could benefit especially in initial stages of the process.

#### **Acknowledgements**

This work was supported by grant SAF2010-21249 from the "Ministerio de Economia y Competitividad" to M.L.-C. and by grant S2010/BMD-2321 from "Comunidad Autónoma de Madrid" to M.L.-C. and R.S. This work was also partially supported by grants PI 09/0776 from "Fondo de Investigaciones Sanitarias" to A.A. RETICS 06/0016 (REDinREN, Fondos FEDER, EU) to R.S and Baxter Grand nº 10CECEU1008 2010 to AA and ML-C.

#### **Author details**

We performed our studies using testing different drugs or anti-MMT strategies. We have developed a PD mouse model, this consist in the intra-abdominal catheter implantation with a subcutaneous chamber localized in the top of mouse back. After, we injected a daily intraperitoneal injection of PD solution (1.5-2 mL) at least for 4 weeks. In-vitro we used MCs isolated from omentum and from PD peritoneal effluent. We managed to inhibit the MMT and its adverse effects from using rBMP7 [40]. With Rapamycin got a specific inhibition of fibrosis and the vessels formation specifically lymphatic vessels (56, 57, our unpublished results). Rosiglitazone showed an inhibitory effect on the accumulation of submesothelial AGEs, also anti-inflammatory action mediated by T-cells was observed [39]. Similarly, celecocib inhibited the peritoneal fibrosis by an anti-cox2 effect [38]. MMT also was prevented by tamoxifen. This drug inhibited the peritoneal fibrosis and increased MCs fibrinolytic capacity [47]. Clinically, tamoxifen also improved survival in patients diagnosed of EPS [58]. Paricalcitol acted on

cin, inhinitors CO2, etc.)

30 The Latest in Peritoneal Dialysis

**Figure 4. Therapeutic approach to MMT.** MMT *in vivo* results from integrated signals that are induced by multiple stimuli. These include elevated glucose and glucose degradation products (GDP) and concentration of PD fluids, which through the formation of advanced glycation-end products (AGE) stimulate the transdifferentiation of MC. The forma‐ tion of AGE may also be due to the uremic status of the PD patients. The low pH of the dialysates and the mechanical injury during PD fluid exchanges may cause tissue irritation and contribute to chronic inflammation of the perito‐ neum, which promote MMT. Episodes of bacterial or fungal infections or hemoperitoneum cause acute inflammation and upregulation of cytokines and growth factors such as TGF-β, IL-1, fibroblast growth factor-2 (FGF-2), TNF-α, and angiotensin-II, among others, which are strong inducers of MMT. The therapeutic strategies may be designed either to prevent or to reverse the MMT itself or to treat its effects such as cellular invasion, fibrosis, or angiogenesis. The dia‐ gram illustrates six steps related to the MMT process of the MC that can be clinically managed, alone or in combina‐ tion, to prevent peritoneal membrane failure. The numbers represent the steps where different drugs or molecules can act. 1: Tamoxifen, AGEs accumulation inhibitors (Rosiglitazone), BMP7 and HGF; 2: BMP7 and HGF; 3: Invasion In‐ hibitors (MMPs blocked); 4: Antifibrotic i, e: rapamycin; 5: Tamoxifen and heparin; 6: Angiogenesis inhibitors (rapamy‐

> Abelardo Aguilera1\*, Jesús Loureiro1 , Guadalupe Gónzalez-Mateo2 , Rafael Selgas2 and Manuel López-Cabrera3

\*Address all correspondence to: abelardo.aguilera@salud.madrid.org aguileraa@terra.es

1 Unidad de Biología Molecular and Servicio de Nefrología. Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

2 Hospital Universitario La Paz, Instituto de Investigación Sanitaria la Paz (IdiPAZ), Ma‐ drid, Spain

3 Centro de Biología Molecular-Severo Ochoa, CSIC-UAM, Cantoblanco, Madrid, Spain

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36 The Latest in Peritoneal Dialysis

1204–1209.

96-207.


**Chapter 3**

**Encapsulating Peritoneal Sclerosis**

Joerg Latus, Christoph Ulmer, Martin Kimmel,

Additional information is available at the end of the chapter

Chronic peritoneal dialysis (PD) can be complicated by encapsulating peritoneal sclerosis (EPS), a rare but the most severe complication associated with long-term PD. Morbidity and mortality are still high (range from 25% to 55%) especially in the first year after diagnosis. The international Society for Peritoneal Dialysis (ISPD) defined EPS by clinical signs of abdominal pain, bowel obstruction or weight loss in late stages of the disease. Clinical symptoms,

During the course of the disease, development of adhesions causing symptoms of bowel obstruction often requires major surgery (figure 1A). Mostly, peritonectomy and enterolysis

Earlier stages of the disease are difficult to detect. Changes in transporter status or ultrafiltra‐ tion failure can be first signs of EPS. The incidence of EPS increases with increasing time on PD, younger age, glucose load and peritonitis rate. EPS may occur when the patient is still on PD, but most patients become symptomatic after cessation of PD. In the minority of cases, EPS symptoms disappear and it seems to be a selflimiting condition. Actually, there exist no evidence based medical and surgical treatment options. Case reports and small case series are dealing with the effectiveness of immunosuppressants or antifibrotic drugs. But evidence for a specific medical treatment option is still lacking and prospective studies are needed.

EPS is a very rare disease and the true incidence is still unknown. It is not exclusively seen in patients on PD but in this chapter we will focus only on PD-patients or former PD-patients.

and reproduction in any medium, provided the original work is properly cited.

© 2013 Latus et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

radiologic findings and histologic criteria are the three diagnostic pillars.

**2. Epidemiology of encapsulating peritoneal sclerosis**

M. Dominik Alscher and Niko Braun

(PEEL) is the surgical treatment of choice.

http://dx.doi.org/10.5772/56052

**1. Introduction**

## **Encapsulating Peritoneal Sclerosis**

Joerg Latus, Christoph Ulmer, Martin Kimmel, M. Dominik Alscher and Niko Braun

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56052

**1. Introduction**

Chronic peritoneal dialysis (PD) can be complicated by encapsulating peritoneal sclerosis (EPS), a rare but the most severe complication associated with long-term PD. Morbidity and mortality are still high (range from 25% to 55%) especially in the first year after diagnosis. The international Society for Peritoneal Dialysis (ISPD) defined EPS by clinical signs of abdominal pain, bowel obstruction or weight loss in late stages of the disease. Clinical symptoms, radiologic findings and histologic criteria are the three diagnostic pillars.

During the course of the disease, development of adhesions causing symptoms of bowel obstruction often requires major surgery (figure 1A). Mostly, peritonectomy and enterolysis (PEEL) is the surgical treatment of choice.

Earlier stages of the disease are difficult to detect. Changes in transporter status or ultrafiltra‐ tion failure can be first signs of EPS. The incidence of EPS increases with increasing time on PD, younger age, glucose load and peritonitis rate. EPS may occur when the patient is still on PD, but most patients become symptomatic after cessation of PD. In the minority of cases, EPS symptoms disappear and it seems to be a selflimiting condition. Actually, there exist no evidence based medical and surgical treatment options. Case reports and small case series are dealing with the effectiveness of immunosuppressants or antifibrotic drugs. But evidence for a specific medical treatment option is still lacking and prospective studies are needed.

### **2. Epidemiology of encapsulating peritoneal sclerosis**

EPS is a very rare disease and the true incidence is still unknown. It is not exclusively seen in patients on PD but in this chapter we will focus only on PD-patients or former PD-patients.

**Figure 1.** A 45-year old male presenting with massive abdominal pain, nausea, vomiting and weight loss over months. He was on PD for 72 months. EPS shows a sticky fibrin coating membrane on top of the bowel containing the brown and thick peritoneum B After an operation time of 420 minutes with peritonectomy and enterolysis (PEEL). Fibrin membranes were resected and restitution of intestinal function was achieved. 72 months after surgery, he has com‐ pletely recovered and is back at work.

Kawanishi et al. reported 2004 and 2005 in their large cohorts, an overall incidence of 2.5% with an even higher incidence of up to 17.2% for patients on PD longer than 15 years. The Scottish Renal Registry included 1238 PD patients and Brown et al. showed that the incidence of EPS increases with time on PD: 2% after three to four years, 8.8% after five to six years and 5% after more than six years on PD. Interestingly, at the time of EPS diagnosis, 26% of the patients were still on PD whereas 72% were not on PD. Recently, Johnson et al. showed in a very large study from Australia and New Zealand a remarkably low incidence of 0.3, 0.8 and 3.9% after three, five and eight years on PD. In this study, the hazard ratio for patients receiving more than eight years PD was 12.1 in this study. It is noteworthy, that all existing data indicate that the majority of patients who are on PD for a long time will not develop EPS. The probability to develop e.g. endocarditis or osteomyelitis is much higher. Nevertheless, several risk factors for the development of EPS are discussed, but the published data are not uniform (table 1).

exposure are common. High transporter status in the peritoneal equilibration test prior to development of EPS has also been described in many EPS patients. These membrane changes are, however, not indicative for EPS, because they are also commonly observed in patients on long-term PD who do not develop EPS. Japanese investigators made an approach to subcate‐ gorize EPS in four stages. The first stage means the so-called pre-EPS stage with ascites followed by an inflammatory stage. Third stage is a stage of encapsulating of the bowel and the final stage includes symptoms of bowel obstruction. Up to now, this staging is not widely

**Table 1.** Possible risk factors for EPS (most confident risk factors are marked in bold)

Signs of Inflammation

Encapsulating Peritoneal Sclerosis http://dx.doi.org/10.5772/56052 41

• Fever • Ascites • General fatigue • Weight loss Peritoneal adhesions • Bloody effluent • Ascites • Abdominal pain • Abdominal mass

accepted in the international PD community.

**Symptoms and clinical findings in EPS patients**

**Table 2.** Common clinical findings in patients EPS

Signs of bowel obstruction

**Longer duration of PD**

High Glucose Exposure Ultrafiltration failure High volume regimen

**Younger age**

Acetate buffer Chlorhexidine Icodextrin use

Smoking status

Absence of residual renal function Inadequate dialysis (low Kt/V)

Cessation of PD (post-transplant)

Medication (ß-Blocker, calcineurin inhibitors)

High Peritonitis Rate (severity/staphylococcus aureus)

• Appetite loss • Nausea and vomiting • Abdominal pain • Abdominal fullness

• Diarrhea • Anorexia • Weight loss • Feeling of heaviness • Constipation • Absent bowel sounds

#### **3. Diagnostic pillars in encapsulating peritoneal sclerosis**

#### **3.1. Clinical features of encapsulating peritoneal sclerosis**

The clinical features of EPS are the result of acute or subacute small bowel obstruction mostly caused by adhesions and signs of systemic inflammation. The clinical findings mostly seen in patients with EPS are summarized in Table 2. In one of our EPS studies, all patients in the severe group (which was defined by the requirement for surgery due to extensive symptoms caused by bowel obstruction) had massive abdominal pain or vomiting. A large proportion in this group had both symptoms. Additionally, weight loss was noted in almost all patients in this group. In earlier stages of the disease, loss of peritoneal ultrafiltration capacity with weight gain (9 out of 31 in our study), a lower residual renal function, a higher glucose and icodextrin


#### **Table 1.** Possible risk factors for EPS (most confident risk factors are marked in bold)

Kawanishi et al. reported 2004 and 2005 in their large cohorts, an overall incidence of 2.5% with an even higher incidence of up to 17.2% for patients on PD longer than 15 years. The Scottish Renal Registry included 1238 PD patients and Brown et al. showed that the incidence of EPS increases with time on PD: 2% after three to four years, 8.8% after five to six years and 5% after more than six years on PD. Interestingly, at the time of EPS diagnosis, 26% of the patients were still on PD whereas 72% were not on PD. Recently, Johnson et al. showed in a very large study from Australia and New Zealand a remarkably low incidence of 0.3, 0.8 and 3.9% after three, five and eight years on PD. In this study, the hazard ratio for patients receiving more than eight years PD was 12.1 in this study. It is noteworthy, that all existing data indicate that the majority of patients who are on PD for a long time will not develop EPS. The probability to develop e.g. endocarditis or osteomyelitis is much higher. Nevertheless, several risk factors for the development of EPS are discussed, but the published data are not uniform (table 1).

**Figure 1.** A 45-year old male presenting with massive abdominal pain, nausea, vomiting and weight loss over months. He was on PD for 72 months. EPS shows a sticky fibrin coating membrane on top of the bowel containing the brown and thick peritoneum B After an operation time of 420 minutes with peritonectomy and enterolysis (PEEL). Fibrin membranes were resected and restitution of intestinal function was achieved. 72 months after surgery, he has com‐

(A) (B)

The clinical features of EPS are the result of acute or subacute small bowel obstruction mostly caused by adhesions and signs of systemic inflammation. The clinical findings mostly seen in patients with EPS are summarized in Table 2. In one of our EPS studies, all patients in the severe group (which was defined by the requirement for surgery due to extensive symptoms caused by bowel obstruction) had massive abdominal pain or vomiting. A large proportion in this group had both symptoms. Additionally, weight loss was noted in almost all patients in this group. In earlier stages of the disease, loss of peritoneal ultrafiltration capacity with weight gain (9 out of 31 in our study), a lower residual renal function, a higher glucose and icodextrin

**3. Diagnostic pillars in encapsulating peritoneal sclerosis**

**3.1. Clinical features of encapsulating peritoneal sclerosis**

pletely recovered and is back at work.

40 The Latest in Peritoneal Dialysis

exposure are common. High transporter status in the peritoneal equilibration test prior to development of EPS has also been described in many EPS patients. These membrane changes are, however, not indicative for EPS, because they are also commonly observed in patients on long-term PD who do not develop EPS. Japanese investigators made an approach to subcate‐ gorize EPS in four stages. The first stage means the so-called pre-EPS stage with ascites followed by an inflammatory stage. Third stage is a stage of encapsulating of the bowel and the final stage includes symptoms of bowel obstruction. Up to now, this staging is not widely accepted in the international PD community.


#### **3.2. Radiological findings in encapsulating peritoneal sclerosis**

A CT-scan is mandatory in all patients with suspected EPS, but it is noteworthy, that no single diagnostic feature on CT-scan exists and any of the mentioned features can be found in scans of PD-patients without EPS. There is rarely more than one feature and in the majority of cases of low severity. Therefore, current evidence does not support the use of CT scanning to screen for EPS. Table 3 summarizes the typical imaging features of EPS and figure 2 shows an example of a 59-year old male with late-stage EPS. In very rare cases, x-rays show massive calcification (figure 3). Other studies like ultrasound, MRI or abdominal X-ray are insufficiently sensitive, rarely typical features are found.

Adhesion of bowel loops Peritoneal thickening Peritoneal calcification Peritoneal enhancement Bowel dilatation Change of bowel calibre Fluid loculation/septation Thickening of the bowel wall

**Table 3.** Computed tomographic findings of EPS patients

**3.3. Histological criteria for encapsulating peritoneal sclerosis**

to establish standardized histological criteria for EPS.

**4. Pathogenic models of encapsulating peritoneal sclerosis**

**4.1. Epithelio-mesenchymal transformation (EMT) and the so-called two-hit-model**

Over the years, the non-physiological properties of the PD fluids (glucose load, acidic pH, GDP`s affects the integrity of the peritoneal membrane. The insult of the serosa leads to

The third diagnostic pillar of EPS is based on the evaluation of peritoneal biopsies. The diagnosis of PD-associated pathologies, especially of EPS, is an interdisciplinary process, which requires, nephrologists and pathologists. The two most relevant pathologies of longterm PD are simple sclerosis (SS), which is a very common finding in PD- and EPS- patients. For a histological diagnosis, reproducible histological criteria are needed that can be used to differentiate the two entities. In 2003 and 2005 Honda and colleagues investigated peritoneal biopsies of 12 EPS patients. Fibrin deposition, fibroblast swelling, capillary angiogenesis and mononuclear cell infiltration were significantly more common in EPS than in peritonitis, ultrafiltration failure, uremia and so called "pre-EPS". Regarding the degree of these param‐ eters, only fibroblast swelling and fibrin deposition exhibited were statistically significant different in their study. Several markers for fibroblast proliferation were also investigated. Garosi and colleagues investigated 224 peritoneal biopsies of non-EPS patients and compared the morphological findings with the biopsies of 39 patients with EPS. Significant findings in patients with EPS were thickening of the submesothelial cell layer, vasculopathy, arterial occlusion, inflammation, tissue calcification and ossification and arterial calcification and ossification (figure 4). In 2008 Sherif and colleagues compared peritoneal biopsies of 12 EPS patients with 23 non-EPS patients. Only fibrin deposition and the thickness of the compacta were significantly different between EPS patients and non-EPS patients. Actually, there is one main problem associated with most of the published data. In these previous studies, data acquisition was not standardized, observers were not blinded to the diagnosis and intra- and inter-observer variability was not given. Up to now there is no established method to differ‐ entiate between EPS and simple sclerosis. Especially in this field, further studies are needed

Encapsulating Peritoneal Sclerosis http://dx.doi.org/10.5772/56052 43

**Figure 2.** A CT scan showing typical "cocooning" with heavy calcifications and bowel obstruction (arrow). B Thickening, calcification and enhancement of the peritoneal membrane (black arrow). Loculated fluid collection (white arrow).

**Figure 3.** Peritoneal calcification (arrow) in a patient with established EPS after 22 years on PD.


**Table 3.** Computed tomographic findings of EPS patients

**3.2. Radiological findings in encapsulating peritoneal sclerosis**

rarely typical features are found.

42 The Latest in Peritoneal Dialysis

A CT-scan is mandatory in all patients with suspected EPS, but it is noteworthy, that no single diagnostic feature on CT-scan exists and any of the mentioned features can be found in scans of PD-patients without EPS. There is rarely more than one feature and in the majority of cases of low severity. Therefore, current evidence does not support the use of CT scanning to screen for EPS. Table 3 summarizes the typical imaging features of EPS and figure 2 shows an example of a 59-year old male with late-stage EPS. In very rare cases, x-rays show massive calcification (figure 3). Other studies like ultrasound, MRI or abdominal X-ray are insufficiently sensitive,

**Figure 2.** A CT scan showing typical "cocooning" with heavy calcifications and bowel obstruction (arrow). B Thickening, calcification and enhancement of the peritoneal membrane (black arrow). Loculated fluid collection (white arrow).

**Figure 3.** Peritoneal calcification (arrow) in a patient with established EPS after 22 years on PD.

#### **3.3. Histological criteria for encapsulating peritoneal sclerosis**

The third diagnostic pillar of EPS is based on the evaluation of peritoneal biopsies. The diagnosis of PD-associated pathologies, especially of EPS, is an interdisciplinary process, which requires, nephrologists and pathologists. The two most relevant pathologies of longterm PD are simple sclerosis (SS), which is a very common finding in PD- and EPS- patients. For a histological diagnosis, reproducible histological criteria are needed that can be used to differentiate the two entities. In 2003 and 2005 Honda and colleagues investigated peritoneal biopsies of 12 EPS patients. Fibrin deposition, fibroblast swelling, capillary angiogenesis and mononuclear cell infiltration were significantly more common in EPS than in peritonitis, ultrafiltration failure, uremia and so called "pre-EPS". Regarding the degree of these param‐ eters, only fibroblast swelling and fibrin deposition exhibited were statistically significant different in their study. Several markers for fibroblast proliferation were also investigated. Garosi and colleagues investigated 224 peritoneal biopsies of non-EPS patients and compared the morphological findings with the biopsies of 39 patients with EPS. Significant findings in patients with EPS were thickening of the submesothelial cell layer, vasculopathy, arterial occlusion, inflammation, tissue calcification and ossification and arterial calcification and ossification (figure 4). In 2008 Sherif and colleagues compared peritoneal biopsies of 12 EPS patients with 23 non-EPS patients. Only fibrin deposition and the thickness of the compacta were significantly different between EPS patients and non-EPS patients. Actually, there is one main problem associated with most of the published data. In these previous studies, data acquisition was not standardized, observers were not blinded to the diagnosis and intra- and inter-observer variability was not given. Up to now there is no established method to differ‐ entiate between EPS and simple sclerosis. Especially in this field, further studies are needed to establish standardized histological criteria for EPS.

#### **4. Pathogenic models of encapsulating peritoneal sclerosis**

#### **4.1. Epithelio-mesenchymal transformation (EMT) and the so-called two-hit-model**

Over the years, the non-physiological properties of the PD fluids (glucose load, acidic pH, GDP`s affects the integrity of the peritoneal membrane. The insult of the serosa leads to

Figure 5. Mesothelial cells undergoing the so-called epithelio-mesenchymal transformation (EMT); MCL mesothelial cell layer; SMC sub

The optimal management of EPS is not clear. Mortality and morbidity are still high (25% to 55%) especially in the first year after diagnosis . Table 4 shows a comparison of epidemiological studies of EPS patients. Up to now, there are no randomized controlled trials and the level of evidence is weak. The choice of surgical or conservative therapy is often based on the stage of the disease and varies quiet a lot between "EPS- centers". There is one prospective registry report from Kawanishi et al., who investigated 48 EPS patients in Japan. They report a recovery rate with total parenteral nutrition, corticosteroids and surgical treatment of 0%, 38.5%

During work-up of patients with EPS, bacterial and fungal peritonitis must be ruled out before treatment might be considered.

(Japan 1996) 1980-1994 62 RS/MC 5.1 43.5

(Korea 2003) 1981-2002 31 RS/MC 5.8 25.8

al. (UK 2005) 1998-2003 27 RS/SC 6.1 29.6

(UK 2009) 2000-2007 46 RS/MC 5.4 56.5

(Australia 1995-2007 33 RS/MC 4.5 55

1980-1994 54 RS/MC 4.3 56

1999-2001 17 PS/MC 10 35

1999-2003 48 PS/MC 4.3 37.5

1997-2008 111 RS/MC 6.9 53

**Mean PD duration (years)** 

Encapsulating Peritoneal Sclerosis http://dx.doi.org/10.5772/56052 45

**Mortality rate (%)**

and 58.3%, respectively. All together, 37.5% of the patients in this study died, 45.8% of the patients recovered .

**Date of study EPS cases Study design**

mesothelial cells; ICS interstitial cell space. Adapted from Aroeira et al. .

**5. Management and outcome in encapsulating peritoneal sclerosis**

cell layer; SMC sub mesothelial cells; ICS interstitial cell space. Adapted from Aroeira et al..

Treatment options include surgery and/or medical therapy.

Nomoto et al.

Rigby et al. (Australia 1998)

recovered.

**5.1. Medical therapy**

Lee et al.

Kawanishi et al. (Japan 2001)

Kawanishi et al. (Japan 2004)

Summers et

Brown et al.

Balasubrama niam et al. (UK 2009)

Johnson et al.

**5. Management and outcome in encapsulating peritoneal sclerosis** 

The optimal management of EPS is not clear. Mortality and morbidity are still high (25% to 55%) especially in the first year after diagnosis. Table 4 shows a comparison of epidemiological studies of EPS patients. Up to now, there are no randomized controlled trials and the level of evidence is weak. The choice of surgical or conservative therapy is often based on the stage of the disease and varies quiet a lot between "EPS- centers". There is one prospective registry report from Kawanishi et al., who investigated 48 EPS patients in Japan. They report a recovery rate with total parenteral nutrition, corticosteroids and surgical treatment of 0%, 38.5% and 58.3%, respectively. All together, 37.5% of the patients in this study died, 45.8% of the patients

During work-up of patients with EPS, bacterial and fungal peritonitis must be ruled out before treatment might be considered. Treatment options include surgery and/or medical therapy.

*Steroids:* Data about the use of steroids are not uniform, especially concerning dose and duration of therapy. Some studies suggested the administration of methylprednisolone pulse therapy with a dose of 500 – 1000 mg daily for 2-3 days, resulting in a reduction of inflammation and improvement of symptoms of bowel obstruction. Other groups recommend a dose of 0.5– 1mg prednisolone per kilogram of body weight daily for 2-4 weeks. In our referral- center we recommend an initial dose of 1 mg prednisolone per kilogram body weight for 4 weeks,

**Figure 5.** Mesothelial cells undergoing the so-called epithelio-mesenchymal transformation (EMT); MCL mesothelial

**Figure 4.** Peritoneal biopsies of EPS patients A HE staining showing an increased cellularity, round cells and fibroblast like cells (arrows). EPS, original magnification x400 B HE staining showing a decreased cellularity, fibrin deposits and a complete denudation of the mesothelial cell layer with fibrin exudations (arrows). EPS, original magnification x100 C HE staining showing a decreased cellularity with intracellular matrix (arrows), complete mesothelial denudation with fibrin exudations. EPS, original magnification x200 D HE staining showing fibroblast like cells, eosinophils, plasma cells and round cells (arrows). EPS, original magnification x400

secretion and production of different profibrinogenic mediators like transforming growth factor (TGF)-ß and of angiogenic factors like vascular endothelial growth factor (VEGF). The profibrinogenic factors lead to an increased fibrin deposition and neoangiogenesis. Addition‐ ally, the degradation of fibrin is reduced due to the loss of mesothelial cells and mast cells, which under normal circumstances produce fibrinolytic substances. This results in a so-called epithelio-mesenchymal transformation (EMT) (figure 5). As a consequence mesothelial cells change their function and become a more myofibroblast-like phenotype, which leads to the deposition of extracellular matrix and the promotion of fibrosis (figure 5). The described mechanisms lead to peritoneal fibrosis (PF), but do not necessarily proceed to EPS.

In the so-called two-hit-model of the pathogenesis of simple peritoneal fibrosis (PF) and EPS, it is postulated that PD itself is the first hit leading to the damage of the peritoneal membrane. When the second hit (e.g. an inflammatory stimulus (like a bacterial peritonitis)) occurs, EPS can develop. Others state, that EPS occurs in every patient on PD depending on the time on PD. Peritonitis rates, glucose load of the PD solutions and other factors might only influence this process.

Figure 5. Mesothelial cells undergoing the so-called epithelio-mesenchymal transformation (EMT); MCL mesothelial cell layer; SMC sub mesothelial cells; ICS interstitial cell space. Adapted from Aroeira et al. . **Figure 5.** Mesothelial cells undergoing the so-called epithelio-mesenchymal transformation (EMT); MCL mesothelial cell layer; SMC sub mesothelial cells; ICS interstitial cell space. Adapted from Aroeira et al..

**5. Management and outcome in encapsulating peritoneal sclerosis** 

trials and the level of evidence is weak. The choice of surgical or conservative therapy is often based on the stage of the disease and

(Korea 2003) 1981-2002 31 RS/MC 5.8 25.8

(Australia 1995-2007 33 RS/MC 4.5 55

1997-2008 111 RS/MC 6.9 53

#### The optimal management of EPS is not clear. Mortality and morbidity are still high (25% to 55%) especially in the first year after diagnosis . Table 4 shows a comparison of epidemiological studies of EPS patients. Up to now, there are no randomized controlled **5. Management and outcome in encapsulating peritoneal sclerosis**

varies quiet a lot between "EPS- centers". There is one prospective registry report from Kawanishi et al., who investigated 48 EPS patients in Japan. They report a recovery rate with total parenteral nutrition, corticosteroids and surgical treatment of 0%, 38.5% and 58.3%, respectively. All together, 37.5% of the patients in this study died, 45.8% of the patients recovered . During work-up of patients with EPS, bacterial and fungal peritonitis must be ruled out before treatment might be considered. Treatment options include surgery and/or medical therapy. **Date of study EPS cases Study design Mean PD duration (years) Mortality rate (%)** Nomoto et al. (Japan 1996) 1980-1994 62 RS/MC 5.1 43.5 The optimal management of EPS is not clear. Mortality and morbidity are still high (25% to 55%) especially in the first year after diagnosis. Table 4 shows a comparison of epidemiological studies of EPS patients. Up to now, there are no randomized controlled trials and the level of evidence is weak. The choice of surgical or conservative therapy is often based on the stage of the disease and varies quiet a lot between "EPS- centers". There is one prospective registry report from Kawanishi et al., who investigated 48 EPS patients in Japan. They report a recovery rate with total parenteral nutrition, corticosteroids and surgical treatment of 0%, 38.5% and 58.3%, respectively. All together, 37.5% of the patients in this study died, 45.8% of the patients recovered.

Rigby et al. (Australia 1998) 1980-1994 54 RS/MC 4.3 56 During work-up of patients with EPS, bacterial and fungal peritonitis must be ruled out before treatment might be considered. Treatment options include surgery and/or medical therapy.

Lee et al.

Kawanishi et

Balasubrama niam et al. (UK 2009)

Johnson et al.

#### **5.1. Medical therapy**

secretion and production of different profibrinogenic mediators like transforming growth factor (TGF)-ß and of angiogenic factors like vascular endothelial growth factor (VEGF). The profibrinogenic factors lead to an increased fibrin deposition and neoangiogenesis. Addition‐ ally, the degradation of fibrin is reduced due to the loss of mesothelial cells and mast cells, which under normal circumstances produce fibrinolytic substances. This results in a so-called epithelio-mesenchymal transformation (EMT) (figure 5). As a consequence mesothelial cells change their function and become a more myofibroblast-like phenotype, which leads to the deposition of extracellular matrix and the promotion of fibrosis (figure 5). The described

**Figure 4.** Peritoneal biopsies of EPS patients A HE staining showing an increased cellularity, round cells and fibroblast like cells (arrows). EPS, original magnification x400 B HE staining showing a decreased cellularity, fibrin deposits and a complete denudation of the mesothelial cell layer with fibrin exudations (arrows). EPS, original magnification x100 C HE staining showing a decreased cellularity with intracellular matrix (arrows), complete mesothelial denudation with fibrin exudations. EPS, original magnification x200 D HE staining showing fibroblast like cells, eosinophils, plasma cells

In the so-called two-hit-model of the pathogenesis of simple peritoneal fibrosis (PF) and EPS, it is postulated that PD itself is the first hit leading to the damage of the peritoneal membrane. When the second hit (e.g. an inflammatory stimulus (like a bacterial peritonitis)) occurs, EPS can develop. Others state, that EPS occurs in every patient on PD depending on the time on PD. Peritonitis rates, glucose load of the PD solutions and other factors might only influence

mechanisms lead to peritoneal fibrosis (PF), but do not necessarily proceed to EPS.

and round cells (arrows). EPS, original magnification x400

44 The Latest in Peritoneal Dialysis

this process.

al. (Japan 2001) 1999-2001 17 PS/MC 10 35 Kawanishi et al. (Japan 2004) 1999-2003 48 PS/MC 4.3 37.5 Summers et al. (UK 2005) 1998-2003 27 RS/SC 6.1 29.6 Brown et al. (UK 2009) 2000-2007 46 RS/MC 5.4 56.5 *Steroids:* Data about the use of steroids are not uniform, especially concerning dose and duration of therapy. Some studies suggested the administration of methylprednisolone pulse therapy with a dose of 500 – 1000 mg daily for 2-3 days, resulting in a reduction of inflammation and improvement of symptoms of bowel obstruction. Other groups recommend a dose of 0.5– 1mg prednisolone per kilogram of body weight daily for 2-4 weeks. In our referral- center we recommend an initial dose of 1 mg prednisolone per kilogram body weight for 4 weeks,


thickening and ultrafiltration failure. Up to now, there exist no data regarding the use of angiotensin receptor blockers (ARB) or angiotensin converting enzyme (ACE) inhibitors in patients with EPS. But due to the low rate of adverse events and the widespread use of this medication in PD patients, inhibition of the RAAS should be the cornerstone of prevention of simple sclerosis and EPS. Tamoxifen, another antifibrotic drug, commonly used in the treat‐ mentofbreast cancer,hasbeeninvestigatedinEPSpatients.Tamoxifenrevealedpositive results inotherfibrosingsyndromes suchas retroperitonealfibrosis,fibrosingmediastinitisordesmoid tumors. Individual case reports and small case series supported the use of tamoxifen in EPS patients, mostly in combination with corticosteroids or as monotherapy. Recently, Korte and colleagues demonstrated in a retrospective analysis a survival advantage for patients with EPS treatedwithtamoxifen.Ofthewell-matched63patientswithEPS,24weretreatedwithtamoxifen and 39 were not. The mortality rate was significantly reduced in the tamoxifen group com‐ pared to the non-tamoxifen group (45.8% vs. 74.4%). The exact mechanism of action of tamoxi‐ fen in EPS is not understood. Some data suggest that an enhancement of transforming growth factor-ß(TGF-ß1)productionstimulatesmetalloproteinase-9todegrade type IVcollagen.Other studies demonstrated an overexpression of TGF-ß1 which promoted fibrosis, peritoneal thickening and a loss of the capability of peritoneal repair. Therefore one mechanism of action oftamoxifencouldbe the inhibitionofTGF.Otherreports abouttheuse of antifibroticdrugs like

Encapsulating Peritoneal Sclerosis http://dx.doi.org/10.5772/56052 47

cholchicine or pirfenidone did not achieve acceptance in the PD community.

**5.2. Surgical therapy**

small bowel obstruction.

If medical therapy fails to improve the symptoms of EPS, surgical therapy must be considered.

Most data of operative treatment of EPS involve only small series or case reports. Macroscop‐ ically, late-stage EPS consists of two layers: a grossly thickened, leather-like peritoneum (EPSmembrane) and a white and opaque EPS-capsule covering the whole abdominal cavity. In contrast to the first description of the disease by Winne et al., EPS-capsule is the result of a dynamic process of shrinking. As a consequence, stricturing of the small bowel, sclerotic loopto-loop adhesions and severe kinking of multiple bowel loops occur, causing symptoms of

Although associated with a high morbidity and mortality rate, operative treatment probably represents the only realistic and potentially curative treatment for patients with late-stage disease. Because EPS is a rare disease, not all surgeons are familiar with the natural history of EPS and the required operative therapy. EPS is a disease of the visceral peritoneum and the serosa. Therefore, the operative treatment involves a complex procedure comprising *peritonec‐ tomy and intestinal enterolysis* (PEEL). Basic requirements of PEEL are the restitution of intesti‐ nal function and the prevention of recurrent disease. Simple adhesiolysis is not the treatment of choice. In fact, PEEL includes a demanding resection of EPS-capsule and EPS-membrane, whereasapartialresectionofthesmallbowelserosaisunavoidable.Resectionlinesofteninvolve theserosaorarelocatedbetweentheserosaandmuscularis.Withanincidenceupto20%,fistulas or anastomotic leaks are the leading complications after PEEL. Regarding this high morbidity rate, some authors suggest a protective stoma proximal to the first suture of bowel wall defects or anastomoses.Recently,we reviewedthe treatment of 26 late-stageEPSpatients at ourreferral

**Table 4.** Comparison of epidemiological studies of EPS; RS, retrospective; PS, prospective; MC, multi-center; SC, singlecenter;

followed by a slow tapering over months depending on clinical symptoms and signs of inflammation. Especially in the so-called inflammatory period of the disease steroids may be useful. A prospective study demonstrated clinical improvement in 35.7% of cases treated with prednisolone. In patients with late-stage disease, histological analysis of peritoneal biopsies showed less acute or chronic inflammation. Therefore, the use of steroids is questionable.

*Immunosuppression:* The present evidence for the use of immunosuppressants (e.g. mycopheno‐ late or azathioprine) is mainly based on case reports. An increasing number of post-transplant EPS has been reported. One reason for the development of post-transplant EPS could be the widespread use of calcineurin inhibitors and the profibrotic potential of these drugs.

*Antifibrotic agents:* Several different antifibrotic agents are currently under investigation concerningdevelopmentofperitonealfibrosisandEPS.Inanimalmodels,inhibitionofthereninangiotensin-aldosteronesystem(RAAS)resultsinadecreasedprogressionofperitonealfibrosis. IninducedEPSinrats,theblockageofRAASresultedinadecreaseofneoangiogenesis,peritoneal

thickening and ultrafiltration failure. Up to now, there exist no data regarding the use of angiotensin receptor blockers (ARB) or angiotensin converting enzyme (ACE) inhibitors in patients with EPS. But due to the low rate of adverse events and the widespread use of this medication in PD patients, inhibition of the RAAS should be the cornerstone of prevention of simple sclerosis and EPS. Tamoxifen, another antifibrotic drug, commonly used in the treat‐ mentofbreast cancer,hasbeeninvestigatedinEPSpatients.Tamoxifenrevealedpositive results inotherfibrosingsyndromes suchas retroperitonealfibrosis,fibrosingmediastinitisordesmoid tumors. Individual case reports and small case series supported the use of tamoxifen in EPS patients, mostly in combination with corticosteroids or as monotherapy. Recently, Korte and colleagues demonstrated in a retrospective analysis a survival advantage for patients with EPS treatedwithtamoxifen.Ofthewell-matched63patientswithEPS,24weretreatedwithtamoxifen and 39 were not. The mortality rate was significantly reduced in the tamoxifen group com‐ pared to the non-tamoxifen group (45.8% vs. 74.4%). The exact mechanism of action of tamoxi‐ fen in EPS is not understood. Some data suggest that an enhancement of transforming growth factor-ß(TGF-ß1)productionstimulatesmetalloproteinase-9todegrade type IVcollagen.Other studies demonstrated an overexpression of TGF-ß1 which promoted fibrosis, peritoneal thickening and a loss of the capability of peritoneal repair. Therefore one mechanism of action oftamoxifencouldbe the inhibitionofTGF.Otherreports abouttheuse of antifibroticdrugs like cholchicine or pirfenidone did not achieve acceptance in the PD community.

If medical therapy fails to improve the symptoms of EPS, surgical therapy must be considered.

#### **5.2. Surgical therapy**

followed by a slow tapering over months depending on clinical symptoms and signs of inflammation. Especially in the so-called inflammatory period of the disease steroids may be useful. A prospective study demonstrated clinical improvement in 35.7% of cases treated with prednisolone. In patients with late-stage disease, histological analysis of peritoneal biopsies showed less acute or chronic inflammation. Therefore, the use of steroids is questionable.

**Table 4.** Comparison of epidemiological studies of EPS; RS, retrospective; PS, prospective; MC, multi-center; SC, single-

**Date of study EPS cases Study design**

1980-1994 62 RS/MC 5.1 43.5

1980-1994 54 RS/MC 4.3 56

1981-2002 31 RS/MC 5.8 25.8

1999-2001 17 PS/MC 10 35

1999-2003 48 PS/MC 4.3 37.5

1998-2003 27 RS/SC 6.1 29.6

2000-2007 46 RS/MC 5.4 56.5

1997-2008 111 RS/MC 6.9 53

1995-2007 33 RS/MC 4.5 55

1993-2010 181 RS/MC 10.5 35.4

1998-2011 42 RS/SC 6.5 21.4

Nomoto et al. (Japan 1996)

46 The Latest in Peritoneal Dialysis

Rigby et al. (Australia 1998)

2003)

2005)

2009)

Lee et al. (Korea

Kawanishi et al. (Japan 2001)

Kawanishi et al. (Japan 2004)

Summers et al. (UK

Brown et al. (UK

Balasubramaniam et al. (UK 2009)

Johnson et al. (Australia 2010)

Kawanishi et al. (Japan 2011)

Latus et al. (Germany 2012)

center;

**Mean PD duration**

**(years) Mortality rate (%)**

*Immunosuppression:* The present evidence for the use of immunosuppressants (e.g. mycopheno‐ late or azathioprine) is mainly based on case reports. An increasing number of post-transplant EPS has been reported. One reason for the development of post-transplant EPS could be the

*Antifibrotic agents:* Several different antifibrotic agents are currently under investigation concerningdevelopmentofperitonealfibrosisandEPS.Inanimalmodels,inhibitionofthereninangiotensin-aldosteronesystem(RAAS)resultsinadecreasedprogressionofperitonealfibrosis. IninducedEPSinrats,theblockageofRAASresultedinadecreaseofneoangiogenesis,peritoneal

widespread use of calcineurin inhibitors and the profibrotic potential of these drugs.

Most data of operative treatment of EPS involve only small series or case reports. Macroscop‐ ically, late-stage EPS consists of two layers: a grossly thickened, leather-like peritoneum (EPSmembrane) and a white and opaque EPS-capsule covering the whole abdominal cavity. In contrast to the first description of the disease by Winne et al., EPS-capsule is the result of a dynamic process of shrinking. As a consequence, stricturing of the small bowel, sclerotic loopto-loop adhesions and severe kinking of multiple bowel loops occur, causing symptoms of small bowel obstruction.

Although associated with a high morbidity and mortality rate, operative treatment probably represents the only realistic and potentially curative treatment for patients with late-stage disease. Because EPS is a rare disease, not all surgeons are familiar with the natural history of EPS and the required operative therapy. EPS is a disease of the visceral peritoneum and the serosa. Therefore, the operative treatment involves a complex procedure comprising *peritonec‐ tomy and intestinal enterolysis* (PEEL). Basic requirements of PEEL are the restitution of intesti‐ nal function and the prevention of recurrent disease. Simple adhesiolysis is not the treatment of choice. In fact, PEEL includes a demanding resection of EPS-capsule and EPS-membrane, whereasapartialresectionofthesmallbowelserosaisunavoidable.Resectionlinesofteninvolve theserosaorarelocatedbetweentheserosaandmuscularis.Withanincidenceupto20%,fistulas or anastomotic leaks are the leading complications after PEEL. Regarding this high morbidity rate, some authors suggest a protective stoma proximal to the first suture of bowel wall defects or anastomoses.Recently,we reviewedthe treatment of 26 late-stageEPSpatients at ourreferral

center regarding perioperative morbidity, mortality, and long term outcome. In our study, overall morbidity was 44% with minor complications in 2 patients (7%) and major complica‐ tionsin11patients(31%).Threepatients(10%)diedwithinthefirstyearafteroperativetreatment. These data suggest, that PEEL is a treatment option in patients with late-stage EPS that can be performed with acceptable morbidity (unpublished data).

**References**

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60-4.

66-9.

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(2009). Epub 2009/06/23., 4(7), 1222-9.

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[1] Brown, M. C, Simpson, K, Kerssens, J. J, & Mactier, R. A. Encapsulating peritoneal sclerosis in the new millennium: a national cohort study. Clin J Am Soc Nephrol.

Encapsulating Peritoneal Sclerosis http://dx.doi.org/10.5772/56052 49

[2] Johnson, D. W, Cho, Y, Livingston, B. E, Hawley, C. M, Mcdonald, S. P, Brown, F. G, et al. Encapsulating peritoneal sclerosis: incidence, predictors, and outcomes. Kidney

[3] Summers, A. M, Clancy, M. J, Syed, F, Harwood, N, Brenchley, P. E, Augustine, T, et al. Single-center experience of encapsulating peritoneal sclerosis in patients on peri‐ toneal dialysis for end-stage renal failure. Kidney Int. (2005). Epub 2005/10/14., 68(5),

[4] Rigby, R. J, & Hawley, C. M. Sclerosing peritonitis: the experience in Australia.

[5] Kawanishi, H, Kawaguchi, Y, Fukui, H, Hara, S, Imada, A, Kubo, H, et al. Encapsu‐ lating peritoneal sclerosis in Japan: a prospective, controlled, multicenter study. Am J

[6] Kawaguchi, Y, Kawanishi, H, Mujais, S, Topley, N, & Oreopoulos, D. G. Encapsulat‐ ing peritoneal sclerosis: definition, etiology, diagnosis, and treatment. International Society for Peritoneal Dialysis Ad Hoc Committee on Ultrafiltration Management in

[7] Summers, A. M, Abrahams, A. C, Alscher, M. D, Betjes, M, Boeschoten, E. W, Braun, N, et al. A collaborative approach to understanding EPS: the European perspective.

[8] Kawanishi, H, Moriishi, M, & Tsuchiya, S. Experience of 100 surgical cases of encap‐ sulating peritoneal sclerosis: investigation of recurrent cases after surgery. Advances in peritoneal dialysis Conference on Peritoneal Dialysis. (2006). Epub 2006/09/21., 22,

[9] Kawanishi, H, Moriishi, M, Ide, K, & Dohi, K. Recommendation of the surgical op‐ tion for treatment of encapsulating peritoneal sclerosis. Peritoneal dialysis interna‐ tional : journal of the International Society for Peritoneal Dialysis. (2008). Suppl

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[11] Nomoto, Y, Kawaguchi, Y, Kubo, H, Hirano, H, Sakai, S, & Kurokawa, K. Sclerosing encapsulating peritonitis in patients undergoing continuous ambulatory peritoneal

Peritoneal Dialysis. Perit Dial Int. (2000). Suppl 4:SEpub 2000/12/01., 43-55.

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Perit Dial Int. (2011). Epub 2011/05/11., 31(3), 245-8.

Over a study period of two to 19 years, reported mortality rates vary from 25.5 to 56.6% especially in the first year after diagnosis (table 2). In our study including only late-stage EPS patients, three patients (10%) died within the first year after operative treatment, which is a favourable mortality rate (unpubslihed data). The overall mortality rate in our study with 42 EPS patients (31 of them required major surgery due to bowel obstruction) was 21.4%. To achieve such good outcome data, we believe, that these patients should be treated in special‐ ized referral centers.

#### **6. Conclusion**

EPS is a rare complication of PD. There are three diagnostic pillars in EPS. clinical, radiological and histologic criteria. However a standardized approach is still lacking, histological analysis of peritoneal biopsies is important tool in the diagnosis of EPS. Peritoneal biopsies should be taken from all patients on PD at any time of surgery (e.g. catheter insertion, correction of a catheter malposition, catheter removal or any other abdominal surgery). Immunosuppressive therapy in patients with advanced disease might not be mandatory due to low degree of acute inflammation in these stages and the lack of prospective trials. Remarkably, time of first clinical symptoms consistent with to requirement of major surgery is very short. Therefore earlier diagnosis of the disease is mandatory, even in asymptomatic patients. Optimized operative therapy with PEEL represents a favourable treatment option in late stage EPS patients, which results in a low mortality and an acceptable morbidity rate.

Compared to the mortality rate of an age-matched dialysis population, outcome of patients even with severe EPS is not worse, if these patients are treated in specialized referral centers.

#### **Author details**

Joerg Latus1 , Christoph Ulmer2 , Martin Kimmel1 , M. Dominik Alscher1 and Niko Braun1\*

\*Address all correspondence to: Niko.braun@rbk.de

1 Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stutt‐ gart, Germany

2 Department of General, Visceral and Trauma Surgery, Robert-Bosch-Hospital, Stuttgart, Germany

#### **References**

center regarding perioperative morbidity, mortality, and long term outcome. In our study, overall morbidity was 44% with minor complications in 2 patients (7%) and major complica‐ tionsin11patients(31%).Threepatients(10%)diedwithinthefirstyearafteroperativetreatment. These data suggest, that PEEL is a treatment option in patients with late-stage EPS that can be

Over a study period of two to 19 years, reported mortality rates vary from 25.5 to 56.6% especially in the first year after diagnosis (table 2). In our study including only late-stage EPS patients, three patients (10%) died within the first year after operative treatment, which is a favourable mortality rate (unpubslihed data). The overall mortality rate in our study with 42 EPS patients (31 of them required major surgery due to bowel obstruction) was 21.4%. To achieve such good outcome data, we believe, that these patients should be treated in special‐

EPS is a rare complication of PD. There are three diagnostic pillars in EPS. clinical, radiological and histologic criteria. However a standardized approach is still lacking, histological analysis of peritoneal biopsies is important tool in the diagnosis of EPS. Peritoneal biopsies should be taken from all patients on PD at any time of surgery (e.g. catheter insertion, correction of a catheter malposition, catheter removal or any other abdominal surgery). Immunosuppressive therapy in patients with advanced disease might not be mandatory due to low degree of acute inflammation in these stages and the lack of prospective trials. Remarkably, time of first clinical symptoms consistent with to requirement of major surgery is very short. Therefore earlier diagnosis of the disease is mandatory, even in asymptomatic patients. Optimized operative therapy with PEEL represents a favourable treatment option in late stage EPS patients, which

Compared to the mortality rate of an age-matched dialysis population, outcome of patients even with severe EPS is not worse, if these patients are treated in specialized referral centers.

1 Department of Internal Medicine, Division of Nephrology, Robert-Bosch-Hospital, Stutt‐

2 Department of General, Visceral and Trauma Surgery, Robert-Bosch-Hospital, Stuttgart,

, M. Dominik Alscher1

and Niko Braun1\*

, Martin Kimmel1

performed with acceptable morbidity (unpublished data).

results in a low mortality and an acceptable morbidity rate.

, Christoph Ulmer2

\*Address all correspondence to: Niko.braun@rbk.de

ized referral centers.

48 The Latest in Peritoneal Dialysis

**6. Conclusion**

**Author details**

Joerg Latus1

gart, Germany

Germany


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**Section 3**

**Systemic Complications Associated to Peritoneal**

**Dialysis**


**Systemic Complications Associated to Peritoneal Dialysis**

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[38] Nakamoto, H, Imai, H, Fukushima, R, Ishida, Y, Yamanouchi, Y, & Suzuki, H. Role of the renin-angiotensin system in the pathogenesis of peritoneal fibrosis. Perit Dial

[39] Van Bommel, E. F, Hendriksz, T. R, Huiskes, A. W, & Zeegers, A. G. Brief communi‐ cation: tamoxifen therapy for nonmalignant retroperitoneal fibrosis. Ann Intern Med.

[40] del Peso GBajo MA, Gil F, Aguilera A, Ros S, Costero O, et al. Clinical experience with tamoxifen in peritoneal fibrosing syndromes. Advances in peritoneal dialysis

[41] Eltoum, M. A, Wright, S, Atchley, J, & Mason, J. C. Four consecutive cases of perito‐ neal dialysis-related encapsulating peritoneal sclerosis treated successfully with ta‐

[42] Korte, M. R, Fieren, M. W, Sampimon, D. E, Lingsma, H. F, Weimar, W, & Betjes, M. G. Tamoxifen is associated with lower mortality of encapsulating peritoneal sclerosis: results of the Dutch Multicentre EPS Study. Nephrol Dial Transplant. (2010). Epub

[43] Suga, H, Teraoka, S, Ota, K, Komemushi, S, Furutani, S, Yamauchi, S, et al. Preven‐ tive effect of pirfenidone against experimental sclerosing peritonitis in rats. Exp Toxi‐

[45] Braun, N, Alscher, M. D, Kimmel, M, Amann, K, & Buttner, M. Encapsulating perito‐ neal sclerosis- an overview. Nephrol Ther. (2011). Epub 2011/04/05., 7(3), 162-71. [46] Gandhi, V. C, Humayun, H. M, Ing, T. S, Daugirdas, J. T, Jablokow, V. R, Iwatsuki, S, et al. Sclerotic thickening of the peritoneal membrane in maintenance peritoneal dial‐ ysis patients. Archives of internal medicine. (1980). Epub 1980/09/01., 140(9), 1201-3.

[47] Celicout, B, Levard, H, Hay, J, Msika, S, Fingerhut, A, & Pelissier, E. Sclerosing en‐ capsulating peritonitis: early and late results of surgical management in 32 cases. French Associations for Surgical Research. Digestive surgery. (1998). Epub

Conference on Peritoneal Dialysis. (2003). Epub 2004/02/07., 19, 32-5.

moxifen. Perit Dial Int. (2006). Epub 2006/04/21., 26(2), 203-6.

col Pathol. (1995). Epub 1995/09/01., 47(4), 287-91. [44] incapsulata) WPÜZpcfBrunns Beitr Klin Chir. (1921).

Perit Dial Int. (2008). Suppl 5:SEpub 2008/12/17., 38-42.

Int. (2008). Suppl 3:SEpub 2008/09/20., 83-7.

(2006). Epub 2006/01/19., 144(2), 101-6.

2010/06/30.

1998/12/09., 15(6), 697-702.

Epub 2005/06/29., 25(3), 285-7.

52 The Latest in Peritoneal Dialysis

**Chapter 4**

**Inflammation in Peritoneal Dialysis**

Joseph C.K. Leung, Loretta Y. Y. Chan, Kar Neng Lai and Sydney C.W. Tang

http://dx.doi.org/10.5772/55964

**1. Introduction**

Additional information is available at the end of the chapter

**2. Inflammatory response during peritoneal dialysis**

The prevalence of kidney disease has grown continuously. The loss of kidney function during acute kidney disease may occur rapidly and reversibly, and most unfortunately, may progress to end-stage renal disease (ESRD) in which renal replacement therapy (RRT) is required. Due to the short supply of donor kidneys, RRT is now dominated by dialysis. Dialysis can be applied intermittently or continuously using extracorporeal (hemodialysis or HD) or para‐ corporeal (peritoneal dialysis or PD) methods. Among patients with ESRD, the choice of PD or HD varies considerably from country to country and is related to non-medical factors such as finance, physician preferences, and social culture [1]. It has been suggested that PD should be offered as the first-line dialysis modality [2]. Compared with HD, PD offers better preser‐ vation of residual renal function, lower risk of infection with hepatitis B and C, better outcome after transplantation, preservation of vascular access, easy to place on home therapy, simplicity of the technique, and lower costs [3, 4]. The predominant problems associated with PD are ultrafiltration failure and peritonitis. Dialysis patients after an episode of peritonitis may still be affected by prolonged systemic chronic inflammation [5]. Likewise, PD maintains a state of intraperitoneal micro-inflammation that affects the structure and function of the peritoneal membrane, and impairs ultrafiltration efficiency. An understanding of the mechanism in peritoneal inflammation will provide new insight to better preserve the function of the peritoneum membrane, with a goal to improve the quality of life in patients under PD.

Inflammation is the body's natural defense involving cascades of immediate immunological responses towards various stimuli, including pathogens, necrotic cells, injury, or irritants.

and reproduction in any medium, provided the original work is properly cited.

© 2013 Leung et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Chapter 4**

## **Inflammation in Peritoneal Dialysis**

Joseph C.K. Leung, Loretta Y. Y. Chan, Kar Neng Lai and Sydney C.W. Tang

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55964

#### **1. Introduction**

The prevalence of kidney disease has grown continuously. The loss of kidney function during acute kidney disease may occur rapidly and reversibly, and most unfortunately, may progress to end-stage renal disease (ESRD) in which renal replacement therapy (RRT) is required. Due to the short supply of donor kidneys, RRT is now dominated by dialysis. Dialysis can be applied intermittently or continuously using extracorporeal (hemodialysis or HD) or para‐ corporeal (peritoneal dialysis or PD) methods. Among patients with ESRD, the choice of PD or HD varies considerably from country to country and is related to non-medical factors such as finance, physician preferences, and social culture [1]. It has been suggested that PD should be offered as the first-line dialysis modality [2]. Compared with HD, PD offers better preser‐ vation of residual renal function, lower risk of infection with hepatitis B and C, better outcome after transplantation, preservation of vascular access, easy to place on home therapy, simplicity of the technique, and lower costs [3, 4]. The predominant problems associated with PD are ultrafiltration failure and peritonitis. Dialysis patients after an episode of peritonitis may still be affected by prolonged systemic chronic inflammation [5]. Likewise, PD maintains a state of intraperitoneal micro-inflammation that affects the structure and function of the peritoneal membrane, and impairs ultrafiltration efficiency. An understanding of the mechanism in peritoneal inflammation will provide new insight to better preserve the function of the peritoneum membrane, with a goal to improve the quality of life in patients under PD.

#### **2. Inflammatory response during peritoneal dialysis**

Inflammation is the body's natural defense involving cascades of immediate immunological responses towards various stimuli, including pathogens, necrotic cells, injury, or irritants.

© 2013 Leung et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acute inflammation is a protective machinery by which the injurious stimuli will be removed and the healing process initiated. On the other hand, chronic inflammation develops if the conditions causing acute inflammation is not resolved over a period of time. Intriguingly, chronic inflammation may be due to excessive physiological responses, such as the wound repairing process, which are intrinsically essential for maintaining normal life. Certain stimuli may directly provoke chronic rather than acute inflammation. Peritoneal inflammation of the microenvironment in the peritoneal cavity during PD generally presents in two major forms: (i) acute inflammation triggered by microbial infection, and (ii) low-grade inflammation or "para-inflammation" under various exogenous or endogenous stimulations during PD. These two forms of inflammation affects the membrane structure and function, and is associated with increased mortality.

and high glucose [21]. PDF also contains toxic substance like glucose degradation products (GDP) generated during the sterilization process and the advanced glycation end products (AGE), which can be formed by amadori reaction between sugar and protein during long-term PD [22]. Dialysis patients are likely to gain fat mass following absorption of glucose from the peritoneal dialysate [23]. Adipocyte in adipose tissue is the major source of adipokines such as leptin, adiponectin and other inflammatory mediators. Adipose tissue is also an important contributor to the peritoneal and systemic inflammation [24, 25]. Exposure of peritoneal cells to the non-physiological dialysate during CAPD leads to "para-inflammation" [26], which is a protective mechanism helping the peritoneum to adapt to the noxious conditions during PD and to restore peritoneum functionality. Regrettably, after repeated exposure to various insults in PDF, dysregulated para-inflammation may eventually develop chronically to inflammatory states associated with ultrafiltration failure. A key feature of chronic inflammation is peritoneal fibrosis [27, 28], in which fibroblasts proliferate or are recruited to the inflamed peritoneum

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 57

The inflammatory pathway of PD consists of modulators, mediators and effectors. A simplified schema for PD-related inflammation is illustrated in Figure 1. The complex interaction among the components involved and the related machinery will determine the outcome of the

Modulators of PD-related inflammation can be exogenous or endogenous. It should be noted that exogenous modulators may promote or amplify the effects of the endogenous modulators during the process of PD-related inflammation. Intriguingly, the interaction between modu‐ lators and the ongoing inflammatory events may form a vicious cycle to amplify the inflam‐

The innate immune system recognized catheters used for PD as the foreign bodies. Severe biofilm formation on the catheters have been observed in PD patients without detectable infection [31]. Histologic and functional evidences obtained from rodent model have shown that the catheter insertion may have induced a classic inflammatory reaction characterized by formation of fibrin clots in the peritoneum [32]. Mechanical stress during PD is related to the infiltration of large volume of PDF, especially for achieving specific target of small solute clearance. Volume stress during PD are associated with significant increments in endothelin (ET)-1, a vasoactive peptide that may induce peritoneal fibrosis and indirectly contribute to technique failure in CAPD [33]. ET-1 induces the release of proinflammatory cytokines and increases the deposition of extracellular matrix (ECM) by regulating production and turnover of matrix components. In addition, high fill volumes increase circulating norepinephrine levels

with the activation of cascades of inflammatory or fibrotic cytokines [29, 30].

**3. The Mechanisms and pathways of inflammation in PD**

immune response induced by PD.

**3.1. Modulators:**

matory process.

*3.1.1. Exogenous modulators*

#### **2.1. Acute inflammation in PD**

The most common form of acute inflammation of peritoneum in PD is peritonitis, which is a serious and the most frequent complication leading to hospitalization and catheter loss [6, 7]. Peritonitis causes a high infection-related mortality in PD patients [8, 9]. The leading cause of PD-associated peritonitis is contamination, predominately with the microorganisms from skin and environment, which is most commonly occur during the dialysis procedure such as PD exchange [10]. Exit site infection (ESI) in which transmigration of microorganisms from the exit site along the PD catheter into the peritoneal cavity, may cause tunnel infections and peritonitis [11, 12]. Enteric peritonitis is a less common cause but important, due to the severity of the inflammation process [13]. Fungal peritonitis accounts for about 4–6% of episodes of the total incidence of the peritonitis, and is with high mortality [14]. Rapidly resolving the infection is the primary approach to treat peritonitis, even if this involve the need for prompt removal of the peritoneal catheter. Before the causative microorganism is identified, initial therapy with broad spectrum antibiotic which is active against the most commonly occurring organisms, will be given according to the guideline from the International Society for Peritoneal Dialysis (ISPD) [9]. It is recommended that in addition to the standard initial protocol, specific regime tailored to the geographic and cultural characteristics, the relevant organisms and their antibiotic resistance pattern should be considered [15]. Detailed examination of the causality of infection-related peritonitis is important for the management. The molecular pathways of inflammation induced by different microbial pathogens are somehow redundant, yet also complex and diverse [16, 17].

#### **2.2. Chronic inflammation in PD**

An inherent immune dysfunction in PD patients and the continuous non-specific immune cell stimulation by dialysis procedure contribute to the chronic inflammatory state of patients under the long-term dialysis [18]. Patients on maintenance PD have increased intra-peritoneal levels of hyaluronan and cytokines including interleukin (IL)-1β, IL-6 and transforming growth factor-β (TGF-β) [19, 20]. Chronic inflammation remains an important cause of morbidity in patients with ESRD. During continuous ambulatory peritoneal dialysis (CAPD), peritoneal cells are repeatedly exposed to non-physiologic dialysis fluid (PDF) with low pH and high glucose [21]. PDF also contains toxic substance like glucose degradation products (GDP) generated during the sterilization process and the advanced glycation end products (AGE), which can be formed by amadori reaction between sugar and protein during long-term PD [22]. Dialysis patients are likely to gain fat mass following absorption of glucose from the peritoneal dialysate [23]. Adipocyte in adipose tissue is the major source of adipokines such as leptin, adiponectin and other inflammatory mediators. Adipose tissue is also an important contributor to the peritoneal and systemic inflammation [24, 25]. Exposure of peritoneal cells to the non-physiological dialysate during CAPD leads to "para-inflammation" [26], which is a protective mechanism helping the peritoneum to adapt to the noxious conditions during PD and to restore peritoneum functionality. Regrettably, after repeated exposure to various insults in PDF, dysregulated para-inflammation may eventually develop chronically to inflammatory states associated with ultrafiltration failure. A key feature of chronic inflammation is peritoneal fibrosis [27, 28], in which fibroblasts proliferate or are recruited to the inflamed peritoneum with the activation of cascades of inflammatory or fibrotic cytokines [29, 30].

### **3. The Mechanisms and pathways of inflammation in PD**

The inflammatory pathway of PD consists of modulators, mediators and effectors. A simplified schema for PD-related inflammation is illustrated in Figure 1. The complex interaction among the components involved and the related machinery will determine the outcome of the immune response induced by PD.

#### **3.1. Modulators:**

Acute inflammation is a protective machinery by which the injurious stimuli will be removed and the healing process initiated. On the other hand, chronic inflammation develops if the conditions causing acute inflammation is not resolved over a period of time. Intriguingly, chronic inflammation may be due to excessive physiological responses, such as the wound repairing process, which are intrinsically essential for maintaining normal life. Certain stimuli may directly provoke chronic rather than acute inflammation. Peritoneal inflammation of the microenvironment in the peritoneal cavity during PD generally presents in two major forms: (i) acute inflammation triggered by microbial infection, and (ii) low-grade inflammation or "para-inflammation" under various exogenous or endogenous stimulations during PD. These two forms of inflammation affects the membrane structure and function, and is associated with

The most common form of acute inflammation of peritoneum in PD is peritonitis, which is a serious and the most frequent complication leading to hospitalization and catheter loss [6, 7]. Peritonitis causes a high infection-related mortality in PD patients [8, 9]. The leading cause of PD-associated peritonitis is contamination, predominately with the microorganisms from skin and environment, which is most commonly occur during the dialysis procedure such as PD exchange [10]. Exit site infection (ESI) in which transmigration of microorganisms from the exit site along the PD catheter into the peritoneal cavity, may cause tunnel infections and peritonitis [11, 12]. Enteric peritonitis is a less common cause but important, due to the severity of the inflammation process [13]. Fungal peritonitis accounts for about 4–6% of episodes of the total incidence of the peritonitis, and is with high mortality [14]. Rapidly resolving the infection is the primary approach to treat peritonitis, even if this involve the need for prompt removal of the peritoneal catheter. Before the causative microorganism is identified, initial therapy with broad spectrum antibiotic which is active against the most commonly occurring organisms, will be given according to the guideline from the International Society for Peritoneal Dialysis (ISPD) [9]. It is recommended that in addition to the standard initial protocol, specific regime tailored to the geographic and cultural characteristics, the relevant organisms and their antibiotic resistance pattern should be considered [15]. Detailed examination of the causality of infection-related peritonitis is important for the management. The molecular pathways of inflammation induced by different microbial pathogens are somehow redundant, yet also

An inherent immune dysfunction in PD patients and the continuous non-specific immune cell stimulation by dialysis procedure contribute to the chronic inflammatory state of patients under the long-term dialysis [18]. Patients on maintenance PD have increased intra-peritoneal levels of hyaluronan and cytokines including interleukin (IL)-1β, IL-6 and transforming growth factor-β (TGF-β) [19, 20]. Chronic inflammation remains an important cause of morbidity in patients with ESRD. During continuous ambulatory peritoneal dialysis (CAPD), peritoneal cells are repeatedly exposed to non-physiologic dialysis fluid (PDF) with low pH

increased mortality.

56 The Latest in Peritoneal Dialysis

**2.1. Acute inflammation in PD**

complex and diverse [16, 17].

**2.2. Chronic inflammation in PD**

Modulators of PD-related inflammation can be exogenous or endogenous. It should be noted that exogenous modulators may promote or amplify the effects of the endogenous modulators during the process of PD-related inflammation. Intriguingly, the interaction between modu‐ lators and the ongoing inflammatory events may form a vicious cycle to amplify the inflam‐ matory process.

#### *3.1.1. Exogenous modulators*

The innate immune system recognized catheters used for PD as the foreign bodies. Severe biofilm formation on the catheters have been observed in PD patients without detectable infection [31]. Histologic and functional evidences obtained from rodent model have shown that the catheter insertion may have induced a classic inflammatory reaction characterized by formation of fibrin clots in the peritoneum [32]. Mechanical stress during PD is related to the infiltration of large volume of PDF, especially for achieving specific target of small solute clearance. Volume stress during PD are associated with significant increments in endothelin (ET)-1, a vasoactive peptide that may induce peritoneal fibrosis and indirectly contribute to technique failure in CAPD [33]. ET-1 induces the release of proinflammatory cytokines and increases the deposition of extracellular matrix (ECM) by regulating production and turnover of matrix components. In addition, high fill volumes increase circulating norepinephrine levels

factor (VEGF) production and peritoneal vascularization [48]. GDP decrease the expression of tight junction associated protein, zonula occludens protein 1 (ZO-1), in human peritoneal mesothelial cells (HPMC) *via* the VEGF [49]. Glucose or GDP in PDF may cause AGE formation, which further provoke additional inflammatory stimuli on the peritoneal environment under PD [22, 50, 51]. Contamination and the inherent poor immune status of the PD patients contribute to the microbial stress during PD. Microbial contamination or ESI during PD may evolve to peritonitis, which elicits a virulent acute inflammatory response and is an important cause of hospitalization, catheter loss, and technique failure. The most common contaminated micro-organisms are coagulase-negative *Staphylococcus, S. aureus, Streptococcus*, and Gramnegative bacteria. Much less common are mycobacterium and fungal peritonitis. Skin organ‐ isms contamination including *Staphylococcus, Corynebacterium, and Bacillus* species cause mild inflammatory responses. Exit site infection with *Staphylococcus epidermidis* or *Pseudomonas aeruginosa* is difficult to treat, with frequent progression to tunnel infections and peritonitis. Fungal peritonitis generally requires catheter removal. It is worth mentioned that sustained inflammation is observed in patients on PD with peritonitis even after resolution of the clinical symptoms of peritonitis [52]. The C-reactive protein (CRP) remains significantly higher than baseline by day 42 after an episode of peritonitis [5]. Release of neutrophil gelatinase-associated lipocalin (NGAL) into the peritoneal dialysate effluent (PDE) by HPMC is induced following an acute episode of CAPD-related peritonitis, and is related to the up-regulation of the IL-1β concentration [53]. Lipopolysaccharide (LPS), a major component of Gram-negative bacterial cell walls, is a potent immuno-stimulatory product [54]. Endotoxemia is common in PD patients and circulating LPS may derived from the gastrointestinal tract during enteric peritonitis [55]. The level of circulating LPS correlates with the severity of systemic inflam‐ mation, suggesting that endotoxemia may contribute to accelerated atherosclerosis in PD

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 59

Uremia is associated with the immune dysfunction and is a significant risk factor for cardio‐ vascular abnormalities and death in chronic kidney disease (CKD) patients [56], and this risk is further increased when CKD has progressed to ESRD requiring dialysis. Dialysis decreases the impact of uremia, yet does not remove it completely. In PD patients, uremia fuels the inflammatory state and introduces stress on the peritoneum due to the formation of carbonyl products. It accelerates the formation of advanced oxidation protein products (AOPP) and AGE, that induces an upregulation of the receptors of advanced glycation end products (RAGE) [57]. Binding of AGE to RAGE alone [58], or in combination with the Toll-like receptor (TLR)s, elicits the inflammatory activity [59]. It has been suggested that the high-mobility group box 1 protein (HMGB1) may play a central role in mediating inflammation, and interactions involving the HMGB1-TLR-RAGE axis trigger NF-κB activation and proinflam‐ matory cytokines induction [60]. Cytotoxic injury to mesothelial cells induces ROS, depletes ATP, and triggers the extracellular release of HMGB1, which initiates a chronic inflammatory response [61]. Serum adipokine levels are significantly elevated in uremic patients with CKD [62], and elevated plasma concentrations of adiponectin and leptin have been reported [63, 64]. Leptin activates immune system and serves as a mediator of inflammation [65]. Glucose-

patients.

*3.1.2. Endogenous modulators*

**Figure 1.** Pathway of the development of PD-related inflammation

[34], blood pressure, intraperitoneal pressure [35], and elicit proinflammatory effects by increasing peritoneal IL-6 and tumor necrosis factor-α (TNF-α) concentration [36]. During PD, cells lining the peritoneal cavity are exposed from time to time to the hyperosmotic environ‐ ment, and this osmotic stress induces apoptosis of the peritoneal cells [37, 38]. Local acidosis occurs artificially during PD due to the non-physiological properties of PDF which has an acidic pH value. Exposure of macrophages to an acidic environment leads to the increased production of TNF-α through the up-regulation of inducible nitric oxide synthase (iNOS) activity and the activation of nuclear factor-κB (NF-κB) [39]. On the contrary, low pH PDF lead to rapid intracellular acidification and suppression of host defense activity [40, 41]. The acidic PDF induces stress on the endoplasmic reticulum (ER) and suppresses the induction of monocyte chemotactic protein-1 (MCP-1) in the peritoneum through de-activation of NF-κB pathway [42, 43], and this may impair the peritoneal defense mechanisms by interfering with migration of phagocytic cells. Obviously, further study is needed to clarify the role of acidicstress on PD-related inflammation. High glucose content in PDF induces immunological, structural and functional abnormalities in peritoneal cells during CAPD [44, 45]. High glucose induces vascular inflammatory processes through up-regulation of endothelial cell adhesion molecules, reduction of nitric oxide (NO) release, activation of reactive oxygen species (ROS) and NF-κB [46, 47]. Storage or heat sterilization of PDF generates the toxic substances GDP. Dialysis with GDP-containing PDF is associated with increased vascular endothelial growth factor (VEGF) production and peritoneal vascularization [48]. GDP decrease the expression of tight junction associated protein, zonula occludens protein 1 (ZO-1), in human peritoneal mesothelial cells (HPMC) *via* the VEGF [49]. Glucose or GDP in PDF may cause AGE formation, which further provoke additional inflammatory stimuli on the peritoneal environment under PD [22, 50, 51]. Contamination and the inherent poor immune status of the PD patients contribute to the microbial stress during PD. Microbial contamination or ESI during PD may evolve to peritonitis, which elicits a virulent acute inflammatory response and is an important cause of hospitalization, catheter loss, and technique failure. The most common contaminated micro-organisms are coagulase-negative *Staphylococcus, S. aureus, Streptococcus*, and Gramnegative bacteria. Much less common are mycobacterium and fungal peritonitis. Skin organ‐ isms contamination including *Staphylococcus, Corynebacterium, and Bacillus* species cause mild inflammatory responses. Exit site infection with *Staphylococcus epidermidis* or *Pseudomonas aeruginosa* is difficult to treat, with frequent progression to tunnel infections and peritonitis. Fungal peritonitis generally requires catheter removal. It is worth mentioned that sustained inflammation is observed in patients on PD with peritonitis even after resolution of the clinical symptoms of peritonitis [52]. The C-reactive protein (CRP) remains significantly higher than baseline by day 42 after an episode of peritonitis [5]. Release of neutrophil gelatinase-associated lipocalin (NGAL) into the peritoneal dialysate effluent (PDE) by HPMC is induced following an acute episode of CAPD-related peritonitis, and is related to the up-regulation of the IL-1β concentration [53]. Lipopolysaccharide (LPS), a major component of Gram-negative bacterial cell walls, is a potent immuno-stimulatory product [54]. Endotoxemia is common in PD patients and circulating LPS may derived from the gastrointestinal tract during enteric peritonitis [55]. The level of circulating LPS correlates with the severity of systemic inflam‐ mation, suggesting that endotoxemia may contribute to accelerated atherosclerosis in PD patients.

#### *3.1.2. Endogenous modulators*

[34], blood pressure, intraperitoneal pressure [35], and elicit proinflammatory effects by increasing peritoneal IL-6 and tumor necrosis factor-α (TNF-α) concentration [36]. During PD, cells lining the peritoneal cavity are exposed from time to time to the hyperosmotic environ‐ ment, and this osmotic stress induces apoptosis of the peritoneal cells [37, 38]. Local acidosis occurs artificially during PD due to the non-physiological properties of PDF which has an acidic pH value. Exposure of macrophages to an acidic environment leads to the increased production of TNF-α through the up-regulation of inducible nitric oxide synthase (iNOS) activity and the activation of nuclear factor-κB (NF-κB) [39]. On the contrary, low pH PDF lead to rapid intracellular acidification and suppression of host defense activity [40, 41]. The acidic PDF induces stress on the endoplasmic reticulum (ER) and suppresses the induction of monocyte chemotactic protein-1 (MCP-1) in the peritoneum through de-activation of NF-κB pathway [42, 43], and this may impair the peritoneal defense mechanisms by interfering with migration of phagocytic cells. Obviously, further study is needed to clarify the role of acidicstress on PD-related inflammation. High glucose content in PDF induces immunological, structural and functional abnormalities in peritoneal cells during CAPD [44, 45]. High glucose induces vascular inflammatory processes through up-regulation of endothelial cell adhesion molecules, reduction of nitric oxide (NO) release, activation of reactive oxygen species (ROS) and NF-κB [46, 47]. Storage or heat sterilization of PDF generates the toxic substances GDP. Dialysis with GDP-containing PDF is associated with increased vascular endothelial growth

**Figure 1.** Pathway of the development of PD-related inflammation

58 The Latest in Peritoneal Dialysis

Uremia is associated with the immune dysfunction and is a significant risk factor for cardio‐ vascular abnormalities and death in chronic kidney disease (CKD) patients [56], and this risk is further increased when CKD has progressed to ESRD requiring dialysis. Dialysis decreases the impact of uremia, yet does not remove it completely. In PD patients, uremia fuels the inflammatory state and introduces stress on the peritoneum due to the formation of carbonyl products. It accelerates the formation of advanced oxidation protein products (AOPP) and AGE, that induces an upregulation of the receptors of advanced glycation end products (RAGE) [57]. Binding of AGE to RAGE alone [58], or in combination with the Toll-like receptor (TLR)s, elicits the inflammatory activity [59]. It has been suggested that the high-mobility group box 1 protein (HMGB1) may play a central role in mediating inflammation, and interactions involving the HMGB1-TLR-RAGE axis trigger NF-κB activation and proinflam‐ matory cytokines induction [60]. Cytotoxic injury to mesothelial cells induces ROS, depletes ATP, and triggers the extracellular release of HMGB1, which initiates a chronic inflammatory response [61]. Serum adipokine levels are significantly elevated in uremic patients with CKD [62], and elevated plasma concentrations of adiponectin and leptin have been reported [63, 64]. Leptin activates immune system and serves as a mediator of inflammation [65]. Glucosebased PDF induces a higher leptin secretion by a murine adipocyte cell line 3T3-L1 compared to dialysate with physiological glucose concentration *via* the hexosamine pathway [66]. We have demonstrated that the full-length isoform of leptin receptor, Ob-Rb, is expressed in HPMC and its expression is up-regulated following exposure to glucose [67]. Glucose increases leptin synthesis by peritoneal adipocytes and the adipocyte-derived leptin can induce TGF-β production by HPMC through the Ob-Rb [67]. Adiponectin exerts protective functions on innate and adaptive immunity, including the reduction of phagocytic activity, IL-6 and TNFα production by macrophage, T-cell response, and the induction of anti-inflammatory cytokines by monocytes, macrophages and dendritic cells [68]. In a recent study using rat PD model, glucose-based PDF down-regulates adiponectin synthesis by adipocytes through an increased ROS generation [69].

which recruits caspase-1 to the inflammasome. In macrophage, soluble BGN induces the NLRP3 inflammasome, activating caspase-1 and releasing mature IL-1β [90]. Most notably, the pro-inflammatory events initiated by HA or BGN are also ROS dependent [91]. Figure 2 illustrates the complex interaction amount various endogenous modulators in relation to

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 61

**Figure 2.** Endogenous modulators in the regulation of peritoneal inflammation

An array of inflammatory mediators is significantly induced or up-regulated following PD, and is known to modulate the structure and function of the peritoneal membrane, as well as the function of the downstream effectors of the inflammatory pathway. Of equally important, these mediators also play a central role in the maintenance of homeostasis in peritoneum. These mediators are either derived from plasma proteins or secreted by infiltrating or resident peritoneal cells. While many of these inflammatory mediators have overlapped effects on the

peritoneal inflammation.

**4. Mediators**

In uremic patients under PD, chronic inflammatory processes induce the oxidative stress, generating excess ROS, reactive nitrogen species (RNS), and DNA-reactive aldehydes. These pro-oxidants overwhelm *in vivo* antioxidant defenses, and lead to increased oxidative damage of peritoneal structure and function [70]. The link between oxidative stress and inflammation has been demonstrated in liver injury, where oxidative stress induces the proinflammatory signaling and macrophage activation [71]. In HPMC, ROS amplifies the high glucose-induced expression of fibronectin [72], angiotensin II (AngII) and TGF-β [44].

Heat-shock proteins (HSP), a marker of the cellular stress response, is the main effector of the cellular reparative machinery. Induction of HSP expression will counteract cellular injury caused by PDF exposure. PDF induces HSP release by cultured HPMC [73, 74]. In an experi‐ mental model of PD, PDF infusion causes cellular injury but also up-regulates HSP-72 [75]. In HPMC under sublethal injury, secretion of HSP-72 correlates with the release of proinflam‐ matory IL-8 [76].

Breakdown products of the ECM during tissue injury, may serve as the endogenous modulator of inflammation. There is growing evidence that ECM molecules may deliver proinflammatory signals [77, 78]. In the context of PD, expression and release of hyaluronan (HA) and biglycan (BGN) is well recognized. HPMC synthesize and secrete ECM proteins including BGN and HA, which are detectable in PDE [19, 79, 80]. Under physiological conditions, HA is present as an inert high-molecular-weight polymer. Upon tissue injury, HA is broken down into inflammatory low-molecular-weight fragments, which activate the TLR4 and promote either an inflammatory or a tissue-repair response [81, 82]. Other than HA, BGN also implicate in modulating the proinflammatory functions. BGN can act as a "danger" motif, a potential innate antigen analogous to pathogen-associated molecular pattern (PAMP), which signal through TLR4 and TLR2 to initiate the inflammatory cascade [83]. BGN binds with TGF-β and TNF-α to regulate the proinflammatory cytokine activity [84, 85]. Markedly elevated TNF-α and IL-1β is found in PDE from CAPD patients with peritonitis [86]. The activity of proinflamma‐ tory master cytokine IL-1β is regulated by sequentially synthesis and cleavage of pro-IL-1 by caspase-1 (also named as IL-1 converting enzyme) [87, 88]. The production of pro-IL-1 is signaled by TLR and the activation of caspase-1 requires the assembly and activity of a cytosolic multi-protein complex known as the inflammasome, consisting of nucleotide-binding oligo‐ merization-like receptor family members (NLRs) [89]. NLRP3 is the best characterized NLRs which recruits caspase-1 to the inflammasome. In macrophage, soluble BGN induces the NLRP3 inflammasome, activating caspase-1 and releasing mature IL-1β [90]. Most notably, the pro-inflammatory events initiated by HA or BGN are also ROS dependent [91]. Figure 2 illustrates the complex interaction amount various endogenous modulators in relation to peritoneal inflammation.

**Figure 2.** Endogenous modulators in the regulation of peritoneal inflammation

#### **4. Mediators**

based PDF induces a higher leptin secretion by a murine adipocyte cell line 3T3-L1 compared to dialysate with physiological glucose concentration *via* the hexosamine pathway [66]. We have demonstrated that the full-length isoform of leptin receptor, Ob-Rb, is expressed in HPMC and its expression is up-regulated following exposure to glucose [67]. Glucose increases leptin synthesis by peritoneal adipocytes and the adipocyte-derived leptin can induce TGF-β production by HPMC through the Ob-Rb [67]. Adiponectin exerts protective functions on innate and adaptive immunity, including the reduction of phagocytic activity, IL-6 and TNFα production by macrophage, T-cell response, and the induction of anti-inflammatory cytokines by monocytes, macrophages and dendritic cells [68]. In a recent study using rat PD model, glucose-based PDF down-regulates adiponectin synthesis by adipocytes through an

In uremic patients under PD, chronic inflammatory processes induce the oxidative stress, generating excess ROS, reactive nitrogen species (RNS), and DNA-reactive aldehydes. These pro-oxidants overwhelm *in vivo* antioxidant defenses, and lead to increased oxidative damage of peritoneal structure and function [70]. The link between oxidative stress and inflammation has been demonstrated in liver injury, where oxidative stress induces the proinflammatory signaling and macrophage activation [71]. In HPMC, ROS amplifies the high glucose-induced

Heat-shock proteins (HSP), a marker of the cellular stress response, is the main effector of the cellular reparative machinery. Induction of HSP expression will counteract cellular injury caused by PDF exposure. PDF induces HSP release by cultured HPMC [73, 74]. In an experi‐ mental model of PD, PDF infusion causes cellular injury but also up-regulates HSP-72 [75]. In HPMC under sublethal injury, secretion of HSP-72 correlates with the release of proinflam‐

Breakdown products of the ECM during tissue injury, may serve as the endogenous modulator of inflammation. There is growing evidence that ECM molecules may deliver proinflammatory signals [77, 78]. In the context of PD, expression and release of hyaluronan (HA) and biglycan (BGN) is well recognized. HPMC synthesize and secrete ECM proteins including BGN and HA, which are detectable in PDE [19, 79, 80]. Under physiological conditions, HA is present as an inert high-molecular-weight polymer. Upon tissue injury, HA is broken down into inflammatory low-molecular-weight fragments, which activate the TLR4 and promote either an inflammatory or a tissue-repair response [81, 82]. Other than HA, BGN also implicate in modulating the proinflammatory functions. BGN can act as a "danger" motif, a potential innate antigen analogous to pathogen-associated molecular pattern (PAMP), which signal through TLR4 and TLR2 to initiate the inflammatory cascade [83]. BGN binds with TGF-β and TNF-α to regulate the proinflammatory cytokine activity [84, 85]. Markedly elevated TNF-α and IL-1β is found in PDE from CAPD patients with peritonitis [86]. The activity of proinflamma‐ tory master cytokine IL-1β is regulated by sequentially synthesis and cleavage of pro-IL-1 by caspase-1 (also named as IL-1 converting enzyme) [87, 88]. The production of pro-IL-1 is signaled by TLR and the activation of caspase-1 requires the assembly and activity of a cytosolic multi-protein complex known as the inflammasome, consisting of nucleotide-binding oligo‐ merization-like receptor family members (NLRs) [89]. NLRP3 is the best characterized NLRs

expression of fibronectin [72], angiotensin II (AngII) and TGF-β [44].

increased ROS generation [69].

60 The Latest in Peritoneal Dialysis

matory IL-8 [76].

An array of inflammatory mediators is significantly induced or up-regulated following PD, and is known to modulate the structure and function of the peritoneal membrane, as well as the function of the downstream effectors of the inflammatory pathway. Of equally important, these mediators also play a central role in the maintenance of homeostasis in peritoneum. These mediators are either derived from plasma proteins or secreted by infiltrating or resident peritoneal cells. While many of these inflammatory mediators have overlapped effects on the vasculature and on the recruitment of leukocytes, other mediators may perform additional specific functions and are produced directly in response to particular stimulation by PDrelated modulators. It should be noted that some mediators can induce the production of other inflammatory mediators and it is important to understand the logic underlying this hierarchy of mediators induction. The soluble mediators of PD-related inflammation classified according to their biochemical properties is shown in Table 1.

proinflammatory role in activating monocyte chemotactic protein [92]. Data from studies on endothelial cells, monocytes-macrophages and smooth muscle cells support a direct role for CRP in atherogenesis [93-95]. NGAL has been evaluated as an urinary biomarker for detecting the early onset of renal tubular cell injury [96]. In CAPD, NGAL in PDE is a marker for neutrophil-dependent bacterial peritonitis, and is also synthesized by HPMC induced specifically by IL1-β [53]. NGAL directly involves in the pathogenesis of CKD and cardiovas‐

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 63

cular abnormality [97].

**Table 2.** Effectors in PD-related Inflammation

**4.2. Chemokines and circulating adhesion molecules**

In response to modulators of peritoneal inflammation, chemokines are produced by peritoneal cells including HPMC [98], macrophages [43], adipocytes [99], to control leukocyte extrava‐ sation and chemotaxis towards the affected tissues. These chemokines includes IL-8 [98, 100], MCP-1 [98, 101], macrophage inhibitory factor (MIF) [102], and regulated upon activation normal T cell expressed and secreted (RANTES) [98, 101]. Strikingly, HPMC express the αchemokine stromal derived factor-1 (SDF-1) [103]. The expression levels of SDF-1 is upregulated by TGF-β1 treatment, resulting in an increased migratory potential of HPMC, which is suggested to be involved in the re-epithelialization of denuded basement membrane at the


There are many other members in each category, only those commonly reported are listed.

**Table 1.** Mediators of PD-related inflammation

#### **4.1. Acute phase proteins**

Emerging evidences have suggested that acute phase proteins generated during PD may have additional function instead of just serving as the markers of inflammation. CRP plays a proinflammatory role in activating monocyte chemotactic protein [92]. Data from studies on endothelial cells, monocytes-macrophages and smooth muscle cells support a direct role for CRP in atherogenesis [93-95]. NGAL has been evaluated as an urinary biomarker for detecting the early onset of renal tubular cell injury [96]. In CAPD, NGAL in PDE is a marker for neutrophil-dependent bacterial peritonitis, and is also synthesized by HPMC induced specifically by IL1-β [53]. NGAL directly involves in the pathogenesis of CKD and cardiovas‐ cular abnormality [97].


**Table 2.** Effectors in PD-related Inflammation

vasculature and on the recruitment of leukocytes, other mediators may perform additional specific functions and are produced directly in response to particular stimulation by PDrelated modulators. It should be noted that some mediators can induce the production of other inflammatory mediators and it is important to understand the logic underlying this hierarchy of mediators induction. The soluble mediators of PD-related inflammation classified according

to their biochemical properties is shown in Table 1.

62 The Latest in Peritoneal Dialysis

There are many other members in each category, only those commonly reported are listed.

Emerging evidences have suggested that acute phase proteins generated during PD may have additional function instead of just serving as the markers of inflammation. CRP plays a

**Table 1.** Mediators of PD-related inflammation

**4.1. Acute phase proteins**

#### **4.2. Chemokines and circulating adhesion molecules**

In response to modulators of peritoneal inflammation, chemokines are produced by peritoneal cells including HPMC [98], macrophages [43], adipocytes [99], to control leukocyte extrava‐ sation and chemotaxis towards the affected tissues. These chemokines includes IL-8 [98, 100], MCP-1 [98, 101], macrophage inhibitory factor (MIF) [102], and regulated upon activation normal T cell expressed and secreted (RANTES) [98, 101]. Strikingly, HPMC express the αchemokine stromal derived factor-1 (SDF-1) [103]. The expression levels of SDF-1 is upregulated by TGF-β1 treatment, resulting in an increased migratory potential of HPMC, which is suggested to be involved in the re-epithelialization of denuded basement membrane at the site of peritoneal injury [104]. Soluble adhesion molecules including soluble intercellular adhesion molecule-1 (sICAM-1) [105] and soluble vascular cell adhesion molecule-1 (sVCAM-1) [106] are produced by endothelial cells during PD, and their concentration correlates with atherogenesis or cardiovascular functions.

**4.5. Lipid mediators**

and superoxide [120].

fibrosis [126, 127].

**4.7. Vasoactive substances**

**4.6. Proteolytic enzymes**

Two major classes of lipid mediators, eicosanoids and platelet-activating factors (PAF), are derived from phosphatidylcholine, a member of the phospholipid family that is present in the inner leaflet of cellular membranes. Prostaglandins E2 (PGE2) is generated from eicosanoids, whereas PAF is produced by the acetylation of lysophosphatidic acid. PGE2 causes vasodila‐ tion and modulates the change of peritoneal permeability in PD after peritonitis [118]. PAF activates several processes that occur during the inflammatory response, including the recruitment of leukocytes, vascular permeability and platelet activation. Oxidative stress during PD causes unrestrained synthesis of PAF through interfering the proper function of alpha 1-proteinase inhibitor, a PAF inhibitor, [119]. Esterified eicosanoids are produced from 5-Lipoxygenase (5-LOX) by neutrophils after peritonitis, and enhance the generation of IL-8

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 65

Proteolytic enzymes have diverse roles in inflammation, in part through degrading ECM and basement-membrane proteins. These proteases have important roles in many processes, including host defense, tissue remodeling and leukocyte migration. Matrix metalloproteinase (MMP) is the most important family of proteolytic enzymes in mesothelial homeostasis and wound repair. Of equal important is the endogenous tissue inhibitors of metalloproteinase (TIMP), which moderate MMP activity. The balance between MMPs and TIMPs, helps to regulate ECM turnover during tissue remodeling in PD. MMP-2 has been associated with the oxidative stress marker in PD [121]. Activation of MMP-2 causes peritoneal injury during peritoneal dialysis in rats [122]. Neutral-pH PDF improves peritoneal function and decreases MMP-2 in patients undergoing CAPD [123]. MMP-2 and TIMP-1 levels in peritoneal effluents reflect solute transport rate and are associated with peritoneal injury [124]. Regression analysis revealed that both the MMP-7 and TIMP-1, are excellent predictors of cellular stress in dialyzed patients using HSP-27 as the marker [125]. The number of mast cells is increased in PD patients [126], and mast cell tryptase is a serine protease implicated in promoting angiogenesis and

Vasoactive amines modulate the vascular permeability, vasodilation, or vasoconstriction of the peritoneal vasculature during PD, and are produced in an all-or-none manner during degranulation from mast cells and platelets. PDF induces peritoneal histamine release from mast cells [128], and this further causes calcium flux, which activates HPMC and influences cytoskeleton organization [129]. The neuropeptide substance P exaggerates the affected microvascular tone, albumin loss and reduced ultrafiltration in a rat PD model [128]. Plasma levels of atrial natriuretic peptide (ANP), pro-renin activity (PRA), and ET are increased in uremic patients on long-term CAPD, and suggesting the risk of development of myocardial function [130]. AngII activates macrophages and fibroblast to secrete proinflammatory cytokines, chemokines, and VEGF [131]. AngII plays important roles in regulating peritoneal

extracellular volume and in the development of peritoneal fibrosis [132, 133].

#### **4.3. Complement components**

Complement activation during PD plays key roles in the maintenance of host homeostasis by eliminating infectious microorganisms and injured cells. Complement activation releases a number of biologically active products that drive peritoneal inflammation [107]. The comple‐ ment fragments, C3a, C4a and C5a (also known as anaphylatoxins), are produced by several pathways of complement activation. These complement components promote the recruitment of granulocytes and monocytes, and induce mast-cell degranulation, thereby affecting the vasculature of the peritoneum in PD. The synthesis of C3 and C4 by HPMC are regulated by PDF [108]. In rodent model, blocking C5a reduces influx of neutrophils and improve ultrafil‐ tration [109]. Inhibiting the complement activation by complement regulators (CRegs), Crry and CD59, may protect the peritoneal membrane from long-term PD injury [110].

#### **4.4. Cytokines and adipokines**

Numerous cytokines are produced by peritoneal cells, infiltrating macrophages or mast cells (Table 1). These cytokines play pluripotent pleiotropic roles in the peritoneal inflammation, participate in the host defense mechanisms and the induction of the acute-phase response. During peritonitis, there is increased release of IL-1β, IL-6, TGF-β and TNF-α by HPMC [52]. These cytokines may autocrinally induce epithelial to mesenchymal transition (EMT) in HPMC, and this further promotes peritoneal inflammation and fibrosis [29, 111, 112]. In the uremic pre-dialysis and PD patients, there is increased peritoneal expression of the fibroblast growth factor-2 (FGF-2) and VEGF [113]. Compared to patients dialysed with low-GDP containing PDF, patients dialysed with less-biocompatible PDF have increased concentration of TNF-α, hepatocyte growth factor (HGF), and IL-6 in the dialysate [102]. AGE and GDP in PDF differentially regulate the synthesis of connective tissue growth factor (CTGF) by peritoneal resident cells. The CTGF synthesis by HPMC can be further amplified by TGF-β released from peritoneal fibroblast or endothelial cells [114]. Crosstalk among peritoneal cells and their cytokines may amply the inflammatory cascade. The differential activation of different transcriptional factors and the diverse response of HPMC towards CTGF, TGF-β and VEGF, suggest that peritoneal cytokines have an overlapping and yet distinct role on peritoneal target cells. Other than the cytokines, peritoneal adipocytes can mediate various physiological processes through the secretion of an array of adipokines including leptin, adiponectin, apelin, retinol-binding protein-4 (RBP-4) [103, 115]. These adipokines have distinct functions on peritoneum during PD. For example, leptin augments myofibroblastic conversion of HPMC [116]. The relative levels of leptin and adiponectin in dialysate from PD patients may indicate the risk of cardiovascular disease [117].

#### **4.5. Lipid mediators**

site of peritoneal injury [104]. Soluble adhesion molecules including soluble intercellular adhesion molecule-1 (sICAM-1) [105] and soluble vascular cell adhesion molecule-1 (sVCAM-1) [106] are produced by endothelial cells during PD, and their concentration

Complement activation during PD plays key roles in the maintenance of host homeostasis by eliminating infectious microorganisms and injured cells. Complement activation releases a number of biologically active products that drive peritoneal inflammation [107]. The comple‐ ment fragments, C3a, C4a and C5a (also known as anaphylatoxins), are produced by several pathways of complement activation. These complement components promote the recruitment of granulocytes and monocytes, and induce mast-cell degranulation, thereby affecting the vasculature of the peritoneum in PD. The synthesis of C3 and C4 by HPMC are regulated by PDF [108]. In rodent model, blocking C5a reduces influx of neutrophils and improve ultrafil‐ tration [109]. Inhibiting the complement activation by complement regulators (CRegs), Crry

and CD59, may protect the peritoneal membrane from long-term PD injury [110].

Numerous cytokines are produced by peritoneal cells, infiltrating macrophages or mast cells (Table 1). These cytokines play pluripotent pleiotropic roles in the peritoneal inflammation, participate in the host defense mechanisms and the induction of the acute-phase response. During peritonitis, there is increased release of IL-1β, IL-6, TGF-β and TNF-α by HPMC [52]. These cytokines may autocrinally induce epithelial to mesenchymal transition (EMT) in HPMC, and this further promotes peritoneal inflammation and fibrosis [29, 111, 112]. In the uremic pre-dialysis and PD patients, there is increased peritoneal expression of the fibroblast growth factor-2 (FGF-2) and VEGF [113]. Compared to patients dialysed with low-GDP containing PDF, patients dialysed with less-biocompatible PDF have increased concentration of TNF-α, hepatocyte growth factor (HGF), and IL-6 in the dialysate [102]. AGE and GDP in PDF differentially regulate the synthesis of connective tissue growth factor (CTGF) by peritoneal resident cells. The CTGF synthesis by HPMC can be further amplified by TGF-β released from peritoneal fibroblast or endothelial cells [114]. Crosstalk among peritoneal cells and their cytokines may amply the inflammatory cascade. The differential activation of different transcriptional factors and the diverse response of HPMC towards CTGF, TGF-β and VEGF, suggest that peritoneal cytokines have an overlapping and yet distinct role on peritoneal target cells. Other than the cytokines, peritoneal adipocytes can mediate various physiological processes through the secretion of an array of adipokines including leptin, adiponectin, apelin, retinol-binding protein-4 (RBP-4) [103, 115]. These adipokines have distinct functions on peritoneum during PD. For example, leptin augments myofibroblastic conversion of HPMC [116]. The relative levels of leptin and adiponectin in dialysate from PD patients may indicate

correlates with atherogenesis or cardiovascular functions.

**4.3. Complement components**

64 The Latest in Peritoneal Dialysis

**4.4. Cytokines and adipokines**

the risk of cardiovascular disease [117].

Two major classes of lipid mediators, eicosanoids and platelet-activating factors (PAF), are derived from phosphatidylcholine, a member of the phospholipid family that is present in the inner leaflet of cellular membranes. Prostaglandins E2 (PGE2) is generated from eicosanoids, whereas PAF is produced by the acetylation of lysophosphatidic acid. PGE2 causes vasodila‐ tion and modulates the change of peritoneal permeability in PD after peritonitis [118]. PAF activates several processes that occur during the inflammatory response, including the recruitment of leukocytes, vascular permeability and platelet activation. Oxidative stress during PD causes unrestrained synthesis of PAF through interfering the proper function of alpha 1-proteinase inhibitor, a PAF inhibitor, [119]. Esterified eicosanoids are produced from 5-Lipoxygenase (5-LOX) by neutrophils after peritonitis, and enhance the generation of IL-8 and superoxide [120].

#### **4.6. Proteolytic enzymes**

Proteolytic enzymes have diverse roles in inflammation, in part through degrading ECM and basement-membrane proteins. These proteases have important roles in many processes, including host defense, tissue remodeling and leukocyte migration. Matrix metalloproteinase (MMP) is the most important family of proteolytic enzymes in mesothelial homeostasis and wound repair. Of equal important is the endogenous tissue inhibitors of metalloproteinase (TIMP), which moderate MMP activity. The balance between MMPs and TIMPs, helps to regulate ECM turnover during tissue remodeling in PD. MMP-2 has been associated with the oxidative stress marker in PD [121]. Activation of MMP-2 causes peritoneal injury during peritoneal dialysis in rats [122]. Neutral-pH PDF improves peritoneal function and decreases MMP-2 in patients undergoing CAPD [123]. MMP-2 and TIMP-1 levels in peritoneal effluents reflect solute transport rate and are associated with peritoneal injury [124]. Regression analysis revealed that both the MMP-7 and TIMP-1, are excellent predictors of cellular stress in dialyzed patients using HSP-27 as the marker [125]. The number of mast cells is increased in PD patients [126], and mast cell tryptase is a serine protease implicated in promoting angiogenesis and fibrosis [126, 127].

#### **4.7. Vasoactive substances**

Vasoactive amines modulate the vascular permeability, vasodilation, or vasoconstriction of the peritoneal vasculature during PD, and are produced in an all-or-none manner during degranulation from mast cells and platelets. PDF induces peritoneal histamine release from mast cells [128], and this further causes calcium flux, which activates HPMC and influences cytoskeleton organization [129]. The neuropeptide substance P exaggerates the affected microvascular tone, albumin loss and reduced ultrafiltration in a rat PD model [128]. Plasma levels of atrial natriuretic peptide (ANP), pro-renin activity (PRA), and ET are increased in uremic patients on long-term CAPD, and suggesting the risk of development of myocardial function [130]. AngII activates macrophages and fibroblast to secrete proinflammatory cytokines, chemokines, and VEGF [131]. AngII plays important roles in regulating peritoneal extracellular volume and in the development of peritoneal fibrosis [132, 133].

#### **5. Effectors**

The effectors of PD inflammatory response are the residential peritoneal cells and the recruited leukocytes. Residential peritoneal effector cells are adipocytes, endothelial cells, fibroblasts, macrophages, mast cells and mesothelial cells. Recruited leukocytes include polymorphonu‐ clear cells (PMN), T or B lymphocytes, macrophages and mast cells. Table 2 shows the cell types and their released mediators, which are of relevance to the PD-induced inflammation.

and catheter malfunction may be decreased with better patient education, optimal exit site care, the use of oral prophylactic antibiotics after wet contamination, and the use of the disconnect systems. The inflammatory modulators in the conventional PDF may be reduced or removed by using novel PDF-based replacement of glucose with icodextrin and amino acids,

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 67

There are potential therapeutic options to minimize peritoneal inflammation in PD patients, but yet need extensive research for further confirmation [151]. Acute peritonitis may be prevented by the use of chemokine receptor blockers, mast cell stabilizers or corticosteroid to block excessive macrophage activity. Chronic PD-related inflammation may be targeted by inhibiting various signaling pathways involved in the inflammatory cascade, or by the introduction of anti-inflammatory agents including anti-RAGE antibodies, bone morphoge‐

Desperately, if patients have not been given kidney transplant, peritoneum fibrosis will be developed eventually with long term PD. Even after kidney transplant, the restoration and repair of the already injured and thickened peritoneum are still required. Thus, the uppermost challenge is to preserve and at the best, to restore the peritoneum function. Stem cells trans‐ plantation either from bone marrow or using mesenchymal stem cells, although still in its infancy, may be an attractive intervention for the repair or replenishment of the cellular reservoir of multi-potential cells of the damaged peritoneal tissue. Further investigation along

lactate with bicarbonate at a neutral to physiological pH.

netic protein-7 (BMP-7) or Smad7 transgene delivery.

this direction is warranted.

**List of abbreviations**

ANP Atrial natriuretic peptide

CKD Chronic kidney disease CRegs Complement regulators

CRP C-reactive protein

ECM Extracellular matrix

Ang II Angiotensin II

BGN Biglycan

AGE Advanced glycation end products

AOPP Advanced oxidation protein products

CAPD Continuous ambulatory peritoneal dialysis

BMP-7 Bone Morphogenetic Protein-7

GDP Glucose degradation products

EMT Epithelial to mesenchymal transition

Upon PD, both the exogenous or endogenous modulators activate peritoneal adipocytes, macrophages and mesothelial cells, which produce inflammatory cytokines, adipokines and growth factors. These mediators will further promote the secretion of angiogenic factors, fibrotic cytokines and growth factors, by fibroblasts, endothelial cells and mast cells through paracrine interaction. In the meantime, residential HPMC, adipocyte and macrophage also release chemotatic mediators to recruit the exogenous inflammatory immune effectors. All these events orchestrate to amplify the inflammatory cascades and eventually lead to the loss of ultrafiltration and development of peritoneal fibrosis.

#### **6. New PDF and immune responses**

Emerging evidences suggest the beneficial effects on peritoneal function by using new PDF with decreasing acidity, reducing GDP concentration, and with non-glucose osmotic agents such as amino acids or glucose polymers. *In vitro* cell culture studies have demonstrated enhanced biocompatibility with improved survival of peritoneal cells exposed to new PDF [134-136]. Data from animal models of PD using new PDF also have shown reduced fibrosis and neoangiogenesis, improved macrophage function, and better maintained ultrafiltration [137, 138]. In humans, the use of glucose-polymer-based solution reduced the cholesterol levels with enhanced lipid oxidation and improved serum profiles of adipokines [139-141]. Despite these beneficial effects, use of glucose-polymer-based solution may increase levels of AGE and other immune mediators including IL-6, TNF-α and HA [142-144]. The use of amino-acidbased PDE improves protein malnutrition but exerts negative metabolic effects of increasing serum urea and homocysteine levels [145]. Moreover, PDE level of IL-6 is increased, reflecting the activation of inflammatory response of the peritoneal membrane [146]. The use of glucosebased neutral pH PDF achieves less activation of peritoneal membrane the best preservation of its integrity. The levels of AGE, HA, VEGF and IL-6 are not altered and the effluent-derived macrophage phagocytic function is enhanced [147-150].

#### **7. Conclusion**

The PD-related inflammation is an exceedingly complex process. Although some of the destructive events of PD-induced inflammation can be prevented, nevertheless, other longterm damage is understandably unavoidable. The incidences of peritonitis, exit site infection and catheter malfunction may be decreased with better patient education, optimal exit site care, the use of oral prophylactic antibiotics after wet contamination, and the use of the disconnect systems. The inflammatory modulators in the conventional PDF may be reduced or removed by using novel PDF-based replacement of glucose with icodextrin and amino acids, lactate with bicarbonate at a neutral to physiological pH.

There are potential therapeutic options to minimize peritoneal inflammation in PD patients, but yet need extensive research for further confirmation [151]. Acute peritonitis may be prevented by the use of chemokine receptor blockers, mast cell stabilizers or corticosteroid to block excessive macrophage activity. Chronic PD-related inflammation may be targeted by inhibiting various signaling pathways involved in the inflammatory cascade, or by the introduction of anti-inflammatory agents including anti-RAGE antibodies, bone morphoge‐ netic protein-7 (BMP-7) or Smad7 transgene delivery.

Desperately, if patients have not been given kidney transplant, peritoneum fibrosis will be developed eventually with long term PD. Even after kidney transplant, the restoration and repair of the already injured and thickened peritoneum are still required. Thus, the uppermost challenge is to preserve and at the best, to restore the peritoneum function. Stem cells trans‐ plantation either from bone marrow or using mesenchymal stem cells, although still in its infancy, may be an attractive intervention for the repair or replenishment of the cellular reservoir of multi-potential cells of the damaged peritoneal tissue. Further investigation along this direction is warranted.

#### **List of abbreviations**

**5. Effectors**

66 The Latest in Peritoneal Dialysis

The effectors of PD inflammatory response are the residential peritoneal cells and the recruited leukocytes. Residential peritoneal effector cells are adipocytes, endothelial cells, fibroblasts, macrophages, mast cells and mesothelial cells. Recruited leukocytes include polymorphonu‐ clear cells (PMN), T or B lymphocytes, macrophages and mast cells. Table 2 shows the cell types and their released mediators, which are of relevance to the PD-induced inflammation. Upon PD, both the exogenous or endogenous modulators activate peritoneal adipocytes, macrophages and mesothelial cells, which produce inflammatory cytokines, adipokines and growth factors. These mediators will further promote the secretion of angiogenic factors, fibrotic cytokines and growth factors, by fibroblasts, endothelial cells and mast cells through paracrine interaction. In the meantime, residential HPMC, adipocyte and macrophage also release chemotatic mediators to recruit the exogenous inflammatory immune effectors. All these events orchestrate to amplify the inflammatory cascades and eventually lead to the loss

Emerging evidences suggest the beneficial effects on peritoneal function by using new PDF with decreasing acidity, reducing GDP concentration, and with non-glucose osmotic agents such as amino acids or glucose polymers. *In vitro* cell culture studies have demonstrated enhanced biocompatibility with improved survival of peritoneal cells exposed to new PDF [134-136]. Data from animal models of PD using new PDF also have shown reduced fibrosis and neoangiogenesis, improved macrophage function, and better maintained ultrafiltration [137, 138]. In humans, the use of glucose-polymer-based solution reduced the cholesterol levels with enhanced lipid oxidation and improved serum profiles of adipokines [139-141]. Despite these beneficial effects, use of glucose-polymer-based solution may increase levels of AGE and other immune mediators including IL-6, TNF-α and HA [142-144]. The use of amino-acidbased PDE improves protein malnutrition but exerts negative metabolic effects of increasing serum urea and homocysteine levels [145]. Moreover, PDE level of IL-6 is increased, reflecting the activation of inflammatory response of the peritoneal membrane [146]. The use of glucosebased neutral pH PDF achieves less activation of peritoneal membrane the best preservation of its integrity. The levels of AGE, HA, VEGF and IL-6 are not altered and the effluent-derived

The PD-related inflammation is an exceedingly complex process. Although some of the destructive events of PD-induced inflammation can be prevented, nevertheless, other longterm damage is understandably unavoidable. The incidences of peritonitis, exit site infection

of ultrafiltration and development of peritoneal fibrosis.

macrophage phagocytic function is enhanced [147-150].

**7. Conclusion**

**6. New PDF and immune responses**

AGE Advanced glycation end products Ang II Angiotensin II ANP Atrial natriuretic peptide AOPP Advanced oxidation protein products BGN Biglycan BMP-7 Bone Morphogenetic Protein-7 CAPD Continuous ambulatory peritoneal dialysis CKD Chronic kidney disease CRegs Complement regulators CRP C-reactive protein GDP Glucose degradation products ECM Extracellular matrix EMT Epithelial to mesenchymal transition

ER Endoplasmic reticulum ESI Exit site infection ESRD End-stage renal disease ET Endothelin FGF-2 Fibroblast growth factor-2 HA Hyaluronan HD Hemodialysis HGF Hepatocyte growth factor HMGB1High-mobility group box 1 protein HPMC Human peritoneal mesothelial cells HSP Heat-shock proteins iNOS Inducible nitric oxide synthase IFN-γ Interferon- γ IL Interleukin ISPD International Society for Peritoneal Dialysis 5-LOX 5-Lipoxygenase LPS Lipopolysaccharide MCP-1 Monocyte chemotactic protein-1 MMP Metalloproteinase NF-κB Nuclear factor-κB NGAL Neutrophil gelatinase-associated lipocalin NLRs Nucleotide-binding oligomerization-like receptor family members PAF Platelet-activating factors PAMP Pathogen-associated molecular patterns PD Peritoneal dialysis PDE Peritoneal dialysate effluent PGE2 Prostaglandins E2 PDF Peritoneal dialysis fluid PMN Polymorphonuclear cells PRA Pro-renin activity

RAGE Receptors of advanced glycation end products

sICAM-1 Soluble intercellular adhesion molecule-1

sVCAM-1 Soluble vascular cell adhesion molecule-1

RBP-4 Retinol-binding protein-4

RNS Reactive nitrogen species

ROS Reactive oxygen species

RRF Renal replacement therapy

SDF-1 Stromal derived factor-1

TLR Toll-like receptor

TNF-α Tumor necrosis factor-α

ZO-1 Zonula occludens protein-1

**Acknowledgements**

**Author details**

Joseph C.K. Leung<sup>1</sup>

Hong Kong, China

China

TGF-β Transforming growth factor-β

TIMP Tissue inhibitors of metalloproteinases

VEGF Vascular endothelial growth factor

Foundation and the House of INDOCAFE.

, Loretta Y. Y. Chan<sup>1</sup>

\*Address all correspondence to: jckleung@hku.hk

RANTES Regulated upon activation normal T cell expressed and secreted

We apologize to the investigators whose work was not cited due to space limitations. The study was supported by the Baxter Extramural Grant and was partly supported by L & T Charitable

, Kar Neng Lai<sup>2</sup>

1 Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam,

2 Nephrology Center, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong,

and Sydney C.W. Tang<sup>1</sup>

Inflammation in Peritoneal Dialysis http://dx.doi.org/10.5772/55964 69

RAGE Receptors of advanced glycation end products

RANTES Regulated upon activation normal T cell expressed and secreted

RBP-4 Retinol-binding protein-4

RNS Reactive nitrogen species

ER Endoplasmic reticulum

ESRD End-stage renal disease

FGF-2 Fibroblast growth factor-2

HGF Hepatocyte growth factor

HSP Heat-shock proteins

IFN-γ Interferon- γ

5-LOX 5-Lipoxygenase LPS Lipopolysaccharide

MMP Metalloproteinase NF-κB Nuclear factor-κB

PAF Platelet-activating factors

PDE Peritoneal dialysate effluent

PD Peritoneal dialysis

PGE2 Prostaglandins E2

PRA Pro-renin activity

PDF Peritoneal dialysis fluid PMN Polymorphonuclear cells

IL Interleukin

HMGB1High-mobility group box 1 protein HPMC Human peritoneal mesothelial cells

ISPD International Society for Peritoneal Dialysis

NGAL Neutrophil gelatinase-associated lipocalin

PAMP Pathogen-associated molecular patterns

NLRs Nucleotide-binding oligomerization-like receptor family members

iNOS Inducible nitric oxide synthase

MCP-1 Monocyte chemotactic protein-1

ESI Exit site infection

68 The Latest in Peritoneal Dialysis

ET Endothelin

HA Hyaluronan HD Hemodialysis ROS Reactive oxygen species

RRF Renal replacement therapy

SDF-1 Stromal derived factor-1

sICAM-1 Soluble intercellular adhesion molecule-1

sVCAM-1 Soluble vascular cell adhesion molecule-1

TGF-β Transforming growth factor-β

TIMP Tissue inhibitors of metalloproteinases

TLR Toll-like receptor

TNF-α Tumor necrosis factor-α

VEGF Vascular endothelial growth factor

ZO-1 Zonula occludens protein-1

#### **Acknowledgements**

We apologize to the investigators whose work was not cited due to space limitations. The study was supported by the Baxter Extramural Grant and was partly supported by L & T Charitable Foundation and the House of INDOCAFE.

#### **Author details**

Joseph C.K. Leung<sup>1</sup> , Loretta Y. Y. Chan<sup>1</sup> , Kar Neng Lai<sup>2</sup> and Sydney C.W. Tang<sup>1</sup>

\*Address all correspondence to: jckleung@hku.hk

1 Department of Medicine, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong, China

2 Nephrology Center, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong, China

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**Chapter 5**

**The Association with Cardiovascular Events and Residual**

Life expectancy among the patients with chronic kidney disease (CKD), especially among the ones with end-stage renal disease (ESRD) has decreased that is significantly lower than the general population. The leading cause of morbidity and mortality among the dialysis patients with ESRD are cardiovascular disease (CVD) which are reported to be responsible of a 50%

The prevalence of traditional cardiovascular risk factors such as hypertension, hyperlipidemia, diabetes, physical inactivity is higher in dialysis patients. Besides these, there are uremiaspecific, nontraditional risk factors, including volume overload, anemia, disordered mineral metabolism, increased inflammation and oxidative stress, and malnutrition, all of which are associated with higher all-cause and cardiovascular mortality in dialysis patients. Cardiovas‐ cular risk factors that are unique to peritoneal dialysis (PD) patients, including residual renal function (RRF), peritoneal membran integrity, infection, dialysis center size, patient education and training, all of which are also associated with higher all-cause and cardiovascular mortality

In 1995, Maiorca et al were among the first to note an independent relationship between the presence of residual renal function, and survival in patients on dialysis [2]. Several subsequent studies reported similar findings that residual renal function but not the dose of peritoneal

The mechanism underlying survival benefits associated with RRF in PD patients is not clear. RRF has been implicated to be important in maintaining the fluid balance of patients on PD. RRF also plays an important role in phosphorus control, and removal of middle molecular uremic toxins. In addition, loss of RRF is associated with higher arterial pressure, more severe

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© 2013 Kalender and Eren; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

dialysis was a powerful predictor of survival in peritoneal dialysis patients [3-7].

**Renal Function in Peritoneal Dialysis**

Additional information is available at the end of the chapter

Betül Kalender and Necmi Eren

http://dx.doi.org/10.5772/56597

mortality rate in these patients [1].

**1. Introduction**

in dialysis patients.
