**4. Regulation of peritoneal inflammation and leukocyte trafficking**

During acute episodes of peritonitis, there is early activation of proinflammatory cytokines (TNF-, IL-1, and IFN-) and rapid recruitment of neutrophils with subsequent replacement by monocytes. This initial influx of neutrophils is due to the expression of CXC chemokine, MIP-1/KC, and the release of sIL-6R which facilitates the formation of sIL-6R/IL-6 complexes. These trans-signaling complexes suppress the release of other CXC chemokines, ensuring clearance of neutrophils, and simultaneously promoting the secretion of the CC chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and RANTES, triggering the recruitment of mononuclear leukocytes and regulate the process of apoptosis. The IL-6/sIL-6R signaling also selectively promotes T cell recruitment into the peritoneal membrane through a gp130-dependent, STAT1/3-dependent activation pathway (as shown in **Figure 3**).

The most consistent change observed in peritoneal tissues of a patient on PD is an increase in the sub-mesothelial thickness associated with peritoneal fibrosis.

#### **Figure 3.**

*Molecular network that regulate EMT [5]. Courtesy: Gonzalez 2016. Abbreviations: TGF ß—Transforming growth factor ß; GF—growth factor; TKr—Tyrosine kinase receptor; IL-6—interleukin 6; and EMT/MMT— Epithelial/Mesothelial to mesenchymal transition.*

#### **Figure 4.** *Key events during EMT (Courtesy: [6]).*

*Preservation of Peritoneal Membrane Structure and Function in Peritoneal Dialysis DOI: http://dx.doi.org/10.5772/intechopen.111586*

**Figure 5.** *Natural history of peritoneal membrane changes (Courtesy: [5]).*

The use of non-physiologic PD solutions along with uremic milieu, has led to the production of advanced glycation end products (AGEs) in peritoneal tissues which induces vasculogenesis and fibrosis. The interaction between fibrosis and angiogenesis may occur at the level of inducing cytokines; TGF-ß leading to SMAD pathway and inflammatory cytokines induce VEGF and angiogenesis; this is how EMT (epithelial to mesenchymal transition)/MMT (mesothelial to mesenchymal transition) occurs (shown in **Figure 4**).

There are two pathologic types of PD related fibrosis. Most common type is simple peritoneal sclerosis which is seen in almost all patients. The other one is Encapsulating peritoneal fibrosis (EPS) that evolves rapidly with intense fibrosis and inflammation leading to life threatening visceral encapsulation (as shown in **Figure 5**).
