Pathological States and Alterations in the Peritoneal Transport System

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Metastatic Cancer in the Peritoneum

In the patient undergoing intraperitoneal chemotherapy, the peritoneum has been altered by metastasis of the primary tumor. The subdiaphragmatic lymphatics may become obstructed, and the outflow of cellular materials, protein, and fluid may be markedly decreased. In addition, metastasis to the liver may cause an increase in transhepatic ascitic fluid production, which, coupled with the loss of outflow through subdiaphragmatic lymphatics, will result in accumulation of fluid in the peritoneal cavity and marked distention of the abdominal wall with an increase in intraperitoneal volume and pressure. Additionally, metastasis to specific areas of the peritoneum will cause the mesothelium to be altered and will result in adhesions between the parietal and visceral peritoneum or between tumor and normal peritoneum. This leads to reduction of peritoneal volume, dysfunction of the gastrointestinal tract, decreased access of a therapeutic solution to the entire peritoneum, and nonuniform distribution of the peritoneal fluid in the cavity. The presence of ascitic fluid and extensive adhesions decreases the effectiveness of intraperitoneal chemotherapy. Only with radical peritoneal surgery can the cavity be restored to a state appropriate for treatment of metastatic abdominal cancer. Recent evidence has shown that peritoneal stripping of intra-abdominal carcinomatosis results in restoration of the distribution of the therapeutic solution and the anticipated rates of mass transfer across the peritoneum.

Chronic Inflammation from Sterile Dialysis Solutions

With the use of the peritoneal cavity as a dialysis system, the requirements are significantly different from those of chemotherapy, and the types of pathology that alter the tissue barrier are somewhat different. Although some patients have had prior cases of peritonitis or abdominal surgery that have produced adhesions, the vast majority of peritoneal dialysis patients do not have the same problem that patients with peritoneal carcinomatoses have. Over the past 10 years knowledge has grown concerning the chronic state of inflammation that the peritoneum experiences with long-term, continuous peritoneal dialysis. The solutions, which typically have a low pH, a high osmotic pressure due to glucose, and glucose degradation products from heat sterilization, have been shown to cause significant changes in the peritoneum, subperitoneal interstitium, and transport microvasculature. The high glucose content, which varies from 15 to 42.5 g/L, sets up a diabetic state within the cavity. Twenty-four hours a day the mesothelium is bathed with these solutions. The resident macrophages in the peritoneal cavity and the mesothelial cells have both been shown to react to these glucose solutions. Human studies have demonstrated that in as little as 8 months, the peritoneal mesothelium changes from an epithelioid cell type to a fibroblastic phenotype. This is not due to repeated infective peritonitis but merely constant exposure to sterile, hypertonic solutions. Although the low pH and hyperosmolality have been implicated in these changes, current evidence points to glucose degradation products and glucose itself. Biopsy studies of long-term peritoneal dialysis patients have shown that the submesothelial compact zone, which is typically less than 60 to 80 mm thick, increases in thickness to as much as 2,000 mm after 6 to 7 years. Simultaneously, the degree of angiogenesis and vasculopathy in the layer directly under this subcompact mesothelial layer increases in approximately 90 percent of patients after 6 years of exposure. The rate of solute transfer is often enhanced while the rates of fluid removal with osmotic ultrafiltration are markedly depressed. This results in loss of capacity to remove fluid from the patient and necessitates an alternative mode of therapy.

Peritoneal Inflammatory Response

Figure 5 illustrates the peritoneal cellular system and some of the mediators of the inflammatory cascade. Mesothelial cells overlie the connective tissue of the peritoneum, and within the tissue space, there are fibroblasts, muscle (parenchymal) cells, and endothelial cells. The glucose solutions stimulate the production of interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFa) and the peroxidatic activity of macrophages that reside in the peritoneal cavities of dialysis patients. Mesothelial cells also respond directly to glucose solutions and spontaneously release hydrogen peroxide, IL-1, and TNFa. Whereas in vitro exposure of mesothelial cells to low pH dialysis solutions causes marked toxicity, these solutions are buffered in 10 to 15 minutes in vivo. Therefore the solution pH may not be a major factor in a chronic inflammation. However, bicarbonate-buffered solutions have been shown to decrease production of transforming growth factor-1 (TGFb-1) and to improve the overall health of the mesothelium. The muscle cell endothelial cell fibrinogen NOS firbronectin albumin,lgs chemokines PGs

MCPs, ILs PGs, Rantes mesothelial

PGs, interleukins ■> hyaluronan, CA MCP-1, RANTES

muscle cell

PGs, interleukins ■> hyaluronan, CA MCP-1, RANTES

CA125,VEGF TNFa macrophage

PD Solution (glucose, GDPs)

fibrinogen NOS firbronectin albumin,lgs chemokines PGs

MCPs, ILs PGs, Rantes

Figure 5 Cellular system in peritoneal inflammation. Dialysis solutions in the peritoneal cavity contain glucose and glucose degradation products (GDPs) that activate macrophages and mesothelial cells to secrete numerous cytokines. These in turn stimulate fibroblasts and attract leukocytes to migrate through activated endothelium. This chronic inflammatory process results in scarring of the subperitoneal tissue and vasculopathy in the parenchymal vessels. See text for definitions of cytokine acronyms. (see color insert)

CA125,VEGF TNFa macrophage fibroblast

PD Solution (glucose, GDPs)

Peritoneal cavity

Figure 5 Cellular system in peritoneal inflammation. Dialysis solutions in the peritoneal cavity contain glucose and glucose degradation products (GDPs) that activate macrophages and mesothelial cells to secrete numerous cytokines. These in turn stimulate fibroblasts and attract leukocytes to migrate through activated endothelium. This chronic inflammatory process results in scarring of the subperitoneal tissue and vasculopathy in the parenchymal vessels. See text for definitions of cytokine acronyms. (see color insert)

mesothelial cells, once stimulated by glucose or by the IL-1 and TNFa from stimulated macrophages, produce prostaglandins, interleukins, hyaluronan, cancer antigen 125 (CA125, a marker for mesothelial cell number), monocyte chemoattractant protein (MCP-1), RANTES, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and TGFb-1. In vivo gene transfer of an active TGFb-1 into rat mesothelium via an adenoviral vector resulted after 7 days in a markedly thickened peritoneum with increased vascularization and extensive collagen deposition. The infected animals demonstrated an increased transport of solutes and decreased ultrafiltration in response to hypertonic solutions.

Stimulated fibroblasts produce a series of cytokines as well as hyaluronan and collagen. It is likely that they play a major role in the fibrosis in the subcompact area of the peritoneum during long-term peritoneal dialysis. Coupled to cells in the interstitium are activated endothelial cells in the vessels through which white blood cells pass through the endothelium into the tissue space. Nitrogen oxide synthetase (NOS) has been shown to be upregulated and to result in a state of vasodilation. A constant state of hyperosmolality due to high glucose concentrations essentially sets up a diabetic state within the tissue, with the possible formation of advanced glycation end products. These are correlated with many of the fibrotic and angiogenic changes within the tissue. Whether parenchymal muscle cells or other cells such as pericytes associated with endothelium within the tissue take part in this product state of inflammation is unknown.

Intravital microscopy has recently been used to analyze the vasoactive effects of peritoneal dialysis solutions on the mesenteric vessels. Low-GDP solutions have caused transient vasodilation, whereas conventional 4.25 percent dextrose solutions result in maximal vasodilation, doubling of the arterial flow, and a 20 percent increase in perfused capillary length/area. Neutral, lactate-buffered solutions had only transient effects. Peritoneal NOS has been shown to rise fivefold in long-term dialysis patients. It also correlated with increased vascular density and endothelial area in biopsies. VEGF was colocated in the peritoneal endothelium with advanced glycation end products. Filtered dialysis solutions contain far less of the glucose degradation products that occur with heat sterilization. Treatment of patients with these more biocompatible solutions typically produces lower concentrations of hyaluronan (a marker of inflammation) in the peritoneal dialysate, higher concentrations of CA125, and higher concentrations of procollagen-1-C peptide and procollagen-3-N-terminal peptide.

In summary, mesothelial cells that are continually exposed to the high concentrations of heat-sterilized, glucose-based peritoneal dialysis undergo a cellular transition from an epithelial cell type to a fibroblastic pheno-type. High levels of TGFb-1 and VEGF appear to promote fibrosis and angiogenesis in these subperitoneal tissue spaces. Attempts to block specific modulators of this inflammatory system have resulted in decreased proliferation in vitro. In vivo investigation will likely proceed in the next several years.

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