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Part 7: Protection of Peritoneal Membrane |
Department of Nephrology, Haseki Training and Research Hospital, Istanbul, Turkey
Correspondence to: R. Kazancioglu, Haseki Egitim ve Arastirma Hastanesi, Nefroloji Klinigi, Haseki Aksaray 34330 Istanbul, Turkey. drkazancioglu{at}yahoo.com
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ABSTRACT |
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 TOP ABSTRACT CONCLUSIONSREFERENCES |
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It remains to be determined whether the peritoneal dialysis procedure
induces abnormalities in the normal host defenses of the abdominal cavity and
whether these perturbations are important in the pathogenesis of peritonitis.
The peritoneum is a smooth membrane that lines the abdominal cavity and
participates in the diffusion of water and solutes during peritoneal dialysis.
The diaphragmatic lymphatic uptake and the opsonization of micro-organisms,
with phagocytosis and killing by peritoneal macrophages, mesothelial cells,
lymphocytes, polymorphonuclear leukocytes, and newly defined proteins such as
defensins, play a combined role in the peritoneal host defense. Because the
composition of earlier peritoneal dialysis fluids is clearly non-physiologic,
continuous exposure of peritoneal cells to these solutions may result in an
impairment of the local peritoneal host defense mechanisms. However, with the
newer solutions, it has been shown that peritoneal defense mechanisms may
improve.
KEY WORDS: Host defense; opsonic activity; intracellular microbial killing; bacteriostatic activity.
The peritoneum is a smooth, translucent membrane that lines the abdominal cavity and participates in the diffusion of water and solutes during peritoneal dialysis (PD). This membrane is composed of a compact surface layer of mesothelial cells beneath which lies a network of capillary and lymphatic vessels (1). It remains to be determined whether the PD procedure induces abnormalities in the normal host defenses of the abdominal cavity and whether these perturbations are important in the pathogenesis of peritonitis. The diaphragmatic lymphatic uptake and the opsonization of micro-organisms, with phagocytosis and killing by peritoneal macrophages, mesothelial cells, lymphocytes, polymorphonuclear leukocytes, and the newly defined proteins called defensins, play a combined role in the peritoneal host defense (2).
Although diffusion occurs across the entire peritoneal membrane, particulate matter is absorbed chiefly through the lymphatics. In 1944, Steinberg showed that 50% of bacteria injected into the peritoneal cavity in experimental animals appeared in the thoracic duct within 6 minutes and in the blood within 12 minutes [as cited in Brulez and Verbrugh (2)]. Dunn et al. found that ligation of the thoracic duct led to significantly higher numbers of organisms remaining in the peritoneal cavity (3).
The role of peritoneal lymphatic drainage in antibacterial defense was suggested by Glancey et al. (4) during their study analyzing the effect of residual intraperitoneal dialysate volume. All of the available data suggest that peritoneal lymphatics are important in the removal of bacteria from the peritoneal cavity. However, PD interferes with normal mechanisms of lymphatic absorption and thereby impedes the passage of pathogens into the systemic circulation (4). This defect in normal lymphatic function is most likely a result of mechanical factors associated with the instillation of large volumes of fluid into the abdominal cavity (2).
For host defense, recognition and phagocytosis of micro-organisms by peritoneal macrophages is promoted by the coating, with opsonins present in the peritoneal fluid, of the micro-organisms that have entered the peritoneal cavity (2,5). As a result of dilution and removal during PD, the concentration of opsonins in peritoneal effluent is substantially decreased (2,5). In comparison with the normal situation, the titer of opsonins in peritoneal effluent from PD patients was found to be lower by a factor of about 50 – 100. Because the concentration of opsonins rises with increasing intraperitoneal dwell time, a positive correlation is seen between opsonic activity and dwell time (6).
The dialysate type can also influence opsonic activity. When opsonic activity with a 2.27% glucose-based PD solution was compared with activity with a 1.1% amino-acid-based solution after a 4-hour dwell in vitro, bacterial uptake after opsonization of a Staphylococcus epidermidis strain was found to be less in the amino-acid-based effluent (7). The authors of the study suggested that some amino acids from the dialysate could inhibit the classical and alternative pathways of complement activation, leading to lower opsonic activity (2).
It has also been demonstrated in vitro that at least 525 macrophages per milliliter are needed to suppress bacterial growth (8). However, effluent obtained from PD patients contains approximately 104 cells per milliliter (2,8). Fluid exchanges result in dilution and loss of cells. Another hypothesis assumes that polymorphonuclear leukocytes from PD patients are in a state of chronic activation because increased expression of Fc and C5a receptors and enhanced antigen expression of human leukocyte antigen (HLA) DR, HLA DQ, and CD14 are established (2,8).
The peritoneal membrane contributes to inflammation by generating
prostaglandins and cytokines in response to release of tumor necrosis factor
(TNF) and interleukin 1 by polymorphonuclear leukocytes or
directly to (parts of) bacteria
(9). The membrane can also trap
some micro-organisms and recruit peritoneal macrophages
(2).
Lymphocytes are also among the elements of host defense. In the normal peritoneal cavity 5%–10% of the white blood cells are lymphocytes (8). In PD patients, lymphocyte percentages in PD effluent have been found to range between 5% and 77% (2,8). As the disproportion of lymphocytes in PD effluent increases, the cells appear to be functionally impaired, with a significantly lower IL-2 production than is seen with peripheral lymphocytes (8).
The process of PD itself and peritonitis episodes damage the peritoneum. The defensin system could be of significant value against PD-associated peritonitis (10). Defensins are cationic 3 – 5 kDa antimicrobial peptides with a broad spectrum against many bacteria. Grupp et al. (10) demonstrated that many defensins are present in the normal and damaged peritoneum, but that defensin expression is insufficient in PD patients mostly because of PD solutions and reduced mesothelial cell count.
The data generated from in vitro biocompatibility studies have generally substantiated the hypothesis that conventional, glucose-containing PD solutions have deleterious effects on leukocytes and mesothelial cells, contributing to an impaired peritoneal defense. The composition of most PD fluids is clearly non-physiologic because of low pH, hyperosmolality, and high glucose and lactate content; it has therefore been suggested that continuous exposure of peritoneal cells to the same solutions may result in an impairment of the local peritoneal host defense mechanisms. Many in vitro studies have shown adverse effects of PD solutions on various leukocyte functions (11). Some of the studies have identified the initial low pH of the solutions and the lactate buffer as being of primary importance. By contrast, some studies have shown the importance of hyperosmolality and excessive glucose concentration (11). Peritoneal macrophages isolated from effluents tested in vitro have demonstrated impaired function under various conditions. When tested at the original solution pH, respiratory burst activity, phagocytosis, bacterial killing, and cytokine production and release functions are impaired (11).
Furthermore, infection per se, its associated inflammation, and exposure to conventional solutions can all contribute directly or indirectly to changes in peritoneal membrane structure and function (12). This challenge has led in the past to the development of new solutions designed with improved biocompatibility as their striking feature (12).
Posthuma et al. (11) followed 38 patients (19 on glucose solution, 19 on icodextrin solution) for a median of 17 months. Peritoneal defense characteristics and PD-related infections were recorded every 3 months. This long-term clinical study provided evidence that the use of icodextrin solution did not result in deterioration of peritoneal defense determinants more than was seen with glucose, and icodextrin had a positive effect on some aspects of the peritoneal defense system—for example, an increase in absolute numbers and percentages of effluent peritoneal macrophages, which persisted even after 2 years (11).
The solution buffer also plays a role in host defense as important as that with the lack of opsonins and the presence of uremic toxins (13). The conventional buffer, lactate, is inferior to pyruvate on polymorphonuclear cells in vitro and to bicarbonate on peritoneal macrophages ex vivo (11).
A crossover study approved by the Committee of Research Ethics at the Helsinki University Hospital was conducted between January 2001 and January 2003 in 22 patients with a PD duration of 1.5 – 6.3 months (14). All patients were on continuous ambulatory PD and for the first 8 weeks they used either amino-acid-based PD solution or icodextrin. Then, after an 8-week washout period, the patients were started on the alternative solution not used in the first half of the study. An increase in cancer antigen 125 (CA125) during the use of each study solution was observed, indicating a positive effect on mesothelial cells and better preserved host defense (14).
The effect of neutral pH, bicarbonate/lactate–buffered PD on the
peritoneal host defense was examined by Rogachev et al.
(15). Peritoneal macrophages
were exposed to test solutions for 15 – 30 minutes and were then
transferred to growth medium. Secretion of TNF was measured. Use of 1.5
bicarbonate/lactate improved peritoneal macrophage response at both time
points with a significant change from control only at 30 minutes. Thus it was
concluded that bicarbonate/lactate–buffered solutions are more
biocompatible with regard to peritoneal macrophage function, maintaining pH
closer to physiologic levels and preserving cytokine secretion in response to
endotoxins (15).
A more recent study was designed to compare local peritoneal and systemic inflammatory effects of a conventional lactate-based PD solution and a new biocompatible bicarbonate/lactate–based solution having a low concentration of glucose degradation products (GDPs) (16). This prospective, open-label randomized study with a crossover design of two parallel arms compared a standard low-pH lactate-buffered PD solution, Dianeal (Baxter Healthcare, Castlebar, Ireland) with a new physiologic-pH bicarbonate/lactate–buffered PD solution low in GDPs, Physioneal (Baxter Healthcare). The patients were randomized to either 3 months of treatment with Dianeal or to 3 months of treatment with Physioneal. After 3 months, patients switched therapies during further 3 months of treatment. The primary study endpoints were the levels of expression of HLA DR and CD14 molecules on peritoneal macrophages in the dialysis effluent. The secondary endpoints were the changes in serum concentrations of IL-6 and C-reactive protein, appearance rates of IL-6 and CA125 in the dialysis effluent, and concentrations of peritoneal cell types in the dialysis effluent (16). Compared with dialysis using Dianeal, dialysis using Physioneal produced less macrophage cell death and thus contributed to a better state of the defense cells populating the peritoneum (16).
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CONCLUSIONS |
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TOPABSTRACTCONCLUSIONSREFERENCES |
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production by peritoneal macrophages.
Perit Dial Int 1997;17
: 546-53.
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