Host Defense Mechanisms in Chronic Ambulatory Peritoneal Dialysis- Associated Peritonitis

Mark Harrison and William Keane

From the Department of Medicine, and the Division of Nephrology, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota

The proponents of continuous ambulatory peri- toneal dialysis (CAPD) can easily outline the many advantages of this technique, but all would agree that infection is the' most frequent complication ( 1-4). These infections include bacterial and fungal peri- tonitis and catheter tunnel as well as exit site infec- tions. Initially, a high incidence of peritonitis was seen in CAPD patients; however, with technical and training advances, the incidence has decreased to 1.4 episodes per patient year (3). Approximately 25 to 30% of patients are withdrawn from CAPD because of this complication (4). Those patients transferred to alternate ESRD therapies have had a 1.5- to 3- fold higher rate of peritonitis (4). Critical to the continued success of CAPD will be a further decline in the incidence of this complication. A better un- derstanding of the risk factors, pathogenesis, and treatment of peritoneal infections is therefore of great importance.

Clinical-Epidemiological Aspects

Various studies have identified a number of risk factors pertaining to the development of CAPD per- itonitis (Table 1). Diabetic patients have been re- ported to have a higher incidence of peritonitis, although this has not been a universal finding (4-7). The presence of intraabdominal pathology such as diverticular disease also increases the risk of perito- nitis (8). In some patients, infection of the catheter tunnel or exit site are presumed loci for development of peritonitis (8). Interestingly, a lower incidence of CAPD-related peritonitis in patients over 60 years of age has been noted (9). These elderly patients have a higher concentration of IgG in peritoneal dialysis eflluent, possibly explaining this observation (9).

The microbial spectrum in CAPD-related perito- nitis tends to be fairly limited. The most commonly isolated organisms are coagulase-negative staphylo- cocci, representing 40 to 60% of infection. S. aureus, streptococcal species, and Gram negative bacteria

Address correspondence to: Mark Harrison, MD, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue South. Minneapolis, MN 55415. Seminars in DiOlysis-Vol2, No 2 (Apr-Jun) 1989 pp 117-121

are less frequent isolates (10, 11). A minority of peritoneal infections occur as a result of an intraab- dominal event such as diverticular disease, acute cholecystitis, ischemic bowel, or perforated viscus. The presence of Gram negative enteric pathogens or enterococci in peritoneal dialysate eflluent is a clue to these diseases. Fungal peritonitis is a wellde- scribed, serious cause of peritonitis which usually requires catheter removal for effective treatment ( I 2). Fortunately, fungal peritonitis is a relatively uncommon cause of CAPD-associated peritonitis.

An understanding of the pathogenesis of CAPD- associated peritonitis assumes considerable impor- tance in designing approaches to reduce this com- plication. An expanding body of literature has accumulated evaluating peritoneal host defense mechanisms. Particular attention to an understand- ing of cellular and humoral defense against microbial invasion has provided potential methods to prevent peritonitis.

Peritoneal Catheters and Biofilm

The development of the permanent peritoneal di- alysis catheter was of major importance in the evo- lution of CAPD as a practical dialysis method. A consequence of the placement of a peritoneal cath- eter is disruption of the peritoneal cavity integrity. The major portal of entry of microbes into the peritoneal cavity is probably migration around the catheter insertion site ( 13- 15). Catheter exit site and tunnel infections are events frequently associated with recurrent peritonitis and catheter failure. Fur- ther modifications of catheter design, materials, and implantation techniques could probably reduce the rate of peritonitis. CAPD dialysate exchange tech- nology has also evolved in an attempt to reduce peritoneal microbial contamination by the patient.

Another potential pathogenic mechanism that could contribute to peritonitis is the development of catheter biofilm (1 3- 16). Biofilm has been charac- terized as an adherent substance primarily composed of microbial-produced extracellular polysaccharides (EPS). The catheter becomes colonized after inser- tion with microbial contaminants which improve their adherence capability by synthesizing EPS and forming biofilm. Several studies have documented the presence of biofilm on CAPD catheters (17).

117

118 Harrison a n d Keane TABLE 1. Risk factors in CAPD peritonitis

Poor patient compliance Lower socioeconomic status Altered peritoneal host defense mechanisms Intraabdominal pathology Catheter-related infections Diabetes mellitus (?) Catheter biofilm (?)

These catheters were noted to be coated with biofilm in patients, regardless of peritonitis history. Thus, at present, no clear relationship between the presence of biofilm on CAPD catheters and peritonitis has been developed.

An in vitro model of S. epidermidis biofilm grown on silicone to mimic peritoneal dialysis catheters has been developed. The organisms in this biofilm dem- onstrate a high degree of resistance to concentrations of vancomycin well above their MIC, indicating the resistance of this material to standard antimicrobial therapy (18). It has also been suggested that the ability of coagulase-negative staphylococci to pro- duce biofilm might be an important feature that would correlate with their ability to induce perito- nitis (19, 20). However, no consistent pattern has emerged in which the ability to produce biofilm correlates with microbial pathogenicity (2 1). Inter- estingly, this material seems to have adverse effects on a variety of phagocyte and lymphocyte functions (22). Extrapolation of these in vitro observations to the complex interactions leading to peritonitis in patients is, at present, difficult.

Newer connection devices, such as the Y system, use chemical disinfectants in an attempt to decrease contamination of the catheter and peritoneal cavity (23). These agents may also have an effect on biofilm production as well (24).

The role of biofilm in alterations of peritoneal host defense mechanisms has yet to be fully elucidated. Future research in the area of biofilm and its inter- action with peritoneal host defense should shed some light on this interesting aspect of CAPD-associated peritonitis.

Mechanisms of Phagocytosis

The host defense mechanism uses specialized cel- lular and humoral processes to facilitate the recog- nition and phagocytosis of invading pathogens (25). Phagocytic cells, primarily macrophages and neutro- phils, are attracted to an area of infection by chemo- taxis. The recognition and phagocytosis of these invaders is assisted by opsonins. The best understood mechanisms of opsonization involve immunoglob- ulins and complement. Specifically, IgG, a heat- stable opsonin. is primarily involved in facilitating phagocytosis of Gram positive bacteria. The opsonic activity of IgG most likely represents the interaction of subtypes of IgG specific for cell surface antigens. Once attached to the bacterium, the F, portion of IgG attaches to F, receptors on the phagocytic cell surface. Similarly, when complement, a heat-labile opsonin, becomes activated on the microbial cell

surface, the generation of C3b facilitates attachment to this receptor on the phagocytic cell surface. Meat- labile opsonins are important in handling Grab negative bacteria and fungi.

After attachment to the phagocytic cell, microor- ganisms are internalized within a phagocytic vacuole where the process of killing and degradation occurs. In addition, soluble lymphomonokines serve to reg- ulate and amplify the immune response. Each of these various steps in the immune response has been evaluated in relation to the peritoneal cavity to de- termine if alteration in host defenses are operative in the pathogenesis of CAPD-associated peritonitis.

Peritoneal Phagocytic Cells

The normal peritoneal cavity contains less than 50 ml of a clear fluid which contains about 150,000 cells (26). This fluid is in a dynamic state, being continually taken up by subdiaphragmatic lymphat- ics. Peritoneal fluid obtained from uninfected CAPD patients contain roughly 24 x lo6 cells dispersed in 2 liters (26). In both normal peritoneal fluid and peritoneal dialysis effluents, 70 to 80% of the cells are macrophages (26). There are, however, 2- to 3- fold more lymphocytes in peritoneal dialysis effluent compared to normal peritoneal fluid obtained from women at laparoscopy (27). The significance of these cells in CAPD patients is incompletely understood, although recent experimental data suggest that they may have a role in immune modulation of peritoneal cells.

Several studies have attempted to evaluate the effect of peritoneal dialysate on cellular function. An early study noted that fresh peritoneal dialysate sup- pressed phagocytosis of peripheral blood polymor- phonuclear leukocytes (32). This effect decreased when dialysate was allowed to equilibrate in vivo, suggesting suppression from low dialysate pH and high osmolality. Indeed most studies have demon- strated that spent dialysate does not adversely affect leukocyte function (33).

Phagocytic cells derived from peritoneal dialysis effluent have also been evaluated (34). Phagocyte function and, to a lesser degree, cell viability are diminished in unused dialysate, and these effects are directly related to dwell time. These findings suggest that factors removed and/or added with increasing dwell time are important to phagocytic cell function. Indeed, the addition of normal serum to unused dialysate dramatically improved phagocytic cell function, suggesting an important role for serum derived opsonins (28, 29, 35).

Phagocytic Function of Peritoneal Macrophages

Of major importance in evaluation of the perito- neal host defense mechanisms are the phagocytic and killing abilities of peritoneal macrophages (PW) and neutrophils. PM0 obtained from uninfected pa- tients as well as monocytes derived from their cir-

CAPD A N D PERITONITIS 119

culation have been evaluated using both S. epider- midis and E. coli isolated from CAPD patients with peritonitis (26, 28, 29). When opsonized with IgG, S. epidermidis can be readily phagocytized, indicat- ing the importance of a heat-stable opsonin system and, presumably, F, receptor mediated phagocytosis. E. coli, when opsonized with pooled normal human serum as a source of complement, is also readily phagocytized. These data support the contention that the C3b receptor of phagocytic cells is important for phagocytosis of E, coli.

Immunologic defenses are blunted in the uremic patient, including both cellular immunity and phag- ocytic function. Most uremic patients appear to re- cover immunologic function with initiation of CAPD (30). There is, however, a subgroup who continue to have an immunological defect despite adequate treatment of their uremia. These patients appear to be at higher risk for CAPD-associated peritonitis.

Microbicidal Capacity of Peritoneal Macro phages

The final step in the removal of pathogens involves intraphagocytic cell killing. The ability of PM0 to ingest and kill S. epidermidis and E. coli has been evaluated (26, 36). Initially, PMO from uninfected patients were used to evaluate killing of different microbial species. These studies did not demonstrate any important defect in microbial killing (26). Sub- sequently, several studies have demonstrated dimin- ished intracellular killing of certain strains of S. aiireus and S. epidermidis (36-39). These organisms may survive intracellularly where they escape the effects of most antibiotics. Eventually these phago- cytic cells may die, and with cell lysis, release the surviving organisms into the surrounding milieu. Intraphagocytic cell survival of staphylococci has been postulated as a mechanism of relapse in CAPD- associated peritonitis with these organisms (36). The use of antibiotics which penetrate cell membrane such as rifampin and clindamycin may be beneficial when used in the setting of relapsing staphylococcal peritonitis (39, 40).

More recently, intraphagocytic killing of staphy- lococcal species was found to be abnormal in studies of PM0 from patients with an increased incidence of peritonitis (36, 41). The clinical significance of this finding is supported by the correlation of these phag- ocytic cell defects and the incidence of peritonitis (36). One potential mechanism for diminished intra- cellular killing was a decreased production of reactive oxygen species, particularly hydrogen peroxide, by these cells.

Data continue to emerge documenting the patho- genicity of fungal species as a cause of CAPD-asso- ciated peritonitis (12, 42). Considerable difficulties are encountered when PM0 cells are called upon to kill fungal pathogens. Compared to circulating PMN's and monocytes. PM0 from CAPD patients or from laparoscopy appropriately ingest candida

opsonized with pooied human serum (43). However, once phagocytized, intracellular killing of candida by PM0 is considerably less compared to that of circulating cells but greater than laparoscopyderived PMB(27).

Opsonic Activity of Peritoneal Dialysis Effluent

Opsonins are a necessary component of the nor- mal host defenses against infection. Proteins with opsonic activity include IgG, C3, and fibronectin (28, 44, 45). The importance of IgG and C3 in opsonization has been discussed previously. The role of fibronectin in phagocytosis is uncertain; however, it does bind to staphylococci, and a fibronectin recep- tor on the phagocytic cell has been described (46, 47, 48). A lower fibronectin concentration in peri- toneal dialysis emuent may be associated with a higher incidence of peritonitis in CAPD patients (48a).

Several studies have suggested that low levels of opsonin in the peritoneal cavity during CAPD is a major pathogenic factor in the development of per- itonitis (28, 49-52). The most likely reason for re- duced concentration of opsonin in peritoneal dialysis emuent is a dilutional effect from instillation of opsonin-free peritoneal dialysate into the abdominal cavity. Measurement of IgG and C3 levels in peri- toneal dialysis emuent have been found to correlate with opsonic activity (29). These levels are usually quite low and may serve to limit the phagocytic ability of PMO in defense against microorganisms.

Relationship Between Peritonitis and Opsonic Activity

Although the intraperitoneal opsonin levels are important in phagocytosis and a low IgG level is associated with diminished ability to phagocytize Gram positive bacteria, the presence of a high IgG level is not always associated with enhanced phago- cytosis (28). Other qualitative factors, such as anti- body specificity, probably play a role. Indeed, these observations may in part explain the preliminary reports of successful prevention of peritonitis with active immunization (53).

Multiple studies have confirmed a relationship between opsonin activity and the incidence of peri- tonitis (28, 49-52). The concentration of IgG in peritoneal dialysis emuent has been found to in- versely correlate with the incidence of peritonitis in CAPD patients. Levels of IgG and C3 are substan- tially lower in peritoneal dialysis emuent than in serum, and the dialysate concentrations vary from patient to patient. Studies suggest that IgG levels less than 8 to 10 mg/dl in the overnight exchange are associated with a higher incidence of peritonitis.

In a study comparing CAPD patients with a low incidence of peritonitis to those with frequent peri- tonitis, the peritoneal dialysis effluent of the former opsonized S. epidermidis better than peritoneal di- alysis emuent from the latter and, in fact, did so as

120 Harrison and Keane

well as serum (54). There was no difference in serum IgG levels between the two groups, but dialysate IgG levels were higher in those patients with a lower incidence of peritonitis. This suggests that, in part, the pathogenesis of peritonitis may be related to deficient opsonization. As a result, it was suggested that passive immunization of the peritoneal cavity could provide an important preventive approach in reducing the incidence of peritonitis in the high-risk CAPD patient (29,54). Indeed, when human IgG is added to peritoneal dialysate to provide opsonically active substances, phagocytic cells respond to micro- bial challenges in a more usual fashion (28, 29).

Peritoneal Instillation of lgG

Several small and preliminary clinical trials have evaluated the efficacy of instillation of IgG into the peritoneal cavity. In one, six patients with frequent peritonitis and low peritoneal dialysis emuent IgG levels were treated for 18 months with intermittent intraperitoneal IgG and had a nearly four-fold de- crease in the incidence of peritonitis (54). More recently, the daily instillation of IgG in the overnight exchange significantly reduced the incidence of per- itonitis with Gram positive organisms (55). In both trials, the patients tolerated intraperitoneal IgG well. These studies suggest that the patients at risk for Gram positive peritonitis can be identified by their low peritoneal dialysis emuent IgG concentration and, thus, may be candidates for prophylactic ther- apy. The beneficial effects of intraperitoneal IgG may involve humoral and cellular effects. Additional con- trolled, prospective studies are needed to clarify whether IgG therapy will have a role for prevention of CAPD peritonitis.

Immune Modulation of Peritoneal Cells

Recently, studies have been performed to better understand the nature of the peritoneal cellular de- fect associated with frequent episodes of peritonitis. Briefly, the major regulatory system of the immune response involves production of lymphomonokines which act to amplify or suppress the activity of phagocytic cells. These substances include Interleu- kin- 1, Interleukin-2, prostaglandin-E2, and inter- feronq (IFN-7).

Preliminary investigations have demonstrated that the lymphocyte proliferative response to lympho- kines is suppressed in the presence of CAPD-PMO (56). Subsequently, it was shown that PM0 from patients with frequent peritonitis have an exagger- ated production of PGE2 and reduced production of IL- 1, both tending to suppress IFN--y production by lymphocytes (36,4 1,57). IFN-7 is known to activate macrophages so it is not surprising that this decrease in IFN-7 production is associated with a decreased PMO F, receptor expression and reduced intracellu- lar killing. Importantly, when CAPD-PM0 are in- cubated with IFN-7 an increase in killing activity and macrophage F, receptor expression occurs. Fu-

ture studies will be aimed at determining the clinical use of immune modulating substances in the preven- tion of CAPD-associated peritonitis.

CAPD has assumed an increasingly important role in the management of end-stage renal disease. The pertubations of host defense which occur in the peritoneal cavity milieu are being identified. Further insight into these immunologic processes will, it is hoped, aid in the development of effective measures for the prevention of CAPD-associated peritonitis.

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