Factors Increasing Severity of Peritonitisin Long-Term PeritoneaI Dialysis PatientsMinSunPark

Peritonitis is the most frequent complication and a leading cause of discontinuation of peritonealdialysis (PO). Intact epithelial lining, sufficient blood flow, and adequate immunologic responses arevital to eradicate infection. In long-term PO, various pathological.changes such as denudation ofperitoneal mesothelial cells, duplication of submesothelial and/or capillary basement membranes,submesothelial fibrhl deposit, and peritoneal fibrosis have been reported. Causes of these changes ofthe· peritoneum· are ·mulfiféicto·rlili:Commonly used dialysis solutions thatare acidic, hypertonic,containing high conceiifrationsofglücose and lactate, contaminatedby gluéose and/or plasticdegradat¡ollptb1:luCf~¡-¡lI'tr-not·biocompatible and rnayinduce ehronle immune reactionsintheperitoneal ca"ity. long-térmexp()sure of the peritoneum to dialysis solutions, the peritoneal catheter,and reeurrent episodes of peritonitis aUcontribute to peritoneal injury. In addition, long-term exposureofperitoneal cells such as macrophages, mesothelial cells, and fibroblaststo dialysissolutions mayalso alter the normal immunologic reactions against bacteria. Peritoneal concentrationsofopsonins

.... such.asJg, ..cClmplement,.anctpl"otease"are..approximately1%oftheserumJevels.,andfar.b.elowthe.levelsufficient to erilCficate bacteria dueto continuous peritoneal lavage and 'dilution with dialysis

. solutions. Furthermore, glycation of IgG induces chronic activation of macrophages and decreasesnormal opsonic activities against bacteria. Fibrin deposits, collagen accumulation, and cellular desertof the peritoneum observed in long-term peritoneal dialysis patients may serve as asafe shelter forbacteria from contact with inflammatory eells and opsonin and delay eradication of bacteria. Inconclusion, peritonitis is often more severe in patients on long-term PO. In this setting, peritonitisneeds special attention to prevent life-threatening infection and further damage of the peritoneum.e 1998 by the National Kidney Foundation, Inc.Index Words: Long-term peritoneal· dialysis; peritonitis; peritoneal structural changes; functionalchanges; host defense mechanism.

Peritonitis is the most frequent complica-tion and a leading cause of discontinua-

tion of peritoneal dialysis (PO).1-4Peritonitis inPO patients has several differences from thatin patients not receiving PO. In patients notreceiving PO, when the peritoneal cavity iscontaminated by bacteria, rapid proliferationof bacteria and inflammatorycell infiltrationoccurin theclosed cavity.5Fibrinexudationeff~~!i.y.eJy.c2:v'erstheinfe~t~g_N~ª."@,cIJ'r~-vents the spread of infection. Althóughlocal-ization of peritoneal infection is of help inpreventing systemic infection and providingsufficient time for surgical intervention, it actsas a safe shelter for bacteria from contact withinflammatory cells, opsonins, and antibioticsandeventually results in abscess formation."InPÚpatients,continuous Iavageof the perito-neal cavity with dialysis solutions is of help inremoying bacteria and preventing localizationoHnfection and abscess formation. Peritonitisin·PD .is, thetefore, easilycontrólled by usingappropriate antibioticsand doesnotusually

~~._ ..._. _...Ee9.l.li!~surgicalintervention.·· /As ..Péltiel1t and technique survival have

increased in PO, the number of patients onlong-term PO has increased as well. Structuraland functional alterations of the peritoneum inlong-term PO patients have been reported.The clínical manifestations of peritonitis inlong-term PO patients with<strúctural andfunctional alterations of the peritoneum maybe different from those with a normal perito-neum. However, no comparative study in thisregard has been reported to date., In this.-ré~lew~-thep6ss1ble~facfur:s1h~ít-iliterféie·Withprompt eradication of peritoneal infection andthat increase the severity of peritonitis inlong-term PO patients will be discussed.

.. Er9.w.JhdiYQnam KidneyLaboratory, 500n. Chun HyangUniversity, Seoul, Korea.

5upported in part by grants from Korea Research Founda-tion and an Extramural Grant jrom.Baxier.: ce

Address· correspomlence=iir-báirt Sun FUI k;--MfJ;-f'h:&,Assistant Professor '.0f.Medicine, Huonam.Kidneu. Laboratory,500n Chun Hyang UniversÚy, 657 Hannain~d(J1íg, Yongsan-koo; 5eoulNO-743,Korea.

© 1998 by the Naiional KidneycEoundatian;Inc ...1073-4449/98/0503-0005$3.00/0

Advances in Renal Replacement Therapy, Vol 5, No 3 (July), 1998: pp 185-193 185

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villi and cilium and phospholipids act as agood barrier against bacterial colonization ofthe peritoneum.

Reactive responses of the mesothelium todialysis, ie, cuboidal change of cellular shape,increased number of cells per unit area andincreased length of cellular junctions, anddiminution of microvillil! have been reportedin PD patients. Hyperplasia of cytoplasmicorganelles indicates the tissue' s adaptive re-sponse to constant removal of secretory prod-ucts in peritoneal effluent.P Mesothelial denu-dation is observed during active peritonitis16,17

due to permeation of exotoxins or endotoxinsfrom surviving colonies of organisms in oraround the peritoneal catheter.l" In sorne pa-tients, remesothelializatíon fails to occur andthis results in cellular desert."

The peritoneum is continuously exposed todialysis solutions containing unphysiologi-cally high concentrations of glucose duringPD. As a consequence, diabetic changes suchas thickening of basal lamina of the peritonealcapillaries are observed in nondiabetic continu-ous ambulatory peritoneal dialysis (CAPD)patients.16,19 Denudation of mesothelium aftersevere peritonitis may accelerate diabeticchanges in the peritoneum.'? In animal stud-ies, injection of dialysis solutions containing3.86% glucose intraperitoneally for 3 monthsresulted in denudation of mesothelial cells andwidening of the submesothelial space withoutactive peritonitis episodes (Fig 1).20 In thesame study, a group of rats given aminoguani-dine in drinking water during 3 months ofintraperitoneal injection of dialysis solutionsshowed almost intact mesothelial lining withround transformation (Fig 1).20 The observa-tion suggests that the long-term use of highglucose solutions results in accumulation ofadvanced glycosylation end products in theperitoneum and this is, in tum, responsible formesothelial damage in PD.

Loss of cilia and mícrovilli, denudation ofmesothelium,. and decreased concentration ofphospholipíds ~bserved in long':term-PDpa~tients may, therefore, be important predíspos-ing factors allowing bacteria to invade theperitóneummoreeasily-than-in patients withnormal peritoneum.

Min Sun Park

Mesothelial Cell Lining and Secretionof Phospholipids of the Peritoneum

The peritoneum is covered by a single layer ofmesothelial cells. Normal mesothelial cells areflat or discoid and covered by a thick mantle ofmicrovilli and a single motile cílium,"Mesothe-lial cells secrete surface active lubricant materi-als, phospholípids,? that prevent adherence ofthe slowly moving surfaces of intra-abdomi-nal organs. Phosphatidylcholine is the majorcomponent and phosphatidylserine, lysophos-phatidylcholine, and phosphatidylethanol-amine are minor components discovered inperitoneal effluent of PD patients." The concen-tration of phospholipids inperitoneal effluentis fairly consistent from patient topatlenf andlower in patients on long-term PD.9

Mesothelial cells are structurally and func-tionally similar to Type TI pneumocytes inrespiratory tracts that secrete surfactant.l? Bron-chíal trees are continuously exposed to variousnoxious materials such as air pollutants andmicroorganisms." Ciliary structures that coverbronchial epithelium are important in eliminat-ing noxious materials." Mucinous substancessecreted by epithelial cells covering bronchíaltrees are also important for protection of epithe-lial cells from outside stimuli and act as abarrier against bacterial colonization.!' Themost important complication resulting in astructural alterationand a defect in mucinsecretion is pulmonary infection.

The integrity of the epithelial lining cellsand covering mucinous substances are alsoimportant in the urinary tracto Inadequateurine flow, structural and functional urinarytract obstruction, and damage to the epitheliallining cells by urinary tract instrumentationare important predisposing factors in urinarytract infection.F Uromucoid, ie, Tamm-Horse-fall glycoprotein, secreted from tubular epithe-lial cells and detected in normal urine is amajor inhibitor of bacterial adhesion on uri-nary tract epithelial cells."

Peritonitis in PD patients is in sorne wayssimilar to respiratory and urinary tract infec-tions. Continuous lavage of the peritonealcavity allows elimination of bacteria from theperitoneal cavity and is similar to expectora-tion of bronchial secretions and urine flow.Intact mesotheliallining cells covered by micro-

Peritonitis in Long-Term Peritoneal Dialysis 187

Figure 1. Light mícroscopíc fíndings of the parietalperitoneum from Ilohiirufats (control; A)áIldratsafter intraperitoneal injectionof híglt glu-cúse dialy-sis solutions for3 mónthswíthoútjgroup 1;B) andwith (group 2; C) amfnoguanídíne in drinkingwater. A single layer of thin mesothelial cells (m),scanty amount collagen layers (co), a few fibroblasts(f) were noted in normal controlsj A]. Denudedmesothelium (dm), capillary proliferation (ca), andmonocyte infiltration (mo) were notedin group 1(B). Relatively intact mesothelial lining (m) withround transformation and irifiltration of monocytes(mo) were noted in group 2 (C). Hematoxylin eosinstaining, x150.

Figure 2. Iminunochemistry findings using AGE-specific antibody ()(parietal perltoneurnfrolIl.· ratsafterintraperitoneal injection of high glucose díalysis solutions for 3 monthsWithótifamihógliarticlifie:-SttóIlgpositive staining was noted in the entire submesothelial space (sm; A), in capillary wallsinthe submesothelialspace (csm; A) and in the muscularis layer (cm; B), and at the endomesium (e; B).

Glucoseand the PeritoneumA layer of areolar tissue composed of orientedbundles of collagen fibers and retiform elasticlaminae in a ground substance matrix under-

- lies-mesothelíal.Iiníng cells." N ormally, thesubmesothelial tissues are relatively acellularwith a few fibroblasts and mast cells and arenot hlghly vascularized." After several monthsof PD, reduplícation of both mesothelial base-

mentmembranearid.the basement membraneof the microvasculature of Í:he submesotheÍialstroma wereobserved.l,~In Aia1:>etic:-pa~ents,reduplicationef-the-baseméns membrane-w-asobservedonlyin themi!::rov:as~lature::butnotin the .mesothelial layer at the beginning ofperi toneal dialysis, g~c!~p!~~atio_n_Q!=-fi-1-~_sp.the-lial basement membranewas observed afterseveralmonths ofdialysis in diabetic patients

188

complications increased with the duration ofdiabetes and blood glucose level.é? The percent-age of urinary tract infection eaused by Klebsi-ella species (24% v 13%) and Staphylococcusaureus (10% v 5%) was higher in 132 diabeticpatients compared with 383 nondiabetic pa-tients admitted to the internal medicine depart-ment because of a suspected acute infection."In PD patients, a high glucose concentration inthe peritoneal cavity and tissues and diabeticchanges in the peritoneal structures may, there-fore, alter host defense mechanísms againstbacterial infections of the peritoneum. Becausethere is 11.0 dífference inperítonitis incidencebetween diabetic and nondiabetic-patients.? .itcould'Bé hypothesízed thatdue .to uniquediabetic changes of the perítoneum both día-betic and nondiabetic patients on long-termPD may have an increased incidence of perito-nitis caused by more virulent organismssuchas Klebsiella species and / or S aureus than5taphylococcus epidermidis. It should be notedthat S aureus peritonitis is the single mostprobable cause of sclerosing encapsulatingperitonitis."

Min Sun Park

without changes in reduplication of the micro-vascular basement membrane.P Reduplica-tion of basement membrane in mesotheliumand stromal blood vessels observed in PD inboth diabetie and nondiabetie patients6,16,2l-23can be accelerated by denudation of mesothe-lial cells due to peritonitis.16,18These changesmay result from direct exposure of the subme-sothelial tissue to high concentrations of glu-cose."

Advanced glycosylation ería próducts(AGE) produced by nonenzymatic glycosyla-tíon of tissue protein are important in thepathophysiology of diabetie complícatíons."Ie, redüced relasticity in arteries, heartnndlungs,25 and in kidneys." Accumulation. ofAGE increases in the peritoneum and theperitoneal membrane becomes hyperperme-able to small and large molecular weightsolutes with time on CAPD.27In experimentalanimals, intraperitoneal injection of high glu-cose containing dialysis solutions for 3 monthsresulted in increased microvasculature in thesubmesothelial space and strong positive stain-ing of AGE in the submesothelial space andcapillary walls fu both the submesothelialspace and the muscularis layers (Fig 2). Amino-guanidine in drinking water attenuated AGEstaining in vascular walls in both the submeso-thelial space and the muscularis layer (Fig 3).In a control group without intraperitonealinjection of dialysis solution or aminoguani-díne, weakpositive staining of AGE was notedomy~ªt the mesotheliallayer (Fig 4).

ThéeffectoI diabetic changes ·of the perito-neum, ie, neovascularization and reduplica-tion offnesothelial and vascular basementmembranes and accumulation of AGE result-ing from long-term use oí high glucose solu-tions, on peritonitis is yet to be studied. Theoverall incidence of infection and risk of symp-tomátic.urinary tract infection inc1uding acutepyelonephritis is increased in diabetics com-pared with nondiabetics.P Potentially life-threatening infections appear to be uniquelyassociated with diabetés." Increased urinaryglucose coneentration,· a defect in leukocytefunction, neuropathy, and angiopathy are pos-tulated causative factors for this increasedfrequency and severity of urinary tract ínfec-tion.l? The incidence and severity of infectious

Peritonitis and the PeritoneumMesothelium is easily damaged by short expo-sure to drying, rough handling, or ínfection.vExperimental models of peritonitis índuced byintraperitoneal injection ofS aureus showedround transformation of mesothelíal cells insome areas and loss of mesothelium in others,acute inflammatory cell infiltration, and vascu-lar prolíferatíononday 1.17 Irregular arrays ofnew collagen appeared irtthesubrriesótheliallayer on day 4, and thickened submesothelialconnective tissue with accumulation of newcollagen with denudation of mesothelial cellsin sorne areas was noted after 4 weeks oíperitonitis.'? Peritoneal biopsy samples ob-tained from PD patients with active or recentperitonitis showed complete or partialloss ofmesothelium coveredby a layer of fibrin,perivascular extravasation of fibrin togetherwith endoL~liªJ~~lLswel1ing,· a.Iid interstitialedema.l" Complete removal of fibrin anareme-'sothelialization are importanf for completehealing of the peritoneum after a peritonitisepisode. Peritonitis episodes appear tú be re-sponsible forperitoneal accumulation of colla-

Peritonitis in Long- Term Peritoneal Dialysis 189

Figure 3. Irnmunochernlstry findings using AGE-specific antibody of parietal peritoneum from rats afterintraperitoneal injection of high glucose dialysis solutions for 3 months with aminoguanidineinthedrinkingwater. Strong positive staining was noted at the mesothelial area (m). Aminoguanidine atlenuated AGEstaining at the submesothelial¡;IJ:~a (sJ!l),capillary walls in the muscularis layer (cm), and the endomesium (e).

gen. In experimental S aureus peritonitis, in-creased accumulation of Type 1 and Type Incollagen was observed in thickened submeso-thelial connective tissue with partíal regenera-tion of mesothelial cells at 4 weeks.l? In severeperitonitis, extensive deposits of fibrin perme-ate the underlying connective tissue, and thismay interfere with mesothelial regenera-tion.5,14,18 Mesothelial cells have potent fíbrino-lytic actívity.-' and removal of fibrin depositsis, therefore, more difficult after denudation of

Figure 4. Irnmunochemistry findings using AGE--specific-antibody of parietal peritoneum from nor-m¡¡.lr¡¡.tswithout intraperitoneal injection of dialysissolutions or arninoguanidíne in the drinking water.Positive staining was noted only at the mesothelialar~L(lll) and the submesothelíal capillary wall(csm).

Figure 5. Light IIl,icr()!iC()EicfiI].<i~I1g~::9!-ªcP~p:t~l.1ealspecimen.ohtaíned •at allto.pc.:y ftom i) llaíieotwbQhad sclerosing eIlcélPEll1l~t!IlKP~ril0!J:itisand_diedofa cerebrovascular accident showing thíck multiplestratified fibrous bands. Masson-trichrome stainingx150. Abbreviation: pe, peritonealcavity;SM, scle-rosing membrai:íe;SS,stibrn:esoHleIfarspace~ .

190

months compared with patients on PO for lessthan 3 months.P A patient with fivefold andeightfold higher concentrations of Type 1 andID procollagen peptides, respectively, in perito-neal effluent developed sclerosing peritonitis 1month after sampling.P' Fibrin deposits andfibrosis with cellular desert of the peritoneummay interfere with inflammatory cell infiltra-tion, contact of bacteria with opsonins, andbactericidal agents. As a consequence, bacte-rial eradication will be hard to achieve, theperitoneal cavity can easily become an in-fected leather sack, and eventually surgicalintervention will be unavoidable.

Min Sun Park

mesothelial cells during peritonitis. New meso-thelium only appears after the fibrin layer hasundergone resolution by reabsorption or fibro-SiS.IB

Fibrin deposit not removed is graduallyreplaced by granulation tissue, which, in tum,is changed to dense fibrous tissue.F Failure ofremesothelialization was associated with hya-linized, acellular bands of superficial collagen,occasional blood vessels, and focal inflamma-tory cell infiltration." Peritoneal specimensobtained at autopsy of a patient who hadsclerosing encapsulating peritonitis after 7years of CAPO with nine episodes of peritoni-tis and who died of a cerebrovascular accidentshowed thick multiple stratified fibrous bands(Fig 5),33 wliich suggested multi¡:ileepisodes ofperitonitis healing with fibrosis. An ultrasono-gram of the patient showed tethering of bowelIoops to the posterior abdominal wall, a char-acteristic membrane encasing the bowelloops,and ascites withintemal echogenic strands(Fig 6A).On transverse section, a thick opaquemembrane resembling a "cocoon" was eneas-ing the dilated bowelloop (Fig 6B).

Serum concentrations of procollagen pep-tides reflect synthesis rates of parent collagens.The concentration of Type 1and III procollagenpeptídes in dialysis effluent may be a usefulmarker of peritoneal fibrosis and was found tobe high~r in patients on PO for more than 6

Altered Peritoneal CellBiology in PDPeritoneal macrophages and mesothelial cellsare the major resident cells in the peritonealcavity. Peritoneal macrophages are believed toact as the first line of defense against invasionof microorganísms.t" Mesothelial cells are thelargest cell population in the normal perito-neum= and play important roles in the activa-tion, amplification, and control of inflamma-tory processes.F-"Directand indirectinteractionsbetween macrophages and mesothelial cellsare important in the amplification of ínflamma-tory responses and the subsequent recruit-ment of leukocytes into the peritoneal cavity."

Fi~~~6.D1tr~sonogram of abdoirientA) and a gross finding of a transverse section of tárigled bowelloopcovered by a thick membrane (B)of the same patient as in Fig 5. Ultrasonogram showed tethering of bowelloops(B_LJtothe posterior abdominal wall, characteristic membrane (arrowheads_tencasingJhebowellQops,and ascites with internal echogenic strands (arrows; A). On transverse section a thick opaque membrane(arrow heads) tesembling "cocoon" was encasing the dilatédbowélIoopíb).

Peritonitis in Long- Term Peritoneal Dialysis 191

Cornmonly used PO solutions contain highconcentrations of glucose and lactate and areacidic and hypertoníc.s? Glucose breakdownproducts are generated during heat steriliza-tion of these solutíons.v The effects of dialysissolutions on peritoneal cell biology and func-tion in vitro have been extensively studied.Dialysis solutions decreased viability42,43andinhibited phagocytosis of peripheral leuko-cytes in vitro.f High concentrationsof glucoseinduced monocyte chemoattractant proteinmRNA áhdpróteinsyhthéSisliyíi1.ésothelialcells, and this was mediated by activation ofproteín-kínase C.45 High glucose concentra-tion also decreased the function of peritonealmesothelial cells,46peritoneal43~47andperiph-eral Ieukocytes.v' peripheral macrophages.v'and excretion of leukotriene from peritonealleukocytes." Acidity of dialysis solutions de-creased phagocytosis of peritoneal macro-phages in vitro that was recovered when thepH of the dialysis solution was raised to 6.5 orhigher.42 Super-normal concentrations of lac-tate in dialysis solutions decreased intracellu-lar pH, inhibited the respiratory burst of pe-ripheral polymorphonuclear leukocytes.vand increased collagen synthesis of fíbro-blasts/" Glucose degradation products such as5-hydroximethyfurfural (5-HMF), acetalde-hyde, glyoxal, methylglyoxal, formaldehyde,and valeraldehyde contaminating dialysis so-lutions during heat sterilization showed signífí-cantly higher inhibition of cell growth com-pared with filtered dialysis solutíons.PFormaldehyde is one of the well known alde-hydes among those identified and causes aller-gic reactions and hemolysis.F and its concen-tration found in conventional dialysis solutions,0.2 to 0.3 ppm,41 is considerably higher thanthe 0.1 ppm in air recornmended by TheAmerican Industrial Hygiene [oumal.P Theseacute effects of dialysis solutions on viability,cytokine release, chemotactic movement, andphagocytic function of various peripheral andperitoneal cells are responsible for alteredirnmune response in the peritoneal cavity. A

-hlghincidence of peritonitis episodes caused·by~Sepidermidis that is oflow virulence andnormal flora of the skin is an important clinicalIl1~t~~!ªtion. resulting from altered immuneresponse inthe peritoneal cavity.

.ConcentratiünS of opsonins such as C3 and

IgG and their activity are important factors forinfection control. Oialysate concentrations ofC3 and IgG are approximately 1% to 5% oftheir serum levels and believed to be far lowerthan normal opsonic activity.55Long-term useof dialysis solutions further decreased theconcentration of C3 and IgG and opsonicactivity in PD effluent.f The levels of C3 andIgG in PO effluent decreased with time onCAPO compared with the baseline valuesmeasured at the beginning of CAPO in 16patients.é" Low opsonic activity is responsiblefor altered irnmune reaction in the peritonealcavity. The early reportthat the incidence of Sepidermidis peritonitis was significantly lowerin patientswith highperitonealopsonic activ-ity than in those with a lower concentrationsupports the hypothesía=

Incubation of IgG with high glucose dialy-sis solution in vitro induced glycation of IgG.56The proportion of glycated IgG increased withincreasing glucose concentration, acidity ofthe media, and incubation time.56 Comple-ment activation (C3c deposition) and phagocy-tosis by polymorphonuclear leukocytes (PMN)was studied using S aureus Wood as antigen invitrO.56Glycated IgG induced higher C3c depo-sition than nonglycated IgG, while PMNphagocytosis was not affected by IgG glyca-tion." These results may, therefore, indicatethat glycation of IgG may take place. in theperitoneal cavity, leads to enhanced comple-ment activation, and results in a reduction ofcomplement factors for adequate anti-infec-tion mechanisms in dialysate.é"

Continuous lavageofthe peritonealcavitydecreases the concentration of opsonins andthe number of peritoneal cells. The total num-ber of peritoneal monocytes recovered fromovernight dialysate was lower in long-termdialysis patients compared with patients whorecently started CAPO in our unit (unpub-lished data). Moreover, peritoneal macro-phages isolated from peritoneal effluentbe-carne increasingly irnmature with time onCAPO up to Lyear, aridthis wasaccompaniedbya significara modulation oí me abtítryrosecrete inflarnmatorycytókíries;57 - --

In conclusion, altered structure and func-tion .Di the pel"it9_nel1II!c:..ªJ!.~edc12.el"it()I1:~alcellbiology, and impaired irnmune response are.important pred.isposing factors that may in-

192

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26. Lee HB, Cha MK, Song KI, et al: Pathogenic role ofadvanced glycosylation end-products in diabetic ne-phropathy. Kidney Int, 52:560-565, 1~97 (suppI60)

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Min Sun Park

crease the incidence and the severity of perito-nitis in long-term PD patients. Use of morephysiologic solutions and effective preventionof peritonitis may prevent serious complica-tions and support long-term PD.

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