Factors Increasing Severity of Peritonitis

in Long-Term PeritoneaI Dialysis Patients

MinSunPark
Peritonitis is the most frequent complication and a leading cause of discontinuation of peritoneal
dialysis (PO). Intact epithelial lining, sufficient blood flow, and adequate immunologic responses are
vital to eradicate infection. In long-term PO, various pathological.changes
such as denudation of
peritoneal mesothelial cells, duplication of submesothelial and/or capillary basement membranes,
submesothelial fibrhl deposit, and peritoneal fibrosis have been reported. Causes of these changes of
the peritoneum are mulfifictorlili:Commonly used dialysis solutions thatare
acidic, hypertonic,
containing high conceiifrationsofglcose
and lactate, contaminatedby
gluose and/or plastic
degradatollptb1:luCf~-lI'tr-notbiocompatible
and rnayinduce
ehronle immune reactionsinthe
peritoneal ca"ity. long-trmexp()sure
of the peritoneum to dialysis solutions, the peritoneal catheter,
and reeurrent episodes of peritonitis aUcontribute to peritoneal injury. In addition, long-term exposure
ofperitoneal cells such as macrophages, mesothelial cells, and fibroblaststo dialysissolutions may
also alter the normal immunologic reactions against bacteria. Peritoneal concentrationsofopsonins
.... such.asJg, ..cClmplement,.anctpl"otease"are..approximately1%oftheserumJevels.,andfar.b.elowthe.level
sufficient to erilCficate bacteria dueto
continuous peritoneal lavage and 'dilution with dialysis
. solutions. Furthermore, glycation of IgG induces chronic activation of macrophages and decreases
normal opsonic activities against bacteria. Fibrin deposits, collagen accumulation, and cellular desert
of the peritoneum observed in long-term peritoneal dialysis patients may serve as asafe shelter for
bacteria from contact with inflammatory eells and opsonin and delay eradication of bacteria. In
conclusion, peritonitis is often more severe in patients on long-term PO. In this setting, peritonitis
needs special attention to prevent life-threatening infection and further damage of the peritoneum.

1998 by the National Kidney Foundation, Inc.

Index Words: Long-term peritoneal dialysis; peritonitis;
changes; host defense mechanism.

eritonitis is the most frequent complication and a leading cause of discontinuation of peritoneal dialysis (PO).1-4Peritonitis in
PO patients has several differences from that
in patients not receiving PO. In patients not
receiving PO, when the peritoneal cavity is
contaminated by bacteria, rapid proliferation
of bacteria and inflammatorycell infiltration
occurin theclosed cavity.5 Fibrinexudation
eff~~!i.y.eJy.
c2:v'erstheinfe~t~g_N~."@,cIJ'r~vents the spread of infection. Althughlocalization of peritoneal infection is of help in
preventing systemic infection and providing
sufficient time for surgical intervention, it acts
as a safe shelter for bacteria from contact with
inflammatory cells, opsonins, and antibiotics
andeventually results in abscess formation."
InPpatients,continuous Iavageof the peritoneal cavity with dialysis solutions is of help in
remoying bacteria and preventing localization
oHnfection and abscess formation. Peritonitis
inPD .is, thetefore, easilycontrlled by using
appropriate antibioticsand doesnotusually
~~._ ..._. _...Ee9.l.li!~surgicalintervention. /
As ..Pltiel1t and technique survival have

peritoneal

structural

changes;

functional

increased in PO, the number of patients on

long-term PO has increased as well. Structural
and functional alterations of the peritoneum in
long-term PO patients have been reported.
The clnical manifestations of peritonitis in
long-term PO patients with<strctural and
functional alterations of the peritoneum may
be different from those with a normal peritoneum. However, no comparative study in this
regard has been reported to date., In this
p6ss1ble~facfur:s1h~t-iliterfieWith
prompt eradication of peritoneal infection and
that increase the severity of peritonitis in
long-term PO patients will be discussed.

.-r~lew~-the

.. Er9.w.JhdiYQnam KidneyLaboratory, 500n. Chun Hyang

University, Seoul, Korea.
5upported in part by grants from Korea Research Foundation and an Extramural Grant jrom.Baxier.: ce
Address correspomlence=iir-birt Sun FUI k;--MfJ;-f'h:&,
Assistant Professor '.0f.Medicine, Huonam.Kidneu. Laboratory,
500n Chun Hyang Universy, 657 Hannain~d(J1g, Yongsankoo; 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

186

Min Sun Park

Mesothelial Cell Lining and Secretion

of Phospholipids of the Peritoneum
The peritoneum is covered by a single layer of
mesothelial cells. Normal mesothelial cells are
flat or discoid and covered by a thick mantle of
microvilli and a single motile clium,"Mesothelial cells secrete surface active lubricant materials, phospholpids,? that prevent adherence of
the slowly moving surfaces of intra-abdominal organs. Phosphatidylcholine is the major
component and phosphatidylserine, lysophosphatidylcholine, and phosphatidylethanolamine are minor components discovered in
peritoneal effluent of PD patients." The concentration of phospholipids inperitoneal effluent
is fairly consistent from patient topatlenf and
lower in patients on long-term PD.9
Mesothelial cells are structurally and functionally similar to Type TI pneumocytes in
respiratory tracts that secrete surfactant.l? Bronchal trees are continuously exposed to various
noxious materials such as air pollutants and
microorganisms." Ciliary structures that cover
bronchial epithelium are important in eliminating noxious materials." Mucinous substances
secreted by epithelial cells covering bronchal
trees are also important for protection of epithelial cells from outside stimuli and act as a
barrier against bacterial colonization.!' The
most important complication resulting in a
structural alterationand
a defect in mucin
secretion is pulmonary infection.
The integrity of the epithelial lining cells
and covering mucinous substances are also
important in the urinary tracto Inadequate
urine flow, structural and functional urinary
tract obstruction, and damage to the epithelial
lining cells by urinary tract instrumentation
are important predisposing factors in urinary
tract infection.F Uromucoid, ie, Tamm-Horsefall glycoprotein, secreted from tubular epithelial cells and detected in normal urine is a
major inhibitor of bacterial adhesion on urinary tract epithelial cells."
Peritonitis in PD patients is in sorne ways
similar to respiratory and urinary tract infections. Continuous lavage of the peritoneal
cavity allows elimination of bacteria from the
peritoneal cavity and is similar to expectoration of bronchial secretions and urine flow.
Intact mesotheliallining cells covered by micro-

villi and cilium and phospholipids act as a

good barrier against bacterial colonization of
the peritoneum.
Reactive responses of the mesothelium to
dialysis, ie, cuboidal change of cellular shape,
increased number of cells per unit area and
increased length of cellular junctions, and
diminution of microvillil! have been reported
in PD patients. Hyperplasia of cytoplasmic
organelles indicates the tissue' s adaptive response to constant removal of secretory products in peritoneal effluent.P Mesothelial denudation is observed during active peritonitis16,17
due to permeation of exotoxins or endotoxins
from surviving colonies of organisms in or
around the peritoneal catheter.l" In sorne patients, remesothelializaton fails to occur and
this results in cellular desert."
The peritoneum is continuously exposed to
dialysis solutions containing unphysiologically high concentrations of glucose during
PD. As a consequence, diabetic changes such
as thickening of basal lamina of the peritoneal
capillaries are observed in nondiabetic continuous ambulatory peritoneal dialysis (CAPD)
patients.16,19 Denudation of mesothelium after
severe peritonitis may accelerate diabetic
changes in the peritoneum.'? In animal studies, injection of dialysis solutions containing
3.86% glucose intraperitoneally for 3 months
resulted in denudation of mesothelial cells and
widening of the submesothelial space without
active peritonitis episodes (Fig 1).20 In the
same study, a group of rats given aminoguanidine in drinking water during 3 months of
intraperitoneal injection of dialysis solutions
showed almost intact mesothelial lining with
round transformation (Fig 1).20 The observation suggests that the long-term use of high
glucose solutions results in accumulation of
advanced glycosylation end products in the
peritoneum and this is, in tum, responsible for
mesothelial damage in PD.
Loss of cilia and mcrovilli, denudation of
mesothelium,. and decreased concentration of
phospholipds ~bserved in long':term-PDpa~
tients may, therefore, be important predsposing factors allowing bacteria to invade the
peritneummoreeasily-than-in
patients with
normal peritoneum.

Peritonitis in Long-Term Peritoneal Dialysis

187

Figure 1. Light mcroscopc fndings of the parietal

peritoneum from Ilohiirufats (control; A)Ildrats
after intraperitoneal injectionof hglt glu-cse dialysis solutions for3 mnthswthotjgroup
1;B) and
with (group 2; C) amfnoguandne in drinking
water. A single layer of thin mesothelial cells (m),
scanty amount collagen layers (co), a few fibroblasts
(f) were noted in normal controlsj A]. Denuded
mesothelium (dm), capillary proliferation (ca), and
monocyte infiltration (mo) were notedin group 1
(B). Relatively intact mesothelial lining (m) with
round transformation and irifiltration of monocytes
(mo) were noted in group 2 (C). Hematoxylin eosin
staining, x150.

Figure 2. Iminunochemistry findings using AGE-specific antibody ()(parietal perltoneurnfrolIl. ratsafter

intraperitoneal injection of high glucose dalysis solutions for 3 monthsWithtifamihgliarticlifie:-SttIlg
positive staining was noted in the entire submesothelial space (sm; A), in capillary wallsinthe submesothelial
space (csm; A) and in the muscularis layer (cm; B), and at the endomesium (e; B).

Glucoseand the Peritoneum

A layer of areolar tissue composed of oriented
bundles of collagen fibers and retiform elastic
laminae in a ground substance matrix under- lies-mesothelal.Iinng
cells." N ormally, the
submesothelial tissues are relatively acellular
with a few fibroblasts and mast cells and are
not hlghly vascularized." After several months
of PD, reduplcation of both mesothelial base-

mentmembranearid.the
basement membrane
of the microvasculature of :he submesotheial
stroma wereobserved.l,~In Aia1:>etic:-pa~ents,
reduplicationef-the-basemns
membrane-w-as
observedonlyin themi!::rov:as~lature::butnot
in the .mesothelial layer at the beginning of
peri toneal dialysis, g~c!~p!~~atio_n_Q!=-fi-1-~_sp.thelial basement membranewas
observed after
severalmonths ofdialysis in diabetic patients

188

Min

Sun Park

without changes in reduplication of the microvascular basement membrane.P Reduplication of basement membrane in mesothelium
and stromal blood vessels observed in PD in
both diabetie and nondiabetie patients6,16,2l-23
can be accelerated by denudation of mesothelial cells due to peritonitis.16,18These changes
may result from direct exposure of the submesothelial tissue to high concentrations of glucose."
Advanced glycosylation
era prducts
(AGE) produced by nonenzymatic glycosylaton of tissue protein are important in the
pathophysiology of diabetie complcatons."
Ie, redced relasticity in arteries, heartnnd
lungs,25 and in kidneys." Accumulation. of
AGE increases in the peritoneum and the
peritoneal membrane becomes hyperpermeable to small and large molecular weight
solutes with time on CAPD.27In experimental
animals, intraperitoneal injection of high glucose containing dialysis solutions for 3 months
resulted in increased microvasculature in the
submesothelial space and strong positive staining of AGE in the submesothelial space and
capillary walls fu both the submesothelial
space and the muscularis layers (Fig 2). Aminoguanidine in drinking water attenuated AGE
staining in vascular walls in both the submesothelial space and the muscularis layer (Fig 3).
In a control group without intraperitoneal
injection of dialysis solution or aminoguanidne, weakpositive staining of AGE was noted
omy~t the mesotheliallayer (Fig 4).
TheffectoI diabetic changes of the peritoneum, ie, neovascularization and reduplication offnesothelial
and vascular basement
membranes and accumulation of AGE resulting from long-term use o high glucose solutions, on peritonitis is yet to be studied. The
overall incidence of infection and risk of symptomtic.urinary tract infection inc1uding acute
pyelonephritis is increased in diabetics compared with nondiabetics.P Potentially lifethreatening infections appear to be uniquely
associated with diabets." Increased urinary
glucose coneentration, a defect in leukocyte
function, neuropathy, and angiopathy are postulated causative factors for this increased
frequency and severity of urinary tract nfection.l? The incidence and severity of infectious

complications increased with the duration of

diabetes and blood glucose level.? The percentage of urinary tract infection eaused by Klebsiella species (24% v 13%) and Staphylococcus
aureus (10% v 5%) was higher in 132 diabetic
patients compared with 383 nondiabetic patients admitted to the internal medicine department because of suspected acute infection."
In PD patients, a high glucose concentration in
the peritoneal cavity and tissues and diabetic
changes in the peritoneal structures may, therefore, alter host defense mechansms against
bacterial infections of the peritoneum. Because
there is 11.0 dfference inpertonitis incidence
between diabetic and nondiabetic-patients.? .it
could'B hypotheszed thatdue .to unique
diabetic changes of the pertoneum both dabetic and nondiabetic patients on long-term
PD may have an increased incidence of peritonitis caused by more virulent organismssuch
as Klebsiella species and / or S aureus than
5taphylococcus epidermidis. It should be noted
that S aureus peritonitis is the single most
probable cause of sclerosing encapsulating
peritonitis."

Peritonitis and the Peritoneum

Mesothelium is easily damaged by short exposure to drying, rough handling, or nfection.v
Experimental models of peritonitis nduced by
intraperitoneal injection ofS aureus showed
round transformation of mesothelal cells in
some areas and loss of mesothelium in others,
acute inflammatory cell infiltration, and vascular prolferatononday
1.17 Irregular arrays of
new collagen appeared irtthesubrriesthelial
layer on day 4, and thickened submesothelial
connective tissue with accumulation of new
collagen with denudation of mesothelial cells
in sorne areas was noted after 4 weeks o
peritonitis.'? Peritoneal biopsy samples obtained from PD patients with active or recent
peritonitis showed complete or partialloss of
mesothelium coveredby
a layer of fibrin,
perivascular extravasation of fibrin together
with endoL~liJ~~lLswel1ing, a.Iid interstitial
edema.l" Complete removal of fibrin anareme-'
sothelialization are importanf for complete
healing of the peritoneum after a peritonitis
episode. Peritonitis episodes appear t be responsible forperitoneal accumulation of colla-

Peritonitis in Long- Term Peritoneal Dialysis

189

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

gen. In experimental S aureus peritonitis, increased accumulation of Type 1 and Type In

collagen was observed in thickened submesothelial connective tissue with partal regeneration of mesothelial cells at 4 weeks.l? In severe
peritonitis, extensive deposits of fibrin permeate the underlying connective tissue, and this
may interfere with mesothelial regeneration.5,14,18 Mesothelial cells have potent fbrinolytic actvity.-' and removal of fibrin deposits
is, therefore, more difficult after denudation of

Figure 4. Irnmunochemistry findings using AGE-specific-antibody of parietal peritoneum from norm.lr.tswithout intraperitoneal injection of dialysis
solutions or arninoguanidne in the drinking water.
Positive staining was noted only at the mesothelial
ar~L(lll) and the submesothelal capillary wall
(csm).

Figure 5. Light IIl,icr()!iC()EicfiI].<i~I1g~::9!-cP~p:t~l.1eal

specimen.ohtaned at allto.pc.:y ftom i) llaieotwbQ
had sclerosing eIlclPEll1l~t!IlKP~ril0!J:itisand_diedof
a cerebrovascular accident showing thck multiple
stratified fibrous bands. Masson-trichrome staining
x150. Abbreviation: pe, peritonealcavity;SM,
sclerosing membrai:e;SS,stibrn:esoHleIfarspace~ .

190

Min Sun Park

mesothelial cells during peritonitis. New mesothelium only appears after the fibrin layer has
undergone resolution by reabsorption or fibroSiS.IB

Fibrin deposit not removed is gradually

replaced by granulation tissue, which, in tum,
is changed to dense fibrous tissue.F Failure of
remesothelialization was associated with hyalinized, acellular bands of superficial collagen,
occasional blood vessels, and focal inflammatory cell infiltration." Peritoneal specimens
obtained at autopsy of a patient who had
sclerosing encapsulating peritonitis after 7
years of CAPO with nine episodes of peritonitis and who died of a cerebrovascular accident
showed thick multiple stratified fibrous bands
(Fig 5),33 wliich suggested multi:ileepisodes of
peritonitis healing with fibrosis. An ultrasonogram of the patient showed tethering of bowel
Ioops to the posterior abdominal wall, a characteristic membrane encasing the bowelloops,
and ascites withintemal
echogenic strands
(Fig 6A). On transverse section, a thick opaque
membrane resembling a "cocoon" was eneasing the dilated bowelloop (Fig 6B).
Serum concentrations of procollagen peptides reflect synthesis rates of parent collagens.
The concentration of Type 1and III procollagen
peptdes in dialysis effluent may be a useful
marker of peritoneal fibrosis and was found to
be high~r in patients on PO for more than 6

months compared with patients on PO for less

than 3 months.P A patient with fivefold and
eightfold higher concentrations of Type 1 and
ID procollagen peptides, respectively, in peritoneal effluent developed sclerosing peritonitis 1
month after sampling.P' Fibrin deposits and
fibrosis with cellular desert of the peritoneum
may interfere with inflammatory cell infiltration, contact of bacteria with opsonins, and
bactericidal agents. As a consequence, bacterial eradication will be hard to achieve, the
peritoneal cavity can easily become an infected leather sack, and eventually surgical
intervention will be unavoidable.

Altered Peritoneal Cell

Biology in PD
Peritoneal macrophages and mesothelial cells
are the major resident cells in the peritoneal
cavity. Peritoneal macrophages are believed to
act as the first line of defense against invasion
of microorgansms.t" Mesothelial cells are the
largest cell population in the normal peritoneum= and play important roles in the activation, amplification, and control of inflammatory processes.F-"Directand indirectinteractions
between macrophages and mesothelial cells
are important in the amplification of nflammatory responses and the subsequent recruitment of leukocytes into the peritoneal cavity."

Fi~~~6.D1tr~sonogram of abdoirientA) and a gross finding of a transverse section of trigled bowelloop

covered by a thick membrane (B) of the same patient as in Fig 5. Ultrasonogram showed tethering of bowel
loops(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 dilatdbowlIoopb).

Peritonitis in Long- Term Peritoneal Dialysis

Cornmonly used PO solutions contain high

concentrations of glucose and lactate and are
acidic and hypertonc.s? Glucose breakdown
products are generated during heat sterilization of these solutons.v The effects of dialysis
solutions on peritoneal cell biology and function in vitro have been extensively studied.
Dialysis solutions decreased viability42,43and
inhibited phagocytosis of peripheral leukocytes in vitro.f High concentrationsof glucose
induced monocyte chemoattractant protein
mRNA hdprteinsyhthSisliyi1.sothelial
cells, and this was mediated by activation of
proten-knase C.45 High glucose concentration also decreased the function of peritoneal
mesothelial cells,46 peritoneal43~47andperipheral Ieukocytes.v' peripheral macrophages.v'
and excretion of leukotriene from peritoneal
leukocytes." Acidity of dialysis solutions decreased phagocytosis of peritoneal macrophages in vitro that was recovered when the
pH of the dialysis solution was raised to 6.5 or
higher.42 Super-normal concentrations of lactate in dialysis solutions decreased intracellular pH, inhibited the respiratory burst of peripheral polymorphonuclear
leukocytes.v
and increased collagen synthesis of fbroblasts/" Glucose degradation products such as
5-hydroximethyfurfural
(5-HMF), acetaldehyde, glyoxal, methylglyoxal, formaldehyde,
and valeraldehyde contaminating dialysis solutions during heat sterilization showed signfcantly higher inhibition of cell growth compared with filtered dialysis solutons.P
Formaldehyde is one of the well known aldehydes among those identified and causes allergic reactions and hemolysis.F and its concentration found in conventional dialysis solutions,
0.2 to 0.3 ppm,41 is considerably higher than
the 0.1 ppm in air recornmended by The
American Industrial Hygiene [oumal.P These
acute effects of dialysis solutions on viability,
cytokine release, chemotactic movement, and
phagocytic function of various peripheral and
peritoneal cells are responsible for altered
irnmune response in the peritoneal cavity. A
-hlghincidence of peritonitis episodes caused
by~Sepidermidis
that is oflow virulence and
normal flora of the skin is an important clinical
Il1~t~~!tion. resulting from altered immune
response inthe peritoneal cavity.
. ConcentratinS of opsonins such as C3 and

191

IgG and their activity are important factors for

infection control. Oialysate concentrations of
C3 and IgG are approximately 1% to 5% of
their serum levels and believed to be far lower
than normal opsonic activity.55Long-term use
of dialysis solutions further decreased the
concentration of C3 and IgG and opsonic
activity in PD effluent.f The levels of C3 and
IgG in PO effluent decreased with time on
CAPO compared with the baseline values
measured at the beginning of CAPO in 16
patients." Low opsonic activity is responsible
for altered irnmune reaction in the peritoneal
cavity. The early reportthat the incidence of S
epidermidis peritonitis was significantly lower
in patientswith highperitonealopsonic
activity than in those with a lower concentration
supports the hypothesa=
Incubation of IgG with high glucose dialysis solution in vitro induced glycation of IgG.56
The proportion of glycated IgG increased with
increasing glucose concentration, acidity of
the media, and incubation time.56 Complement activation (C3c deposition) and phagocytosis by polymorphonuclear leukocytes (PMN)
was studied using S aureus Wood as antigen in
vitrO.56Glycated IgG induced higher C3c deposition than nonglycated IgG, while PMN
phagocytosis was not affected by IgG glycation." These results may, therefore, indicate
that glycation of IgG may take place. in the
peritoneal cavity, leads to enhanced complement activation, and results in a reduction of
complement factors for adequate anti-infection mechanisms in dialysate."
Continuous lavageofthe peritonealcavity
decreases the concentration of opsonins and
the number of peritoneal cells. The total number of peritoneal monocytes recovered from
overnight dialysate was lower in long-term
dialysis patients compared with patients who
recently started CAPO in our unit (unpublished data). Moreover, peritoneal macrophages isolated from peritoneal effluentbecarne increasingly irnmature with time on
CAPO up to Lyear, aridthis wasaccompanied
bya significara modulation o me abttryro
secrete inflarnmatorycytkries;57 -In conclusion, altered structure and function .Di the pel"it9_nel1II!c:..J!.~edc12.el"it()I1:~al
cell
biology, and impaired irnmune response are
.important pred.isposing factors that may in-

192

Min Sun Park

crease the incidence and the severity of peritonitis in long-term PD patients. Use of more
physiologic solutions and effective prevention
of peritonitis may prevent serious complications and support long-term PD.

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