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EPS: Il Dibattito
Il Mito
Roberto Corciulo
Divisione di Nefrologia e DialisiAzienda Ospedaliero Policlinico
Università di Bari
Bari, 18 marzo 2010Simposio
CAPD originated in Austin, Texas, in 1975, when Robert Popovich and
Jack Moncrief discussed ways to dialyze a patient who was unable to
undergo hemodialysis.
The initial announcements of their clinical findings were not taken
seriously.
But when Popovich and Moncrief presented further clinical successes in
1978, the medical community was convinced. Compared to
intermittent procedures, the methods they developed made it possible
to remove fluids and filter the blood more steadily and continuously.
CAPD and its diffusion
Nolph KD et al, Kidney Int. 1985; 28:198:205Posen G et al, 1983; 4° ISAO Official Satellite Symp on CAPD KyotoWing AJ et al, Proc. Eur Dial Transpl Assoc. 1983; 20:5-67
0
200
400
600
800
1000
1200
1400
1978 1979 1980 1981 19820
1000
2000
3000
4000
5000
6000
7000
8000
9000
1977 1980 1983
1232
20
1700
8532n.
pts
on
PD
0
200
400
600
800
1000
1200
1400
1600
1800
2000
1978 1980 1981 1982
1837
2141
n. p
ts o
n PD
34% of the total dialysis population 12% of the total dialysis population
CAPD and its diffusion
The first description of this complication in patients on peritoneal dialysis was published in 1980 (Denis J et al) and subsequently Gandhi and collegues reported 5 patients who showed sclerotic thickening of the peritoneal membrane.
Encapsulating Peritoneal Sclerosis (EPS) and PD
Denis J et al, Ann Intern Med 1980; 93:508Gandhi VC et al, Arch Intern Med 1980; 140:1201:3
The authors listed these factors as potentially important to the development of the complication: peritonitis, hypertonic dextrose solution, low pH of the dialysis solution, and dissolved plasticizers from the solution container.
Peritoneal sclerosis. A 'sword of Democles' for peritoneal dialysis?Schmidt RW, Blumenkrantz M Arch Intern Med. 1981 Sep;141(10):1265-7.
Richard Westall (1812)
The disease is defined as an:Inflammatory process transforming the peritoneal membrane into thick fibrous tissue, surrounding and compressing bowel loops. At laparoscopy the small bowel was enclosed in a bag or “cocoon” of thickened peritoneum.
The birth of the “myth”
In 1983, Slingeneyer described sclerosing peritonitis that occurred within a few weeks to several years after peritoneal dialysis (PD) discontinuation. In the report, the authors described an overall sclerosing peritonitis incidence of 1.4% (6/431). The authors emphasized that this rare, “life-threatening” complication involved asymptomatic peritoneal thickening and destruction of the mesothelial layer, associated with a loss of ultrafiltration (UF). They cautioned that the peritoneum, a living membrane, was altered more dramatically during long-term PD.
Subsequently, in 1985, Slingeneyer and Elie published the results of an international survey of SEP in 59 cases.
Slingeneyer A et al, Trans Am Soc Artif Intern Organs 1983; 29:633–40.Slingeneyer A, Elie M. Adv Perit Dial. 1985. Proc. of the Fifth Annual CAPD Conference, Missouri. University of Toronto Press, Toronto, 1985:118
EPS – First Links to Peritoneal Dialysis
Cooperative International Study on Sclerosing Encapsulating Peritonitis: Preliminary Report
……SEP appars to be a multifactional complication, but, five factors seem predominate: recurrence and severity of peritonitis, time exposure to peritoneal dialysis, antiseptics, solution buffer and the use of betablockers.
Adapted from A. Slingeneyer, M. Elie Adv Perit Dial 1985; 1:118
n. 59 cases of EPS
0
1
2
3
4
5
6
7
8
<1 1-1,5 1,5-2 2-2,5 2,5-3 3-3,5 3,5-4 4-5 >5
Patients with SEP
Time of diagnosisyears
Incidence/year of peritonitisfor each group of patients
4
3
2
1
Inci
denc
e/ye
ar o
f per
itoni
tis
Pts
with
SEP
Between August 1978 and December 1983, 163 patients (104 males and 59 females) were trained in CAPD in the hospital de la Pitie in Paris. Twelve patients (6 males and 6 females) developed the complication for an incidence of one case of SEP for 16.6 patient/years (7,3%)
The potential risk factors of EPS
Rottembourg J et al, Adv CAPD 1985; 1:109–17.
66,6%
The potential risk factors of EPS
Rottembourg J et al, Adv CAPD 1985; 1:109–17.
The AA. demonstrated that the use of acetate solution was the predominant cause of two outstanding abnormalities: UF loss and morphologic changes in the p.m.
(acetate) (acetate) (lactate) (lactate)
Junor BJR et al, Perit Dial Bull 1985; 5:101
Sclerosing peritonitis: the contribution of chlorhexidine
To prevent possible longterm complications such as sclerosing peritonitis should avoid the introduction into the peritoneal cavity of any unnecessary substance and in particular chlorhexidine in alcohol.
System Spray No. of patients
Peritonitis rate (pat/ months per episode)
Sclerosing peritonitis
Group I Fresenius Chlorhexidine in alcohol
54 6,3 11
Group II Travenol Povidone iodine
43 7,8 0
Group III Fresenius Povidone 65 7,0 0
11/162 pts (6,7%)
Oulès R. et al Nephrol Dial Transplant (1988) 3: 66-69
The EDTA Registry, in 1985, carried out a case control study to determine the cause of EPS. 162 patients, either alive or dead, with SEP diagnosed until the end of 198492 cases (57%) without cocoon; 70 cases (43%) with cocoon; 55 cases for Case-control Study.The mean interval between first peritoneal dialysis and diagnosis of sclerosing peritoneal disease was 30.1 (SD 16) months with a range of 6-78 months.
Case-Control Study to determine the cause of EPS
Analysis using Mc Nemar’s test
Part four: Ultrafiltration Failure and Peritoneal Sclerosis Peritoneal Sclerosis and Ultrafiltration Following 3 Months of CAPD in a Small Animal Model.L.H. Nielsen, K.D. Nolph, R. Khanna, H. MoorePage: lOO Sclerosing Peritonitis -An Experimental Study.lain Henderson, L. Wilson, M. Wallace, L. W. DobbiePage: 107 Loss of Ultrafiltration and Sclerosing Encapsulating Peritonitis During CAPD. Evaluation of the Potential Risk Factors.1. Rottembourg, B.lssad, P. Langlois, B. Tranbaloc, A. Adamou, F. DeGroc, M. LegrainPage: 109 Cooperative International Study on Sclerosing Encapsulating Peritonitis: Preliminary Report.A. Slingeneyer, M. EliePage: 118
Advances inPeritoneal DialysisVol. 1 - 1985
Historical focus of EPS’s risk factors
1 Pusateri R.et al Am J Kidney Dis 1986; 1:56
1980 1988
Dia
gnos
is o
f EPS
(mea
n of
yea
rs)
10
8
6
4
2
0
Acetate,Chlorhexidine,Peritonitis
Risk 1.9/1000Incidence 1,4 -7,3%duration 21,5 mos epis. perit. 2,03/y1
In 1992, Dobbie described a syndrome of peritoneal fibrosis and sclerosis in PD patients that was characterized by a “tanned peritoneum.” The tanning of the peritoneum was believed to consist of degradation products of fibrin, collagen, and other protein components, possibly caused by nonenzymatic glycosylation of glucose in the dialysis solution. Induction of potent intraperitoneal molecules such as interleukins and growth factors by glucose degradation products might promote fibrosis, new membrane formation, and adhesions.The mesothelial monolayer and subjacent stroma were critically involved in the progression of fibrosis, and that loss of mesothelium might result from long-term exposure to bioincompatible dialysis solution, with or without antiseptic agents or bacterial infection also being involved.
EPS Refining pathogenesis and risk factors
Dobbie JW , Perit Dial Int, 1992; Vol. 12, pp. 14-27
1.Early removal of catheter in severe peritonitis, since all evidence points to a continuing "scalded“ peritoneum lesion where mesothelium refuses to recover the surface.2. Reduction in the exposure of the naked stroma to the effects of hypertonic dialysate.3. Resting the peritoneum from dialysis where clinically feasible, and allowing remesothelialization to occur naturally as early as possible.Although CAPD can be used for many years without any significant structural damage, for a safer future, effort should be concentrated in providing a glucose-free physiological and emollient dialysate for the acute and healing phase in severe peritonitis.
Dobbie JW, Perit Dial Int;1992, Vol. 12, pp. 14-27
Recommendations on preventing EPS
In 1994 Campbell performed a cross- sectional study of 15 patients: five had died of sclerosing peritonitis, four had stopped peritoneal dialysis because sclerosing peritonitis was suspected, and six were considered to be at increased risk because of more than 4 years on peritoneal dialysis. The duration of dialysis, number of episodes of peritonitis, strength of peritoneal dialysis bags, the type of dialysate, and the use of beta blockers. were examined.Of the clinical features, only duration of dialysis could be shown to be an important risk factor (five of the six patients with certain sclerosing peritonitis had been on PD for 7 or more years) .
Campbell S. et al, Am J Kidney Dis 1994; 5:819-25
EPS Refining pathogenesis and risk factors
Case No. Status Age yr Sex No. of months on CAPD
No. of episodes of peritonitis
1 deceased 26 F 84 5
2 deceased 61 F 27 1
3 deceased 44 F 96 5
4 deceased 25 F 97 10
5 deceased 37 F 115 5
6 suspected 42 F 111 5
7 suspected 51 M 71 3
8 suspected 41 F 54 1
9 suspected 51 F 61 4
10 at risk 53 F 112 9
11 at risk 54 F 102 5
12 at risk 76 M 85 5
13 at risk 44 F 49 2
14 at risk 70 F 49 4
15 at risk 69 F 48 6
mean 77,4 + 28 4,6 + 2,4
Campbell S. et al, Am J Kidney Dis 1994; 5:819-25
Identification of risk factors
P. Hendricks et al, Perit Dial Int 1997; 17:136-143
Sixteen patients (11 men, 5 women) with PS were investigated with regard to demography, clinical features, risk factors, treatment, and outcome. The time between the start of PD and the time the diagnosis of PS was made was 70 months (range 40 -147 months). The time interval between discontinuation of PD and the diagnosis was 21 months (range 5 -50 months) in 6 patients. In 4 of these patients, it was preceded by renal transplantation, in the other 2 by transfer to hemodialysis because of either persistent peritonitis, or ultrafiltration failure. All patients used lactate-buffered dialysis solutions without disinfectants such as chlorhexidine.
EPS Refining pathogenesis and risk factors
modified P. Hendricks et al, Perit Dial Int 1997; 17:136-143
Demographic data and risk factors in patients with EPS
81%
P. Hendricks et al, Perit Dial Int 1997; 17:136-143
EPS and risk factors
A relation of PS with severe peritonitis may be present in some patients. Peritoneal sclerosis is a complication of long-duration PD and could also become manifest after a successful renal transplant. Patients with PS had lower net ultrafiltration and higher transport rates compared to controls who were matched for duration of PD. Peritoneal sclerosis Controls
Glucose exposure is likely to be an important risk factor for PS.
Historical focus of EPS’s risk factors
1Pusateri R.et al Am J Kidney Dis 1986; 1:562Campbell S. et al, Am J Kidney Dis 1994; 5:819-253Hendricks P. et al, Perit Dial Int 1997; 17:136-143
Dia
gnos
is o
f EPS
(mea
n of
yea
rs)
10
8
6
4
2
0
Incidence 1,4 -7,3%duration 21,5 mos epis. perit. 2,03/y1
1980 1988 1996
incidence 0.9%duration 70,5 mos2,3 epis. perit. 1,33/y2,3
Acetate,Chlorhexidine,
Peritonitis
Long-term treatment, Severe Peritonitis,Glucose exposure
1 1
3 3 34
9
6
11
13
8
0
2
4
6
8
10
12
14
82 83 84 85 86 87 88 89 90 91 92 93 94
A Report of the Japanese Sclerosing Encapsulating Peritonitis Study Group
Yasuo Nomoto et coll., Am J of Kidney Disease, vol.28, 3 1996, 420-27
Among 6,923 patients undergoing CAPD between 1980 and 1994, 62 (0.9%) given CAPD developed SEP.
year
n. o
f pati
ents
A Report of the Japanese Sclerosing Encapsulating Peritonitis Study Group
Yasuo Nomoto et coll., Am J of Kidney Disease, vol.28, 3 1996, 420-27
These 62 pts developed EPS 10 to 138 months (average 65,4 months) after starting CAPDPeritonitis incidence was one episode every 20.0 months in the 62 patients with EPS during the study period. In contrast, peritonitis incidence was one episode every 32.4 months in control patients.5 of 62 patients with EPS had no history of peritonitis. The mechanism of the development of EPS without peritonitis is uncertain. It was suggested that aberrations of the host defense mechanism might play an important role in the development of EPS in PD patients.Incidence of EPS is lower in CAPD patients in Japan. One possible reason is that racial differences might play a role in the development of EPS in CAPD.
n.54/7374 pts (1978-1994)EPS: the experience in Australia
Russel J.Rigby et coll., Nephrol Dial Transplant (1998) 13: 154-59
1,9 4,2
0
5
10
15
20
25
<1 >1 >2 >3 >4 >5 >6 >7 >8 >9
Russel J.Rigby et coll., Nephrol Dial Transplant (1998) 13: 154-59
n.7374 pts (1978-1994)
Duration in years of continuous peritoneal dialysis
% o
f pati
ents
Prevalence of sclerosing peritonitis in Australia
54 patients with EPS were analysed(overall prevalence was 0.7%)
19,4%
n.7374 pts (1978-1994)EPS: the experience in Australia
The median duration of peritoneal dialysis treatment was 48
months for patients developing sclerosing peritonitis.With a reduction in the peritonitis rate over this period, one have
expected the incidence to decrease.Further evidence that the duration of treatment is a major risk
factor for the development of sclerosing peritonitis is the increase in
the prevalence of the disease with duration of treatment, reaching
20% after 9 years of continuous dialysis.
Russel J.Rigby et coll., Nephrol Dial Transplant (1998) 13: 154-59
Historical focus of EPS’s risk factors
1Pusateri R.et al Am J Kidney Dis 1986; 1:562Campbell S. et al, Am J Kidney Dis 1994; 5:8193 Hendricks P. et al, Perit Dial Int 1997; 17:136
Dia
gnos
is o
f EPS
(mea
n of
yea
rs)
10
8
6
4
2
0
Incidence 1,4 -7,3%duration 21,5 mos epis. perit. 2,03/y1
Acetate,Chlorhexidine,
Peritonitis
1980 1988 1996 1998
Long-term treatment, Severe Peritonitis,Glucose exposure
incidence 0.9%duration 77,5 mos2,3 epis. perit. 1,33/y2,3
Risk 1,9-4.2/10004
incidence 0.5-0.8%4,5,6
duration 48-65,4 mos4,5,6
epis. perit. 1,66/y5
5 Y Nomoto et al., Am J of Kidney Dis, vol.28, 3 1996, 4204RJ.Rigby et al., NDT, 1998; 13: 154
Duration of PD, Frequent and Severe Peritonitis,Glucose exposure
6 Afthentopoulos IE et al., Adv Ren Replace Ther. 1998 Jul;5(3):157-67.
Peritoneal dialysis before the new millennium
After more than 20 years’ experience of PD, supported only by retrospective clinical studies, PD-related EPS was considered an iatrogenic complication .Duration of PD, exposure to dialysis solutions with high glucose concentrations, and frequent and severe peritonitis are considered to be risk factors and no one has yet identified the mechanisms for EPS development.
EPS: a time-dipendent complication
EPS Refining epidemiological study and
histomorphological changesAm J Kidney Dis, 2004; 44:729-737.
Clin J Am Soc Nephrol 4: 1222–1229, 2009
Garosi G, Di Paolo N. Peritoneal Sclerosis – An overview
1999;15:185-92
Peritoneal sclerosis. A “sword of
Democles” for peritoneal dialysis?
EPS: complication still able
to influence clinical decisions and therefore
to limit the use of peritoneal dialysis ?