EPS: Il Dibattito Il Mito Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero...

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


Case No. Status Age yr Sex No. of months on CAPD

No. of episodes of peritonitis

1 deceased 26 F 84 5





6 suspected 42 F 111 5

7 suspected 51 M 71 3



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.


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.


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


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.



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 ?

EPS: Il Dibattito Il Mito Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero...

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