1. EPS: Il Dibattito Il Mito Roberto Corciulo Divisione di Nefrologia e Dialisi Azienda Ospedaliero Policlinico Università di Bari Bari, 18 marzo 2010 Simposio

2. 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

3. Nolph KD et al, Kidney Int. 1985; 28:198:205 Posen G et al, 1983; 4° ISAO Official Satellite Symp on CAPD Kyoto Wing AJ et al, Proc. Eur Dial Transpl Assoc. 1983; 20:5-67 1232 20 1700 8532 n. pts on PD 1837 2141 n. pts on PD 34% of the total dialysis population 12% of the total dialysis population CAPD and its diffusion

4. 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; 93:508 Gandhi 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.

5. 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”

6. 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

7. 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 Time of diagnosis years Incidence/year of peritonitis for each group of patients 43214321 Incidence/year of peritonitis Pts with SEP

8. 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%

9. 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) (lactate)

10. 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. SystemSprayNo. of patients Peritonitis rate (pat/ months per episode) Sclerosing peritonitis Group IFreseniusChlorhexidine in alcohol 546,311 Group IITravenolPovidone iodine 437,80 Group IIIFreseniusPovidone657,00 11/162 pts (6,7%)

11. 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 1984 92 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

12. Part four: Ultrafiltration Failure and Peritoneal Sclerosis Peritoneal Sclerosis and Ultrafiltration Following 3 Months of CAPD in a Small Animal Model. Peritoneal Sclerosis and Ultrafiltration Following 3 Months of CAPD in a Small Animal Model. L.H. Nielsen, K.D. Nolph, R. Khanna, H. Moore Page: lOO Sclerosing Peritonitis -An Experimental Study. Sclerosing Peritonitis -An Experimental Study. lain Henderson, L. Wilson, M. Wallace, L. W. Dobbie Page: 107 Loss of Ultrafiltration and Sclerosing Encapsulating Peritonitis During CAPD. Evaluation of the Potential Risk Factors. 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. Legrain Page: 109 Cooperative International Study on Sclerosing Encapsulating Peritonitis: Preliminary Report. Cooperative International Study on Sclerosing Encapsulating Peritonitis: Preliminary Report. A. Slingeneyer, M. Elie Page: 118 Advances in Peritoneal Dialysis Vol. 1 - 1985

13. Historical focus of EPS’s risk factors 1 Pusateri R.et al Am J Kidney Dis 1986; 1:56 1980 1988 Diagnosis of EPS (mean of years) 10 8 6 4 2 0 Acetate, Chlorhexidine, Peritonitis Risk 1.9/1000 Incidence 1,4 -7,3% duration 21,5 mos epis. perit. 2,03/y 1

14. 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

15. 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

16. 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

17. Case No.StatusAge yrSexNo. of months on CAPD No. of episodes of peritonitis 1deceased26F845 2deceased61F271 3deceased44F965 4deceased25F9710 5deceased37F1155 6suspected42F1115 7suspected51 M 713 8suspected41F541 9suspected51F614 10at risk53F1129 11at risk54F1025 12at risk76 M 855 13at risk44F492 14at risk70F494 15at risk69F486 mean77,4 + 284,6 + 2,4 Campbell S. et al, Am J Kidney Dis 1994; 5:819-25 Identification of risk factors

18. 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

19. modified P. Hendricks et al, Perit Dial Int 1997; 17:136-143 Demographic data and risk factors in patients with EPS 81%

20. 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.

21. Historical focus of EPS’s risk factors 1 Pusateri R.et al Am J Kidney Dis 1986; 1:56 2 Campbell S. et al, Am J Kidney Dis 1994; 5:819-25 3 Hendricks P. et al, Perit Dial Int 1997; 17:136-143 Diagnosis of EPS (mean of years) 10 8 6 4 2 0 Incidence 1,4 -7,3% duration 21,5 mos epis. perit. 2,03/y 1 1980 1988 1996 incidence 0.9% duration 70,5 mos 2,3 epis. perit. 1,33/y 2,3 Acetate, Chlorhexidine, Peritonitis Long-term treatment, Severe Peritonitis, Glucose exposure

22. 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. of patients

23. 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 CAPD Peritonitis 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.

24. 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

25. Russel J.Rigby et coll., Nephrol Dial Transplant (1998) 13: 154-59 n.7374 pts (1978-1994) Duration in years of continuous peritoneal dialysis % of patients Prevalence of sclerosing peritonitis in Australia 54 patients with EPS were analysed (overall prevalence was 0.7%) 19,4%

26. 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

27. Historical focus of EPS’s risk factors 1 Pusateri R.et al Am J Kidney Dis 1986; 1:56 2 Campbell S. et al, Am J Kidney Dis 1994; 5:819 3 Hendricks P. et al, Perit Dial Int 1997; 17:136 Diagnosis of EPS (mean of years) 10 8 6 4 2 0 Incidence 1,4 -7,3% duration 21,5 mos epis. perit. 2,03/y 1 Acetate, Chlorhexidine, Peritonitis 1980 1988 1996 1998 Long-term treatment, Severe Peritonitis, Glucose exposure incidence 0.9% duration 77,5 mos 2,3 epis. perit. 1,33/y 2,3 Risk 1,9-4.2/1000 4 incidence 0.5-0.8% 4,5,6 duration 48-65,4 mos 4, 5,6 epis. perit. 1,66/y 5 5 Y Nomoto et al., Am J of Kidney Dis, vol.28, 3 1996, 420 4 RJ.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.

28. 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

29. EPS Refining epidemiological study and histomorphological changes Am 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

30. 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 ?