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Avances en la fisiopatologia de la peritoni2s esclerosante
VII Reunión Nacional de Diálisis Peritoneal Oviedo
Viernes 3 febrero 2012 Dr. Elisabeth W. Boeschoten
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‘Advances’ in our knowledge of Encapsula2ng Peritoneal Sclerosis (EPS)
• Diagnos=c tools EPS • Risk factors for EPS
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• Overall incidence: 0.3% – 3.3% • Incidence aGer 5 years: PD 2.1% – 8.1% • Mortality rate pa=ents with EPS: 25.8 – 56.5%
• 18/33 cases in Australia/NZ: 39% directly related to EPS Johnson et al Kidney Int 2010
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Diagnosis EPS www.epsregistry.eu
• Clinical symptoms of bowel obstruc=on (in the absence of an alterna=ve explana=on; e.g. tumor, peritoni=s, paraly=c ileus)
• Radiological and/or surgical findings consistent with diagnosis EPS
• Diagnosis EPS difficult in early stages
• DD: simple peritoneal fibrosis; fibrosis forma=on aGer peritoni=s
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Clinical symptoms EPS
• Changes in peritoneal membrane transport
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• All long-term (>50 months) PD patiens were included, who stopped PD after 1995 and who had at least 2 SPAs available (1-4) in the 4 yrs before discontinuation
• 10 EPS, 24 UFF, 24 normal UF
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Solute Transport in preEPS
Sampimon et al NDT 2011
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Fluid transport in preEPS
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Risk of EPS aHer the development of UF failure
• Almost all pa=ents with EPS have UF failure
• 50% of pa=ents who con=nue PD for 3 years aGer the development of UFF develop EPS
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Clinical symptoms EPS
• Changes in peritoneal membrane transport • Hemoperitoneum
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Hemoperitoneum: 4/54 = 8%
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Clinical symptoms EPS
• Changes in peritoneal membrane transport • Hemoperitoneum
• Sterile, nonresolving or recurrent ‘peritoni=s’
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Clinical symptoms EPS
• Changes in peritoneal membrane transport • Hemoperitoneum (with/without Ascites)
• Sterile, nonresolving or recurrent ‘peritoni=s’ • Gastrointes=nal symptoms (anorexia, nausea, vomi=ng, weightloss)
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Gastrointes=nal symptoms in pa=ents with EPS
De Freitas et al Perit Dial Int 2008
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Biochemical markers for EPS
• Markers of an inflammatory state; C-‐reac=ve protein, anemia, hypoalbuminemia
• Markers in the effluent
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Radiological diagnosis EPS Ultrasound abdomen
Li et al Am J Radiol 2008
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CT scan abdomen Augus=ne et al Nephron Clin Prac=ce 2009
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CT scan abdomen Tarzi el al Clin J Am Soc Nephrol 2008
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Summary diagnos=c procedures
Rou2nely:
• (at least) yearly measurement of UF (PET, SPA) • (at least) yearly measurement of CA-‐125 and IL-‐6
Suspicion EPS: • Sonography abdomen • CT abdomen
• Laparotomy/laparoscopy macroscopic appearance; histology
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Pathology of EPS
• Histological criteria for EPS are not uniform • Mesothelial denuda=on, inters==al fibrosis, angiogenesis, increased or decreased number of vessels
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Braun et al Perit Dial Int 2010
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Williams et al JASN 2002
Parietal peritoneal biopsies from a normal individual (1a) and a patient who had undergone PD for 9 yr (1b). Compact submesothelial collagenous band and deeper adipose connective tissue. Compact zone markedly thickened in 1b. Toluidine blue. Scale bar, 500µm
Submesothelial compact zone
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Podoplanin is a glycoprotein which is expressed by mesothelial cells and lymphatic vessels. It can bind cytokines and might be involved in the injury process of both simple sclerosis and EPS Podoplanin can be detected by the antibody D2-40, which is suitable for routine staining
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A: Podoplanin in patients on PD. A single layer of mesothelial cells was present on the surface of the biopsy, but with a cuboidal appearance and with gaps between the cells. B: Podoplanin in patients with EPS. The morphological picture of EPS demonstrated the absence of a mesothelial cell layer on the surface. A high number of podoplanin positive cells with the morphological appearance of fibroblasts is embedded in the extracellular matrix of EPS.
Braun et al Nephrol Dial Transplant 2010
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Pathogenesis of EPS
D.G.Struijk, PU University, Amsterdam 2011
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Glucose and/or GDP exposure in the pathogenesis of peritoneal membrane damage
• Diabe=form vascular altera=ons
• Effluent VEGF
• Deposi=on of AGE’s
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Korte et al Perit Dial Int 2011 Risk factors associated with encapsula=ng peritoneal sclerosis Retrospec=ve, nested, mul=center case-‐control study in The Netherlands
Dialysis fluids Any use during the period 1996-‐2007
EPS (n) No EPS (n) p -‐ value
Dianeal 58 107 NS
Physioneal 31 20 0.0001
Icodextrin 49 28 0.0001
Independent of UFF prolonged use of icodextrin was associated with EPS
Protective effect of biocompatible fluids with respect to the prevention of EPS is not yet proven in clinical settings
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Number of peritoni=s episodes is not a risk factor for the development of EPS
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Number of peritoni=s episodes is not a risk factor for the development of EPS
• No difference in peritoni=s incidence between EPS and =me-‐matched controls (Hendriks et al Perit Dial Int 1997)
• No difference in cohort study Scorsh Renal Registry (Brown et al CJASN 2009)
• No difference in matched case-‐control analysis in Australia and New Zealand (Johnson et al Kidney Int 2010)
• No difference in case-‐control analysis in The Netherlands (Korte et al Perit Dial Int 2011)
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Dura=on of peritoneal dialysis
Habib et al Neth J Med 2011
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Dura=on of peritoneal dialysis
Habib et al Neth J Med 2011
Cumulative hazard for developing EPS in incident PD patients in Australia and New Zealand 1995 - 2007
Johnson et al Kidney Int 2010
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Younger age is a risk factor for the development of EPS
Johnson et al Kidney Int 2010
EPS (n=33)
No EPS (n=7585)
p-‐value
Age (yrs) 49.1 58.0 0.002
Korte et al Perit Dial Int 2011
EPS (n=63)
No EPS (n=126)
p-‐value
Age (yrs) 34.7 51.5 0.0001
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Renal Transplanta=on and EPS
About 50% of EPS Cases occur aHer transplanta2on (Korte et al NDT 2007, Brown et al CJASN 2009)
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EPS aGer Renal Transplanta=on
• Promoted by increased use of calcineurin inhibitors and decreased use of cor=costeroids?
• Not a single case of EPS is reported in pa=ents not on calcineurin inhibitor
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Patients with diagnosis EPS after transplatation
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Treatment and outcome
Chin et al Am J Kidney Dis 2006
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A: The whole bowel is trapped in a thick, tough peritoneal cocoon. The arrow points on a slice of the visceral peritoneum. B: After 10 hours of peritonectomy the small intestine is liberated and bowel passage is restored.
Source: Niko Braun et al http://www.epsregistry.eu
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Summary
Risk factors for EPS: • Long stay (> 4 year) on PD • Younger age • UF-‐failure • Calcineurin inhibitors?
E2ology? Treatment?
We need to know more!
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A global EPS registry is necessary to improve our knowledge regarding
this severe complica2on !
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Thank you for your aven=on!
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Clinical Staging of EPS
Nakamoto Perit Dial Int 2005
Succesful in experienced Hands only
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A: CD34-stained section (original magnification ×400) showing a decreased number of vessels and a loss in cellularity with an increased amount of intracellular matrix. B: CD34-stained section (original magnification ×400) showing an increased number of vessels and an increased cellularity with less intracellular matrix.
Braun et al www.epsregistry.eu
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