Avances  en  la  fisiopatologia  de  la  peritoni2s  esclerosante  

VII  Reunión  Nacional  de  Diálisis  Peritoneal  Oviedo  

Viernes  3  febrero  2012  Dr.  Elisabeth  W.  Boeschoten  

‘Advances’  in  our  knowledge  of  Encapsula2ng  Peritoneal  Sclerosis  (EPS)  

•  Diagnos=c  tools  EPS  •  Risk  factors  for  EPS  

•  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  

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  

Clinical  symptoms  EPS  

•  Changes  in  peritoneal  membrane  transport    

•  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

             

Solute  Transport  in  preEPS  

Sampimon et al NDT 2011

Fluid  transport  in  preEPS  

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  

Clinical  symptoms  EPS  

•  Changes  in  peritoneal  membrane  transport    •  Hemoperitoneum    

Hemoperitoneum:  4/54  =  8%  

Clinical  symptoms  EPS  

•  Changes  in  peritoneal  membrane  transport  •  Hemoperitoneum    

•  Sterile,  nonresolving  or  recurrent  ‘peritoni=s’  

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)  

Gastrointes=nal  symptoms  in  pa=ents  with  EPS  

De Freitas et al Perit Dial Int 2008

Biochemical  markers  for  EPS  

•  Markers  of  an  inflammatory  state;  C-­‐reac=ve  protein,  anemia,  hypoalbuminemia    

•  Markers  in  the  effluent  

Radiological  diagnosis  EPS  Ultrasound  abdomen  

Li    et  al  Am  J  Radiol  2008  

CT  scan  abdomen  Augus=ne  et  al  Nephron  Clin  Prac=ce  2009  

CT  scan  abdomen  Tarzi  el  al  Clin  J  Am  Soc  Nephrol  2008  

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  

Pathology  of  EPS  

•  Histological  criteria  for  EPS  are  not  uniform  •  Mesothelial  denuda=on,  inters==al  fibrosis,  angiogenesis,  increased  or  decreased  number  of  vessels  

Braun  et  al  Perit  Dial  Int  2010      

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  

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

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  

Pathogenesis  of  EPS  

D.G.Struijk,  PU  University,  Amsterdam  2011  

Glucose  and/or  GDP  exposure  in  the  pathogenesis  of  peritoneal  membrane  damage  

• Diabe=form  vascular  altera=ons  

• Effluent  VEGF  

• Deposi=on  of  AGE’s  

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

Number  of  peritoni=s  episodes  is  not  a  risk  factor  for  the  development  of  EPS            

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)  

Dura=on  of  peritoneal  dialysis  

Habib  et  al  Neth  J  Med  2011  

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  

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  

Renal  Transplanta=on  and  EPS  

About  50%  of  EPS  Cases  occur  aHer  transplanta2on  (Korte  et  al  NDT  2007,  Brown  et  al  CJASN  2009)  

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  

Patients with diagnosis EPS after transplatation

Treatment  and  outcome  

Chin  et  al  Am  J  Kidney  Dis  2006  

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

Summary    

Risk  factors  for  EPS:    • Long  stay  (>  4  year)  on  PD  • Younger  age  • UF-­‐failure  • Calcineurin  inhibitors?  

E2ology?  Treatment?  

We  need  to  know  more!  

A  global  EPS  registry  is  necessary  to  improve  our  knowledge  regarding  

this  severe  complica2on  !  

Thank  you  for  your  aven=on!  

Clinical  Staging  of  EPS  

Nakamoto  Perit  Dial  Int  2005  

Succesful  in  experienced  Hands  only  

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