Simon Davies University Hospital of North Staffordshire, Stoke-on-Trent Institute for Science and

Simon DaviesUniversity Hospital of North Staffordshire,

Stoke-on-TrentInstitute for Science andTechnology in Medicine

Keele University, UK

Controversies in EPS

Bari, March 2010

What are the controversies surrounding EPS?

• Diagnostic criteria• Are EPS and membrane fibrosis the

same?• Is EPS after transplantation the

same?• Should we screen? How?• Should all patients stop PD at 5

years?• Is surgery the only treatment?

Abdominal Cocoon

Defining EPS – learning form the Japanese experience

• clinical symptoms/signs of obstructive ileus, with or without a systemic inflammatory reaction, (e.g. CRP)

• Presence of peritoneal thickening and encapsulation, intestinal obstruction, cocooning, ± peritoneal calcification, confirmed by radiological investigations or at laparotomy, ± typical biopsy






Davies, SJ, KI, 2004

Are EPS and SS/fibrosis the same?

EPS• Inflammatory• Visceral• Rare• No intermediate• Rapid onset• Triggers• Longevity• Fibrinous exudate

Simple Sclerosis• Non-inflammatory• Parietal• Common• Continuum• Gradual change• No triggers• Longevity• Fibrosis

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Years before EPS/Stopping PD

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* *†

* Stoke PD Study

Longitudinal changes in membrane function for 9 patients developing EPS and controls matched (x4) for duration of completed time (mean 78.5 months) on PD

* P < 0.02

† P = 0.007Lambie et al, KI in press

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Solute transport (D/P creatinine)

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Months on PD

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Lambie et al, KI in press


Longitudinal membrane change in EPS v. patients with normal UF or UF

Failure

Sampimon, DE, Krediet R et al, awaiting publication

Solute transport Net Total UF

Longitudinal membrane change in EPS v. patients with normal UF or UF

Failure

Sampimon, DE, Krediet R et al, awaiting publication

Small pore fluid transport Aquaporin fluid transport

Start PD

Increasing solute transport

Dissociation of solute transport and

osmotic conductance

Ultrafiltration failure

EPS

Variability in membrane function

•Effective contact area

•Osmotic conductanceIncreasing vascularity

Increase in blood flow

Progressive fibrosis

Additional trigger/2nd hit

Stop PD

Peritonitis

Visceral involvement

IL-1/IL-6

VEGF

? TGF

EMT

? Impaired fibrinolysis

Loss RRF

Glucose/GDP

Peritonitis






EPS after transplantation

• Not described in Japan – but low transplantation rates

• Recently described in Europe• Why? Time on treatment/Tx waiting

list? Immunosupression?– Manchester (Summers et al); long time on

PD, immuosupression changes CyA only to include MMF

– Netherlands (Korte et al); long time on PD






Radiological features of EPS (CT scanning)

• peritoneal calcification• bowel distribution• bowel wall thickening and

dilatation • loculation of ascites • peritoneal thickening

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Calcification Bowel Distribution Bowel wall thickening

Loculation Peritoneal Thickening Bowel wall dilatation

Tarzi et al, CJASN, 2008

HD PD EPS HD PD EPS HD PD EPS

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Tarzi et al, CJASN, 2008

CT can diagnose EPS, but...

• Early signs of EPS are not easily identified or agreed by radiologists

• In CT studies several patients had normal CT scans a short time before diagnosis was confirmed – so not useful for screening

What are the mediators/potential biomarkers?

• Protein leak = fibrosis, = inflammation/EPS

• CA125 mesothelial cell health• IL-6 local production transport• VEGF local production

transport• TGF-β driver of EMT• MCP-1, CCL18 local production ?fibrosis• Hyaluronan ? Membrane health/healing• Fibrinolytic system • CRP systemic inflammation EPS






Comparison of estimated EPS risk in 7 studies worldwide conducted by

the Scottish Renal registryStudy

Nomotoet al1996

Rigbyet al1998

Leeet al2003

Kawanishiet al2001

Kawanishiet al2004

Summerset al2005

Brownet al

(current study)

Number of EPS Cases(those meeting ISPD 2000 criteria in brackets)

62 54 (46) 31 17 48 27 (23) 46

Dates of Study1980 - 1994 1980 - 1994 1981 – 2002 1999 - 2001 1999 - 2003 1998 – 2003 2000-2007

Study DesignRetrospectiveMulti-centre

RetrospectiveMulti-centre


ProspectiveMulti-centre

ProspectiveMulti-centre

RetrospectiveSingle-centre


Denominator Population (prevalent + incident PD Patients)

6923 7374 3888 2216 1958 810 1638

Overall Rate0.9% 0.7% 0.8% 0.8% 2.5% 3.3% 2.8%

Mean PD Exposure (yrs)5.1 4.3 5.8 10 4.3 6.1 5.4

Mortality (over study period) 43.5 % 56 % 25.8 % 35 % 37.5 % 29.6 % 56.5%

Incidence and outcome of EPS in relation to time on PD.

PD duration(yrs)

No of pts EPS incidence

Mortality Recovery

<3 337 0%

3 to <5 554 0.7% 0% 100%

5 to <8 576 2.1% 8.3% 83.3%

8 to <10 239 5.9% 28.6% 42.9%

10 to 15 223 5.8% 61.5% 15.3%

>15 29 17.2% 100% 0%

Total 1958 2.5% 37.5% 45.8%

Kawanishi H et al Am J Kid Dis 2004 44:729-37

Stoke PD Study: Risk of developing EPS


Patients are not the same... Imagine two different patients

on PD for 5 years:• 45 yrs, anuric for 2 years, requires 2

2.27% glucose exchanges per day, no live donor – an exit strategy from PD needs to be planned

• 71 yrs, 300 ml urine, 2 comorbidities, enjoys good QOL on PD, also needs 2 2.27% exchanges per day – discussion required but staying on PD is reasonable






Cocoon Opened

Thickened Visceral Membrane Dissected

Released gut

Manchester ExperienceReferrals Jan 2000 – Dec

2008 n = 83 Local - 61

MRI (42) Hope (7) Preston (9) Wythenshawe (3)

National - 18Exeter(3) Dorset (2) London (2) Epsom

St.Helier(1) North Staffs (2) Derby (1) Cumberland (1) Sheffield (1) Bristol (1) Sunderland (1) Birmingham (1) Cardiff (1) Inverness(1)

International - 4Dublin (3) Slovenia (1)

Post Surgery Outcomes

49 ALIVE None on TPN All home 3 patients have symptoms of

colic and early satiety but on oral diet

Suggested Risk Stratification For Surgical Intervention

LENGTH OF DIALYSIS

1-4 YRS 4-8YRS 8-12YRS

SYMPTOMS Mild fullness,discomfort

Distension,fullness,early satiety,vomiting,subacute obstruction

Gross distension, Recurrent subacute obstruction, obstruction*, Peritonitis*, Major Hemoperitoneum*

ALBUMIN Normal Moderate Low

ANEMIA Hb>10gm% Hb 8-10gm%, EPO,Transfusions

Hb<8gm%, Transfusions,EPO

WEIGHT NORMAL SUB-OPTIMAL SIGNIFICANT WEIGHT LOSS

CRP <50 50-100 >100

LENGTH OF SYMPTOMS/ADMISSION

0-4 WEEKS 4-8 WEEKS >8 WEEKS

CT FINDINGS Essentially normal Thickened peritoneum, some fluid,Mild dilatation of small bowel

Thickened calcified peritoneum, retracted mesentry, encapsulation,ascites

TREATMENT OPTIONS MEDICAL MEDICAL/SURGICAL SURGICAL

ABSOLUTE SURGICAL INDICATIONS*

OBSTRUCTION* PERITONITIS* MAJOR HEMOPERITONEUM*

UK approach to EPS management

• Funded supra-regional service – 2 centres of excellence with dedicated expert

teams and funding that follows the patient

• National Guidelines (Renal Association Website)– suspected or diagnosed patients should be

referred for assessment

• UK PD Research network – EPS registry and gene/biomarker bank

• Parenteral feeding to optimise nutrition• CT scanning – diagnosis not screening

Documents

Simon Davies University Hospital of North Staffordshire, Stoke-on-Trent Institute for Science and