!intervenciones!terapéu0cas!! dirigidas!a!preservar!! la...

!Intervenciones!terapéu0cas!!dirigidas!a!preservar!!

la!membrana!peritoneal!

Johann&Morelle,&MD,&PhD&&

Cliniques)universitaires)Saint/Luc)Ins3tut)de)Recherche)Expérimentale)et)Clinique)Université)catholique)de)Louvain,)Bruxelles)

[email protected]))

X&Reunion&Nacional&Dialisis&Peritoneal&San$ago'de'Compostela'–'1'al'3'de'febrero'de'2018'

1.  A'home'

2.  A'pa$ent'<'autonomous'and'

willing'to'do'PD'

3.  A'well<func$oning'

peritoneal'membrane'

Talking&about&indica;ons&and&contra<indica;ons&of&PD,&J.&Bargman&men;ons&what&is&needed&for&a&pa;ent&to&be&eligible&for&PD:&

Is&a&home&really&needed&to&perfom&PD?&

Jean)Louis)Clemendot,)solo)sail)world)tour)while)on)PD:)20)months,)>)2000)PD)dwells)

Is&autonomy&really&needed&to&perform&PD?&

BoLom/line:)What)is)really)needed)to)do)PD)is)a)

peritoneal)membrane)that)works)well…)…at)the)start)of)PD)but)also)during)the)

course)of)treatment!))

m

vWf

The&peritoneal&membrane&–&structure&and&components&

5'

Mesothelium:&•  No'role'in'peritoneal'transport'(not'a'barrier)'

•  Cri$cal'for'the'protec$on'of'the'membrane''

(release'of'pro<inflammatory/angiogenic/fibro$c'

cytokines'and'growth'factors)'

Inters;;um:&•  ‘Scaffold’'

•  Collagen'fibres,'mucopolysaccharides'hydrogel'

•  Fibroblasts,'adipocytes,'immune'cells'

Dense&network&of&capillaries&and&small&vessels:&•  Main'func$onal'barrier'to'solute'and'water'transport'in'

PD'(basal'condi$ons)'

m

vWf

The&peritoneal&membrane&and&the&3<pore&model&

Large pore r ~ 250 Å Small pore r ~ 40-50 Å Ultrasmall pore r ~ 2.5 Å

Capillary lumen

Peritoneal interstitium

6'

Rippe'et'al,'Kidney)Int)1991'

Capillary endothelium

Water&and&solutes&(incl.&Na)&

Free<water&

Discovery&of&water&channels&

•  Peter'Agre'et'coll.,'Bal$more'–'looking'for'the'iden$ty'of'Rhesus'an$gens'

•  Discovery'of'a'small'(28'kDa)'and'abundant'protein'at'the'surface'of'red'blood'cells''

•  Unknown'func$on'of'the'protein'–'also'expressed'in'renal'tubule'cells'

•  Xenopus)laevi)oocytes'–'water'channel!''→'Iden;fica;on&of&aquaporins&(Nobel'prize'in'Chemistry,'2003)'

Vehicle&

CHIP28&

Osmo0c!gradient!

Simple'diffusion'

Facilitated'diffusion'

Func;on&of&aquaporins&

Across)each)channel:)3)billion)water)molecules)every)second!)

Endothelial'AQP1'→'ultrasmall'pore'

50%'of'water'removal'in'PD'

Aquaporin<1&and&water&transport&in&PD&

Devuyst'et'al,'Am)J)Physiol)1998';'Ni'et'al,'Kidney)Int)2005'

m'lumen'

rbc'

Hypertonic'

glucose'

0

25

50

75

Net

ultr

afilt

ratio

n

(µl/g

BW

)

Aqp1+/+ Aqp1-/-

***'

2.4

2.6

2.8

3.0

3.2

3.4

3.6

0 20 40 60 80 100 120

IPV

t (m

l)

Time (min)

0,7

0,8

0,9

1

0 30 60 120

Aqp1+/+ Aqp1-/-

Time (min)

D/P

sod

ium

9'

The)peritoneum))is)a)living)3ssue)

10'Devuyst,'J)Am)Soc)Nephrol)2010;'Davies,'J)Am)Soc)Nephrol)2004'

Altera;ons&of&the&peritoneal&membrane&during&the&course&of&PD&

PD'start'

Devuyst,'J)Am)Soc)Nephrol)2010;'Davies,'J)Am)Soc)Nephrol)2004'

PD'start'

Aber'5'years'on'PD'

•  Loss'of'mesothelial'cell'integrity'

•  Submesothelial'fibrosis'

•  Vascular'prolifera$on/angiogenesis'


n)=)574)incident)PD)pa3ents)Stoke/on/Tent)(UK))cohort)

Progressive)increase)in)solute)transport)

Loss)of)UF)capacity)

Devuyst,'J)Am)Soc)Nephrol)2010;'Davies,'J)Am)Soc)Nephrol)2004'

300'

350'

400'

450'

0' 6' 12' 24' 36' 48' 60' 72' 84'

0,6'

0,65'

0,7'

0,75'

Net'UF'(ml)' PSTR'

PD'start'

Aber'5'years'on'PD'


Courtesy'Prof.'C.'Verger,'T.'Augus$ne'and'E.'Goffin'

Excessive)fibrogenic)response)in)the)peritoneal)membrane)that)eventually)encapsulates)the)bowel,)leading)to)par3al)or)total)bowel)obstruc3on))

Encapsula;ng&peritoneal&sclerosis&(EPS)&

13'

Technique'failure/transfer'to'hemodialysis'Cardiovascular'complica$ons'and'death'

Fluid'and'sodium'overload,'high'blood'pressure'

Ultrafiltra$on'failure'

Peritoneal'remodelling'(angiogenesis/fibrosis)'

Major&complica;ons&of&peritoneal&membrane&damage&

The)peritoneal)membrane))

What)drives)peritoneal)membrane)damage))

How)to)protect)the)peritoneal)membrane))

Innova3ve,)targeted)therapies))to)prevent)membrane)damage)

Rockey'et'al,'N)Engl)J)Med)2015'

Epithelial)cell)injury)→ inflammatory)and)fibrogenic)wound/healing)response)

Fibrosis)→ Organ)failure,))including)the)peritoneal)membrane)

Tissue&injury,&inflamma;on&and&fibrogenic&wound<healing&response:&A&common&pathway&to&organ&dysfunc;on&

Glucose&toxicity&on&the&peritoneal&membrane&

Davies'et'al,'J)Am)Soc)Nephrol)2001'

•  Pa$ents'on'long<term'PD'(>5'years)'

•  Low'baseline/early'loss'of'RKF'

•  Increased'exposure'to'hypertonic'

glucose'in'the'early'stages'of'treatment'

•  Development'of'fast'peritoneal'solute'

transport'rate'and'loss'of'UF'capacity'

‘Too)much)of)a)good)thing’)

‘Bio<incompa;bility’&

High&glucose&concentra;on&

Acidic&pH&

Lactate&buffer&

GDPs&et&AGEs&&(heat&steriliza;on)&

Bio<incompa;bility&of&conven;onal&dialysis&solu;ons:&The&glucose&and&beyond&

•  One'of'the'most'frequent'and'drama$c'

complica$ons'of'PD'

•  Acute'phase:'fast'solute'transport,'loss'of'UF,'increased'morbidity'and'mortality'

•  Longer'term:'func$onal'and'structural'altera$ons'

of'the'membrane'

PD9associated!peritoni0s!

Fried)&)Piraino,)NEJM)2000)Davies)et)al.)Kidney)Int)1998)

Acute&peritoni;s:&structural&changes&

Combet'et'al.'JASN'10:'2185<96,'1999'

Inflammatory&infiltrate& Vascular&prolifera;on&

Control'

Peritoni$s'

Control'

Peritoni$s'

Staph.)epidermidis<induced'peritoni$s'(5'days)'

Fielding,'Jones…Topley,'Jones,'Immunity'2014'

Repeat/severe)episodes)of)peritoni3s→)peritoneal)fibrosis)(IL/6)dependent))

Peritoni;s&and&peritoneal&fibrosis&

Machnik'et'al,'Nat)Med)2009'

Posi$ve'salt'balance'

Osmosensing'by'

macrophages'

Accumula$on'of'sodium'in'

subcutaneous'inters$$um'

Inflamma$on'and'vascular'

prolifera$on'

Accumula;on&of&salt,&osmo<sensing&and&inflamma;on&

‘Buffer'compartment’'to'

prevent/reduce'high'BP'

High'salt'diet''in'non<uremic'rats'

Ple$nck'et'al,'Nephrol)Dial)Transplant)2010'

Peritoneal'angiogenesis''and'fibrosis'

Release'of'TGFβ'and'IL<6'

Peritoneal'inflamma$on'

99.6%!of!base!pairs!are!iden0cal!!from!person!to!person!

Variants)in)genes)encoding/regula3ng)proteins)of)interest))

→)clinical)consequences)and)diseases)

Is&there&a&gene;c&predisposi;on&to&fibrosis?&

In!the!membrane:!!IL6!gene!variants!and!solute!transport!

Gillerot…Devuyst,'Kidney)Int)2005'

Margers'et'al,'Nephrol)Dial)Transplant)2013'

Fibro0c!response!to!TGF9β1!

Gene3c)background)influences)angiogenic)and)fibro3c)responses)

in)the)peritoneal)membrane)

What!drives!peritoneal!membrane!damage!9!summary!

•  Hypertonic'glucose'solu$ons,'as'well'as'uncontrolled'hyperglycemia'

•  ‘Bio<incompa$ble'nature’'of'conven$onal'solu$ons'(glucose,'acidic'pH,'GDPs),'and'the'presence'of'a'catheter'

•  Severe/repeat'episodes'of'peritoni$s'(‘cytokine'storm’)'

•  Sodium'overload'

•  Uremia'

•  Gene$c'predisposi$on'factors?''

ISPD&statement&

&&&'

Length&of&Time&on&Peritoneal&Dialysis&&and&Encapsula;ng&Peritoneal&Sclerosis:&&Posi;on&Paper&for&ISPD&–&Update&2017'

Edwina)A)Brown,)Joanne)Bargman,)Wim)van)Biesen,)Ming/Yang)Chang,)Frederic)O)Finkelstein,)Helen)Hurst,)David)W)Johnson,)Hideki)Kawanishi,)Mark)Lambie,)Thyago)Proença)de)Moraes,)

Johann)Morelle,)Graham)Woodrow)

Peritoneal)Dialysis)Interna3onal)2017)

SUMMARY&STATEMENTS&

5.   No&single&strategy&to&reduce&risk&of&EPS&has&been&proven&in&clinical&trials,&but&there&is&some&evidence&to&support&the&following:&1.   Minimising&dialysate&glucose&exposure,&although&it&is&important&

to&ensure&that&fluid&volume&status&is&not&compromised&as&a&result&&

2.   Preven;ng&acute&PD<related&peritoni;s&using&interven;ons&recommended&by&the&ISPD&Peritoni;s&Guidelines&

3.   Use&of&neutral&pH,&low&glucose<degrada;on&product&dialysis&solu;ons&(low<grade&evidence&only)&


SUMMARY&STATEMENTS&

7.   There&are&no&specific&predictors&for&the&development&of&EPS:&a.   Although&many&pa;ents&with&EPS&have&high&PSTR,&this&is&not&

true&for&all&pa;ents&and&this&is&a&common&finding&in&pa;ents&on&long<term&PD.&

b.   There&is&no&evidence&that&CT&scanning&has&any&value&in&predic;ng&EPS&

c.   Progressive&loss&of&osmo;c&conductance&to&glucose&(uncoupling&between&water&and&solute&transport,&altered&sodium&sieving,&decreased&free<water&transport)&may&reflect&the&development&of&peritoneal&inters;;al&fibrosis&and&may&help&iden;fying&pa;ents&at&risk&of&EPS.&However,&this&needs&to&be&confirmed&in&prospec;ve&studies&


A higher risk of EPS has consistently been associated witha longer duration of PD.1,5 The incidence in this study is inline with this, with a lifetime risk of 8.75% for patients on PDfor more than 5 years, a finding in keeping with the incidencereported by the Scottish Renal Registry.2 One of the strengthsof this study is follow-up data over a long period of time(19 years) allowing us to examine EPS risk after long periodson PD, and the Kaplan–Meier gradient continues to worsenwith longer PD exposure, a similar pattern to that publishedby Kawaguchi et al.6 although in our center the decline inEPS free survival is shorter.

It has been suggested that transplantation is a particularrisk for the development of EPS,7,8 although this does notseem to be the case for our cohort (12 out of 36 controls vs 0

out of 9 EPS cases had a transplant) nor was it the case in thePan-Thames EPS study where 14 out of 65 patients had atransplant.9 The majority of our patients developed thecondition after stopping PD (six out of nine) suggesting that,as has been documented previously,1,10 cessation of PD maybe the main trigger.

The original reports of EPS linked it with an increased rateand/or severity of peritonitis,5,11–13 although this is not thecase in our study. This might be explained by case selectionas, to ensure there was uniformity in the diagnosis of EPS, weexcluded two cases characterized by an early diagnosis aftersevere and prolonged peritonitis. However, there have also

Sol

ute

trans

port

Years before EPS/stopping PD

EPS cases

Controls !

1

0.9

0.8

0.7

0.6

0.5

0.4–9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 2

Figure 2 | Change in membrane solute transport with time onperitoneal dialysis (PD). Solute transport is measured as themean annual dialysate/plasma (D/P) creatinine ratio measured at4 h in standard peritoneal equilibration tests with standard error.The star indicates a difference between groups with P! 0.007.

EPS cases

!

!

!

600

400

300

200

100

0

500

Controls

UF

cap

acity

(m

l)

Years before EPS/stopping PD–9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 2

Figure 3 | Change in ultrafiltration capacity with time onperitoneal dialysis (PD). The ultrafiltration (UF) capacity is theannual mean measured by a 4 h peritoneal equilibration test with2.27% glucose, including approximately 200 ml overfill. Barsrepresent standard error. The stars indicate a difference betweengroups with Po0.05, unpaired t-test.

UF

cap

acity

(m

l)

600

500

400

300

200

100

0

EPS patients

Controls

Solute transport (D/P creatinine)0.5 0.6 0.7 0.8 0.9 1

Figure 4 | Change in membrane solute transport with changein ultrafiltration. Membrane solute transport and ultrafiltration(UF) are measured as the annual mean of measurements of UFcapacity and dialysate/plasma (D/P) creatinine ratio in a 4 hperitoneal equilibration test with 2.27% glucose, includingapproximately 200 ml overfill. Bars represent standard error.

Glu

cose

exp

osur

e(g

per

yea

r)Years before EPS/stopping PD

–9 –8 –7 –6 –5 –4 –3 –2 –1 0 1 2

!

!

Controls

EPS cases

20,000

40,000

60,000

80,000

100,000

120,000

Figure 5 | Glucose exposure with time on peritoneal dialysis(PD). Glucose exposure is measured as the mean of the totalnumber of grams of glucose in the dialysate used by each patientin that year. Bars represent standard error. The stars indicate adifference between groups with Po0.05, unpaired t-test.

4 Kidney International

o r i g i n a l a r t i c l e ML Lambie et al.: Characteristics of EPS patients prediagnosis

Lambie'et'al,'Kidney)Int)2010;'Sampinon'et'al,'Nephrol)Dial)Transplant)2011'

UK'cohort'(2.27%'PETs)'

mal UF in the control groups. The power of this study islimited due to the rarity of EPS. A multi-centre designwould improve the power. However, to our knowledge,we are the only centre that regularly assesses the periton-eal membrane function with a 3.86% glucose dwell incombination with a volume marker. Some of the results

of this study can also be measured with a regular PET.The fast transport status can be assessed with dialysateover plasma ratios of creatinine. For the diagnosis of

Fig. 4. Analysis B: linear mixedmodel estimations (mean and SEM) of thetime course of the net UF (upper panel), TCUF (middle panel) and theELAR (lower panel) in the 3 groups. The number of patients at eachtime point is given below the horizontal axis. Fig. 5. Analysis B: linear mixed model estimations (mean and SEM) of

the time course of solute-coupled water transport (upper panel), FWT at60 min (middle panel) and the contribution of FWT to TCUF (lowerpanel) in the 3 groups. The number of patients at each time point isgiven below the horizontal axis.

Peritoneal transport alterations prior to EPS 297

by Eric Goffin on M

arch 25, 2011ndt.oxfordjournals.org

Dow

nloaded from

Dutch'cohort'(3.86%'PETs)'

Loss)of)UF)capacity)and)UF)failure)frequently)occur)before)the)onset)of)overt)EPS)

31'

EPS&and&loss&of&peritoneal&osmo;c&conductance&

-5 -4 -3 -2 -1

0

2 5 0

5 0 0

7 5 0

1 0 0 0 E P S

C o n tro ls

*

***

Y e a rs p r io r to P D s to p

Ne

t U

F (

ml/

4h

)

0 5 1 0 1 5 2 0 2 5

0

2 5 0

5 0 0

7 5 0

1 0 0 0E P S

P D c o n tro ls

M T A C c r e a t (m l/m in )N

et

UF

(m

l/4

h)

234'incident'PD'pa$ents,'1994<2013,'Saint<Luc'Academic'Hospital,'Brussels'7'pa$ents'with'EPS'versus)28'(4:1)'matched'controls'–'yearly'3.86%'glucose<based'PET'

Morelle…Devuyst,'Goffin,'J)Am)Soc)Nephrol)2015'


-5 -4 -3 -2 -1

0 .0 0 0

0 .0 2 5

0 .0 5 0

0 .0 7 5 E P S

C o n tro ls

****

Y e a rs p r io r to P D s to p

So

diu

m s

iev

ing

EP

S

AQP1 vWF Merge

10'µm'

50'µm'

Pa;ents&with&EPS&•  Loss)of)UF)(uncoupling))•  Altered)sodium)sieving)•  Preserved)expression)of)AQP1)


→!Role!for!peritoneal!fibrosis?!


m'm' m'

m'

m'm'm'

Uremia Long-term PD EPS Normal peritoneum

m'

30 µm

100 µm

100'µm'

Structural&modifica;ons&of&the&membrane&in&pa;ents&with&EPS


Collagen&&

density&&

Uremia Long-term PD EPS

50'µm'

Polarized&&

light&

R e d G r e e n0 .0

0 .5

1 .0

1 .5

2 .0

2 .5U rem ic

P D

E P S

* * **

Re

lati

ve

in

cre

as

ein

re

d a

nd

gre

en

are

as

U r . P D E P S0

1 0

2 0

3 0

4 0

5 0

6 0

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Co

lla

ge

n v

olu

me

fra

cti

on

(% s

ub

me

so

the

lia

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)

Polarized&light& Green& Orange<red&

Fiber'Ø'' 20<40'nm' >'60'nm'

Collagen' Type'III' Type'I'

Wound<healing' Early'stages' Late'stages'

Qualita;ve&changes&in&the&inters;;um&of&pa;ents&with&EPS


0 2 0 0 4 0 0 6 0 0 8 0 00 .0 0

0 .0 2

0 .0 4

0 .0 6

0 .0 8

P D E P SU re m ia

n = 1 5r = -0 .7 1P = 0 .0 0 3

S u b m e s o th e lia l th ic k n e s s

(µm )

So

diu

m s

iev

ing

0 2 0 0 4 0 0 6 0 0 8 0 00

2 5 0

5 0 0

7 5 0

1 0 0 0 n = 1 7r = -0 .6 8P = 0 .0 0 3


(µm )

Ne

t U

F (

ml/

4h

)

0 2 0 0 4 0 0 6 0 0 8 0 00 .0 0

0 .0 2

0 .0 4

0 .0 6

0 .0 8

P D E P SU re m ia

n = 1 5r = -0 .7 1P = 0 .0 0 3


(µm )

So

diu

m s

iev

ing

Increased!thickness!and!density!of!collagen!fibers!in!the!peritoneal!inters00um!is!associated!with!a!reduced!osmo0c!water!transport!

0 1 0 2 0 3 0 4 0 5 0 6 00

2 5 0

5 0 0

7 5 0

1 0 0 0 n=17r= -0 .56P =0 .03

C o lla g e n v o lu m e fra c t io n

(% s u b m e s o th e lia l a re a )

Ne

t U

F (

ml/

4 h

)

0 1 0 2 0 3 0 4 0 5 0 6 00 .0 0

0 .0 2

0 .0 4

0 .0 6

0 .0 8 n=15r= -0 .53P =0 .03

C o lla g e n v o lu m e fra c t io n

(% s u b m e s o th e lia l a re a )

So

diu

m s

iev

ing

Peritoneal&fibrosis&and&water&transport


‘Small)pore’)

AQP1)

Peritoneal)capillary)

Peritoneal))cavity)

Legend)

Endothelium'

Osmo$c'water'flow'

Dialysate'glucose'

Fibro$c'inters$$um'

Inters;;al&fribrosis&restricts&water&transport&in&PD&

0 .0 0 0 .0 2 0 .0 4 0 .0 6 0 .0 8 0 .1 00 .0 0

0 .2 5

0 .5 0

0 .7 5

100 200 300 400

N e t U F (m ls )

S o d iu m s ie v in g

Pr(

EP

S)

Loss!of!sodium!sieving!in!long9term!PD!pa0ents!=!strong!and!independent!predictor!of!EPS!


Mul$variate'analysis'and'

random<effect'models'

Peritoneal&func;on&tes;ng&to&iden;fy&pa;ents&at&risk&for&EPS?&

How!to!protect!the!peritoneal!membrane!9!summary!

•  Reduce'exposure'to'glucose'(while'avoiding'fluid/salt'overload)'•  Successfully'prevent'and'treat'peritoni$s'(ISPD'guidelines)''•  Use'of'‘biocompa$ble’'solu$ons'with'neutral'pH'and'low'GDPs/AGEs'(low'grade'evidence)''

•  Monitoring'of'peritoneal'membrane'func$on'(sodium'sieving/osmo$c'conductance)'to'iden$fy'pa$ents'at'risk'for'EPS'

Yanez<Mo…Lopez<Cabrera,'N)Engl)J)Med)2003;''Aroeira…Selgas,'Lopez<Cabrera,'J)Am)Soc)Nephrol)2007'

Upregula$on'of'MMPs''and'epithelial<to'mesenchymal'transi$on''

→)Breakdown)of)the)basement)membrane)→ Peritoneal)fibrosis)and)membrane)failure)

Effect)of)synthe3c)pep3des)(P17)and)P144))on)peritoneal)remodeling)in)a)mouse)

model)of)chronic)exposure)to)peritoneal)dialysis)fluid)

Blocking)TGF/β1)reduces)fibrosis)and)angiogenesis)and)

improves)peritoneal)func3on))

Loureiro'et'al,'J)Am)Soc)Nephrol)2011'

Horejs*,'St<Pierre*…Lopez<Cabrera,'Stevens,'Nat)Comm)2017'

Electrospun'membrane'biofunc$onalized'

with'a'fragment'of'the'laminin'β1<chain'to'

modulate'the'expression'of'MMP2''

Mouse&model&of&peritoneal&fibrosis&(+TGFβ)&•  Interfacing'of'the'β1<fragment'with'the'

mesothelium'of'the'peritoneal'membrane'

via'a'biomaterial''

•  Abroga$on'the'release'of'ac$ve'MMP2'in'

response'to'

•  Rescue'of'$ssue'integrity'

Liappas…Lopez<Cabrera,!J!Am!Soc!Nephrol!2016&

Lossorio…Selgas,&PLoS!ONE!2017&

Rodriguez<Diez…Ruiz<Ortega,&Kidney!Int!2014&

Busnadiego…Rodriguez<Pascual,&J!Am!Soc!Nephrol!2015&

Sanz…Selgas,&Or;z,&PLoS!ONE!2014&

Zhou…Selgas,&Kidney!Int!2016&

Poten3al)targets)for)the)preven3on/treatment))of)peritoneal)fibrosis)

•  TWEAK'

•  Endothelin<1'

•  Th17'response/IL<17/CD69'

regulatory'protein'

•  Innate'immunity,'macrophages,'

CCL18'

Modula0ng!the!inflammatory!response!during!peritoni0s!!

to!preserve!the!membrane!

…but&also&contributes&to&the&burden&of&peritoni;s&

•  Excess'mortality'

•  Damage'to'the'peritoneal'membrane''

•  Acute'phase:'angiogenesis,'inflammatory'infiltra$on'and'loss'of'ultrafiltra$on''

•  Long<term:'peritoneal'fibrosis,'membrane'and'technique'failure'

Too'much'inflamma$on'→'harmful'

In&PD<associated&peritoni;s,&&the&inflammatory&response&is&a&‘double<edged&sword’'

Control& Peritoni;s&

Inflamma;on&helps&clearing&pathogens…&

IL<1β&release&during&PD<associated&peritoni;s&

Lin'et'al,'J)Am)Soc)Nephrol)2013'

Peritoneal levels in stable PD patients and on day 1 of acute peritonitis

Netea…Dinarello,'Nat)Immunol)2017'

Central&role&of&IL<1&in&the&inflammatory&response&

Effects&of&IL<1β&•  Systemic'response:'fever,'anorexia,'

acute'phase'proteins'

•  Endothelial'ac$va$on/permeability'

•  Chemotaxis/cell'infiltra$on'

•  Link'to'adap$ve'immunity'(ie'Th17)'

Detrimental&effects&of&IL<1β&on&the&membrane&

49'Modified'from'Margers'et'al,'Am)J)Pathol,)2002'

IL<1β'→'leukocytes'infiltra$on,'fibrosis''

and'loss'of'ultrafiltra$on''

Leukocytes'infiltra$on' Fibrosis'

Control'

Overexpression'of'IL<1β'

Control'Overexpression'of'IL<1β'

Adenovirus<mediated'transfec$on'of'IL1β)gene'to'the'rat'peritoneal'membrane'

Schroder'et'al,'Science'2010'

•  Mul$protein'playorm''

•  Cytosol'of'immune'cells'

•  Translates'a'microbial'or'

metabolic'stress'into'a'

potent'inflammatory'

response'

•  Autocleavage'and'ac$va$on'of'caspase<1,'

which'in'turn'cleaves'pro<

IL<1β'into'IL<1β''

The&inflammasome:&responsible&for&the&ac;va;on&of&IL<1β&

Peritoni3s)→)upregula3on)of)inflammasome)components))in)immune)cells)of)the)peritoneal)membrane)

RT<PCR&on&total&leukocytes&'from'PD'pa$ents'with'peritoni$s'(n=5)'vs'

controls'(n=3)'

NLRP3&expression&in&the&membrane&'of'a'pa$ent'with'PD<associated'peritoni$s'vs'

PD'control'

Expression&of&the&inflammasome&in&PD<associated&peritoni;s&

Mouse&models&of&acute&PD<associated&peritoni;s&

Intraperitoneal'LPS'or'E.)coli'

Acute!peritoni0s!in!mice!•  Upregula$on'of'inflammasome'components'

•  Matura$on'and'release'of'IL1β'

•  Peritoneal'inflamma$on'and'angiogenesis,'

increased'PSTR'and'loss'of'UF'

I.P.'LPS,'10'mg/kg'

I.P.'E.)coli,)109/ml''

1' 2' 3' 4' 5' 6'Days'

Nlrp3)knockout'

Protec$on'against'peritoneal'

transport'defects,'incl.'loss'of'UF'

Reduc$on'of'peritoneal'infiltrate'

No'IL<1beta'matura$on'&'release'

Intraperitoneal'LPS'or'E.)coli'

I.P.'LPS,'10'mg/kg'


1' 2' 3' 4' 5' 6'Days'

Mouse&models&of&acute&PD<associated&peritoni;s&

Ne

t U

F (µ

l/g B

W)

0

2 0

4 0

6 0

8 0

V e h ic le - N lrp 3 + /+

V e h ic le - N lrp 3 -/-

L P S - N lrp3 +/+

L P S - N lrp3 - / -***

**

•  Microvascular'endothelium'(CD31+)'

•  Immune'cells'(CD31<)'

IL1<R1'expression''

in'the'peritoneal'membrane'

Anakinra'

(IL<1R'antagonist)'

Interrup$on''

of'signal'transduc$on'

Pharmacological&modula;on&of&the&NLRP3/IL1β&axis?&

IL/1β)→)endothelial)cell)prolifera3on)and)vascular)permeability)Anakinra)→ protec3on)against)microvascular)altera3ons)

Effects&of&IL<1β&and&anakinra&on&endothelial&cells&(HUVECs)!

Angiogenesis'

Cell'prolifera$on' Permeability'

Beneficial&effects&of&anakinra&in!vivo!


1' 2' 3' 4' 5' 6'Days'

I.P.'anakinra,)50'mg/kg'

E. coli Anakinra

E. coli Vehicle

Vehicle

Survival' Membrane'

Hautem*,'Morelle*'et'al,'J)Am)Soc)Nephrol)2017'

Hautem*,'Morelle*'et'al,'J)Am)Soc)Nephrol)2017'

Beneficial&effects&of&anakinra&in!vivo!9!on&top&of&an;bio;cs!

Anakinra!(antag.!IL91R)!•  ↓'inflammatory'infiltrate'

•  ↓'vascular'prolifera$on'•  Preserva$on'of'UF'


1' 2' 3' 4' 5' 6'Days'

I.P.'anakinra,)50'mg/kg'

I.P.'cebazidime,)40'mg/kg'

What&is&true&for&the&porridge&of&&’Goldilocks&and&the&three&bears’&&also&applies&for&inflammasome&ac;vity:&&

‘It)must)be)neither)too)hot)nor)too)cold,)but)

just)right’)

Conclusions&

•  Peritoneal'membrane'→'dialysis'at'home,'efficiently'and'safely''

•  Vulnerable'→'response'to'injury'through'inflamma$on,'angiogenesis'and'fibrosis'

•  Morphological'changes'→ altered'ability'to'transport'solutes'and'water,'complica$ons,'and'technique'failure'in'long<term'PD'pa$ents'

•  Today:''the'most'effec$ve'way'to'prevent'membrane'damage''

•  Ra3onale'prescrip$on'of'PD'(avoid'glucose'exposure'and'hypervolemia);'

•  Adequate'preven$on/treatment'of'peritoni$s'episodes;'

•  Monitoring'of'membrane'func$on'over'$me'(probably)'

•  Tomorrow:''improved'understanding'of'membrane'biology'→'targeted'therapies'

!intervenciones!terapéu0cas!! dirigidas!a!preservar!! la...

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