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!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)
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$on/angiogenesis'
Altera;ons&of&the&peritoneal&membrane&during&the&course&of&PD&
n)=)574)incident)PD)pa3ents)Stoke/on/Tent)(UK))cohort)
Progressive)increase)in)solute)transport)
Loss)of)UF)capacity)
Devuyst,'J)Am)Soc)Nephrol)2010;'Davies,'J)Am)Soc)Nephrol)2004'
300'
350'
400'
450'
0' 6' 12' 24' 36' 48' 60' 72' 84'
0,6'
0,65'
0,7'
0,75'
Net'UF'(ml)' PSTR'
PD'start'
Aber'5'years'on'PD'
Altera;ons&of&the&peritoneal&membrane&during&the&course&of&PD&
Courtesy'Prof.'C.'Verger,'T.'Augus$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?''
The)peritoneal)membrane))
What)drives)peritoneal)membrane)damage))
How)to)protect)the)peritoneal)membrane))
Innova3ve,)targeted)therapies))to)prevent)membrane)damage)
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¬&compromised&as&a&result&&
2. Preven;ng´&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)&
Peritoneal)Dialysis)Interna3onal)2017)
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¬&
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&
Peritoneal)Dialysis)Interna3onal)2017)
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'
EPS&and&loss&of&peritoneal&osmo;c&conductance&
-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)
Morelle…Devuyst,'Goffin,'J)Am)Soc)Nephrol)2015'
→!Role!for!peritoneal!fibrosis?!
EPS&and&loss&of&peritoneal&osmo;c&conductance&
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
Morelle…Devuyst,'Goffin,'J)Am)Soc)Nephrol)2015'
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
* * *
* *
Co
lla
ge
n v
olu
me
fra
cti
on
(% s
ub
me
so
the
lia
l a
rea
)
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
Morelle…Devuyst,'Goffin,'J)Am)Soc)Nephrol)2015'
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
S u b m e s o th e lia l th ic k n e s s
(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
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
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
Morelle…Devuyst,'Goffin,'J)Am)Soc)Nephrol)2015'
‘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!
Morelle…Devuyst,'Goffin,'J)Am)Soc)Nephrol)2015'
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'
The)peritoneal)membrane))
What)drives)peritoneal)membrane)damage))
How)to)protect)the)peritoneal)membrane))
Innova3ve,)targeted)therapies))to)prevent)membrane)damage)
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,⩔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∾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´&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'
I.P.'E.)coli,)109/ml''
1' 2' 3' 4' 5' 6'Days'
Mouse&models&of´&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$on' Permeability'
Beneficial&effects&of&anakinra&in!vivo!
I.P.'E.)coli,)109/ml''
1' 2' 3' 4' 5' 6'Days'
I.P.'anakinra,)50'mg/kg'
E. coli Anakinra
E. coli Vehicle
Vehicle
Survival' Membrane'
Hautem*,'Morelle*'et'al,'J)Am)Soc)Nephrol)2017'
Hautem*,'Morelle*'et'al,'J)Am)Soc)Nephrol)2017'
Beneficial&effects&of&anakinra&in!vivo!9!on&top&of&an;bio;cs!
Anakinra!(antag.!IL91R)!• ↓'inflammatory'infiltrate'
• ↓'vascular'prolifera$on'• Preserva$on'of'UF'
I.P.'E.)coli,)109/ml''
1' 2' 3' 4' 5' 6'Days'
I.P.'anakinra,)50'mg/kg'
I.P.'cebazidime,)40'mg/kg'
What&is&true&for&the&porridge&of&&’Goldilocks&and&the&three&bears’&&also&applies&for&inflammasome∾vity:&&
‘It)must)be)neither)too)hot)nor)too)cold,)but)
just)right’)
Conclusions&
• Peritoneal'membrane'→'dialysis'at'home,'efficiently'and'safely''
• Vulnerable'→'response'to'injury'through'inflamma$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'