Comprendre la Réparation - Alexandre HERTIG Tenon Hospital, Paris, France - SRLF
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Comprendre la
Réparation
Alexandre HERTIG
Tenon Hospital, Paris, France
alexandre.hertig@sorbonne-universite.fr
Mr Pascal S. né en 1955 (67 ans)
Employé des pompes funèbres, tabagisme modéré, éthylisme
2011: état de choc cardiogénique sur cardiopathie dilatée à coronaires saines
IRA / AKI (NTA), récupération complète
Avril 2012: transplantation cardiaque
Créatininémie (µmol/L)
400
300
Echographie RAS
200
Protéinurie tubulaire
100
Sédiment U inactif
0
Traitement au long cours: Cyclosporine, Mycophénolate Mofétil, Corticoïdes
Acute tubular necrosis induced by ischemia reperfusion injury
CORTEX
Cortico-Medullary
Junction
Sham
Surgery
Giemsa
« The severely damaged kidney can completely restore its structure and function »
Thadhani R et al, N Engl J Med 1996
C’est l’épithélium tubulaire survivant qui répare l’épithélium nécrosé
Humphreys BD, Cell Stem Cell 2008
IMPACT OF DELAYED GRAFT FUNCTION
- No DGF
- DGF < 6 days
Severe (> 6 days) DGF - DGF > 6 days
shortens gra6 survival by
4.5 years
Giral M et al, Kidney Int 1998
USRDS DATA (2013): Odds Ratio for graft loss at 5 years: 1.7 (after exclusion of ECD)
Butala et al, Transplantation 2013
Kidney InternaConal, 2014
Medicare (US), année 2000
233 803 patients > 67 ans
3,1% AKI
HR for ESRD: 13 if CKD-free
41 if CKD
(8 if CKD no AKI)
5,3‰ ESRD: 25% ATCD d’AKI
Ishani A, J Am Soc Nephrol 2009 (January)Caifornie, 1996-2003
562 799 H
(GFR pre H > 45 mL/min)
703 AKI HD
295 morts
65 HDC
343 vivants et sortis AKI
de HD
41 ESRD
(0 dans le groupe contrôle)
HR CKD: x 28.1*
(*) variables d’ajustement:
Âge, sex, black, diabetes,
HTA, protéinurie, eGFR < 45 ml/min
avant l’admission
Lo LJ, Kidney Int 2009 (June)1996-2006
All Ontario
3769 AKI HD
X4: 13598 contrôles*
Suivi médian 3 ans
Incidence ESRD
2.63%/an vs 0.91
HR ESRD: x 3.23
(*) appariés sur âge, sexe,
VM, score de propensité à
AKI – 25% CKD
Wald R, JAMA, September 200930 207 patients
Suivis 3 ans en moyenne
1610 reversible AKI
Hazard Ratio of de novo CKD 1,9
Bucaloiu ID, Kidney Int 2012Rapid Occurrence of Chronic Kidney Disease in
Patients Experiencing Reversible Acute Kidney Injury
after Cardiac Surgery
%BWJE-FHPVJT .% 1JFSSF(BMJDIPO .% 1I% "VSÏMJFO#BUBJMMF .% 4ZMWJF$IFWSFU .% 1I%
4PQIJF1SPWFODIÒSF .% "OOF#PVUUFO .% %JNJUSJPT#VLMBT .% +FBO-VD'FMMBIJ .% 1I%
+FBO-VD)BOPV[ .% 1I% "MFYBOESF)FSUJH .% 1I%
ABSTRACT
Background: There is recent evidence to show that patients suffering from acute kidney injury are at increased risk of devel-
oping chronic kidney disease despite the fact that surviving tubular epithelial cells have the capacity to fully regenerate renal
tubules and restore renal function within days or weeks. The aim of the study was to investigate the impact of acute kidney
injury on de novo chronic kidney disease.
Methods: The authors conducted a retrospective population-based cohort study of patients initially free from chronic kidney
disease who were scheduled for elective cardiac surgery with cardiopulmonary bypass and who developed an episode of acute
kidney injury from which they recovered. The study was conducted at two French university hospitals between 2005 and
2015. These individuals were matched with patients without acute kidney injury according to a propensity score for develop-
ing acute kidney injury.
Results: Among the 4,791 patients meeting the authors’ inclusion criteria, 1,375 (29%) developed acute kidney injury and 685
fully recovered. Propensity score matching was used to balance the distribution of covariates between acute kidney injury and non-
acute kidney injury control patients. Matching was possible for 597 cases. During follow-up, 34 (5.7%) had reached a diagnosis of
chronic kidney disease as opposed to 17 (2.8%) in the control population (hazard ratio, 2.3; bootstrapping 95% CI, 1.9 to 2.6).
Conclusions: The authors’ data consolidate the recent paradigm shift, reporting acute kidney injury as a strong risk factor for
the rapid development of chronic kidney disease. (ANESTHESIOLOGY 2017; 126:39-46)
T EN years ago, international experts from the Acute
Dialysis Quality Initiative and the Acute Kidney Injury
Network proposed a unique definition of “acute kidney
What We Already Know about This Topic
t 3FDFOUFWJEFODFTVHHFTUTUIBUQBUJFOUTTVGGFSJOHGSPNBDVUF
LJEOFZJOKVSZ ",* BSFBUJODSFBTFESJTLPGEFWFMPQJOHDISPOJD
injury” (AKI). Thus, a diagnosis of AKI requires either a 1.5- LJEOFZ EJTFBTF $,% EFTQJUF UIF GBDU UIBU TVSWJWJOH UVCV-
fold increase in serum creatinine within 7 days or serum cre- Legouis D et al, Anesthesiology 2017
MBS FQJUIFMJBM DFMMT IBWF UIF DBQBDJUZ UP GVMMZ SFHFOFSBUF SFOBM
atinine increase by more than 0.3 mg/dl (26.5 μmol/l) within UVCVMFTBOESFTUPSFSFOBMGVODUJPOXJUIJOEBZTPSXFFLT
1 t 5IF DVSSFOU TUVEZ JOWFTUJHBUFE UIF JNQBDU PG ",* PO deLegouis D et al., Br J Anesth 2018
Legouis D et al., Br J Anesth 2018
Le pronostic
de l’AKI
n’est pas
systématiquement favorable
même chez ceux qui récupèrentSchématisation de la réparation, ad integrum…ou pas
Chawla LS, N Engl J Med 2014Tout les paCents ne développent pas une CKD post-AKI
Faut-il un deuxième hit ?Bataille A et al., Cell Physiol Biochem 2018
Control IR 20 minutes Sham Surgery IR 20 minutes
Day 0 Day 2 Day 28 Day 28
Masson’s
trichrome
Periodic Acid
Schiff
Giemsa
Sirius red under
polarized light
Bataille A et al., Cell Physiol Biochem 2018Sham–angio2 AKI-angio 2
Sirius red under
polarized light
Sirius red under
polarized light
(Image obtained
with a full scan of
the section)
Bataille A et al., Cell
Physiol Biochem 2018Sham Surgery – angio 2 IR 20 minutes – angio 2
Day 56 Day 56 C
Impact of a resolved AKI on fibrogenesis Morphological comparaison of fibrosis,
blindly assessed by two operators
in the presence of a 2nd hit ?
Sham Surgery – angio 2 IR
Fibrotic effect of Angiotensin 2
20 minutes – angio 2
Day 56 Day 56 Sham Surgery – angio 2 IR 20 minutes – angio 2
Day 56 Day 56
alone history of resolving AKI
DISCUSSION
An ischemic insult on renal tubular epithelium is reponsible of an injury that determ
history of AKI displayed signi0cantly more renal 0brosis.
Genes encoding enzymes involved in metabolic pathways (oxida ve phosphoryla
upregulated in mice with a previous history of AKI.
This suggests that a resolving episode of AKI in:uences the capacity to produce ener
from AKI to CKD.
Financial support : Société Française d’Anesthésie-Réanimation, Fondation pour la Recherche Médic
Bataille A et al., Cell Physiol Biochem 2018Mr Pascal S. né en 1955 (67 ans)
Employé des pompes funèbres, tabagisme modéré, éthylisme
2011: état de choc cardiogénique sur cardiopathie dilatée à coronaires saines
IRA / AKI (NTA), récupération complète
Avril 2012: transplantation cardiaque
Créatininémie (µmol/L)
400
300
Echographie RAS
200
Protéinurie tubulaire
100
Sédiment U inactif
0
Traitement au long cours: Cyclosporine, Mycophénolate Mofétil, CorticoïdesQuelle physiopathologie..? • Anomalies du cycle cellulaire épithélial • Anomalies métaboliques épithéliales • Epi-mutaGons dans les fibroblastes
Quelle physiopathologie..? • Anomalies du cycle cellulaire épithélial • Anomalies métaboliques épithéliales • Epi-mutaGons dans les fibroblastes
Restructuration
de la
chromatineKi67: proliferation BrdU: phase S p-H3+ G2/M
La production de facteurs pro-fibrogéniques par des HK2 bloquées en G2/M est augmentée. Les fibroblastes exposés au surnageant d’HK2 G2/M prolifèrent plus, fabriquent plus de matrice.
Quelle physiopathologie..? • Anomalies du cycle cellulaire épithélial • Anomalies métaboliques épithéliales • Epi-mutaGons dans les fibroblastes
La perte des fonctions épithéliales est peut-être la conséquence directe
des répercussions énergétiques de l’ischémie
Simon N, FronAers Med Res 2015Effondrement de la FAO dans un modèle animal de fibrose rénale
Ce n’est pas un problème de toxicité des lipides
lly cific to PGC1α altered by ischaemia, we examined me
of Comparing sham with post-ischaemic kidneys yield
ial tially abundant metabolites; comparing uninjured Pg
Anomalies similaires dans l’AKI ischémique
of type littermate kidneys yielded 11. Four were shared b
ne
ia, a Normal b Injured
cal
wn
re-
cal
mic
α)
ore c 60
ce IRI/sham
DAGs and TAGs
on 20 P < 0.0001
Tran MT et al., Nature 2016
mes 5
4s1,2. Here
ders H. Berg we3,4 show
, Eliyahu that the mitochondrial
V. Khankin 1,2
, Manojtially abundant
K. Bhasin 2,5 metabolites; comparing
, Wondong Kim6, uninjured Pgc1α
3,4
PGC1α ,1,2,8 is ,aEugene
pivotalP.determinant of M.type littermate kidneys yielded 11. Four were shared betw
LETTER
arumanchi Rhee6,7 & Samir Parikh 1,2
jury by regulating nicotinamide adenine
iosynthesis. Following renal ischaemia, a Normal bdoi:10.1038/nature17184
Injured
−/−
n as Ppargc1a ) mice develop local
ntrating solutes ischaemia (Fig. 1f, Extended Data Fig. 2a–g). To define pathways spe-
precursor
kidney especiallyniacinamide cific(NAM,to PGC1α alsoaltered knownby ischaemia, we examined metabolite profiles.
ked
KI) affects
n. Notably,
PGC1α
fat accumulation,
3% of Comparing
exogenous
drives
NAM
and failure NAD
improves
shambiosynthesis
towith
local
re- post-ischaemic linking kidneys oxidative
yielded six differen-
he mitochondrial tially abundant metabolites; comparing uninjured Pgc1α−/− to wild-
ation, and renal
determinant metabolismoffunction in to
type littermate renal
post-ischaemic kidneys protectionyielded 11. Four were shared between settings,
ble tubular
namide adenine transgenic
Mei T. Tran1,2, Zsuzsannamice (iNephPGC1α)
K. Zsengeller 1,2,3
, Anders H. Berg3,4, Eliyahu V. Khankin1,2, Manoj K. Bhasin2,5, Wondong Kim6,
Clary B. Clish7, Isaac E. Stillman4, S. Ananth Karumanchi1,2,8, Eugene P. Rhee6,7 & Samir M. Parikh1,2
of
renalNAM supplementation,
ischaemia,
RESEARCH LETTER a including
Normal
more b c 60
Injured
Abundance IRI/sham
DAGs and TAGs
accumulation
e developThelocal with better renal function 20 P < 0.0001
energetic burden of continuously concentrating solutes ischaemia (Fig. 1f, Extended Data Fig. 2a–g). To define pathways spe-
α coordinately
NAM, also known against upregulates
gradients along the tubule may therender enzymes 5
the kidney especially cific to PGC1α altered by ischaemia, we examined metabolite profiles.
4
vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of Comparing sham with post-ischaemic kidneys yielded six differen-
endnovo from
failureallto amino
hospitalized acids 1,2 whereas PGC1α
re- patients . Here we show that the mitochondrial tially abundant 3 metabolites; comparing uninjured Pgc1α−/− to wild-
uates the de
M improves novo
biogenesis pathway.
localregulator, PGC1αNAM 3,4
enhances
, is a pivotal 2
determinant of type littermate kidneys yielded 11. Four were shared between settings,
renal recovery from injury by regulating nicotinamide adenine 1
NAMPT and
in post-ischaemic augments
dinucleotide production
(NAD) biosynthesis. Following renal of the ischaemia, a 0 b Normal Injured
β-hydroxybutyrate,
e (iNephPGC1α)
Pgc1α −/− (also known leading
as Ppargc1a to −/−
increased
) mice develop local
d f ** h 4
Significance level (–log10P)
deficiency of the NAD precursor niacinamide (NAM, also known Normal 1.0
n,ndin PGE2as(ref. 5), a secreted autacoid thatto re-
Creatinine (mg dl–1)
including more
nicotinamide),
c
marked fat accumulation,
60
and failure 3
on. NAM treatment reverses
establish normal function. Notably,
established
exogenous NAM improves local
Abundance IRI/sham
DAGs and TAGs
er renal function
NAD levels, fat accumulation, 20andPrenal function in post-ischaemic
< 0.0001
so prevented
ates the enzymes Pgc1α AKI
−/−
in
mice. Induciblean unrelated
tubular
5 toxic
transgenic mice (iNephPGC1α)
0.5 2
recapitulate the effects of NAM 4 supplementation, including more c
ydroxybutyrate
whereas local NADsignalling
PGC1α or prostaglandin 60
** 1
Abundance IRI/sham
DAGs and TAGs
and less fat accumulation
3 with better renal function 20 P < 0.0001
olishes
y. NAM PGC1α-dependent
after Figure
enhances
Extended Data ischaemia. PGC1αrenal
10 | Relative 2 renoprotection.
coordinately
expression upregulates
for NAMPT theinenzymes
5
4
0
wild-type that synthesize
(WT) mice beforeNADandde
24novo 1from
h after IRIamino acids
(n = 6 per whereas PGC1α
group). WT KO WT KO 0
of mitochondrial of thenothealth in0theageing and the
3
roductionError bars,deficiency
s.e.m.; NS,or significant.
AKI attenuates de novo pathway. NAM enhances 2 Basal IRI
–10 –5
Mean ex
ly active organs, the results
NAMPT implicate NAMof the
1
NAD via the enzyme and augments production
ding to increased fat breakdown product d β-hydroxybutyrate, Normal leading to increased f ed1.0 Injured**
0
h ** 4 gh 6
Significance level (–log10P)
Significance level (–log10P)
i 2.0
4
f
rs for achieving PGC1α-dependent stress
Significance level (–log10P)
Normal IRI Sham WT 1.0
ted autacoid that
IRI Sham
production of prostaglandin PGE (ref. 5), a secreted autacoid that KO
Creatinine (mg dl–1)
Creatinine (mg dl–1)
2 3
Creatinine (mg dl–1)
maintains renal function. NAM treatment reverses established 3
erses established ischaemic AKI and also prevented AKI in an unrelated toxic 4
1.5
0.5 2
ule returns ∼140
unrelated toxicl perof β-hydroxybutyrate
model. Inhibition day of filtered signalling plasma
or prostaglandin 0.5 ** 2 1.0 1
production similarly abolishes PGC1α-dependent renoprotection.
ion by establishing energy-intensive
of mitochondrial healthelectro-
0
or prostaglandin 2 WT KO WT KO 0
Given the importance in ageing and the ** 1 0.5 Basal IRI
–10 –5 0 5 10
een the filtrate and vasculature. The kidney is
Mean expression diff. (log2)
function of metabolically active organs, the results implicate NAM
t renoprotection. e 0 g 6
Significance level (–log10P)
and NAD as key effectors for achieving PGC1α-dependent stress
Injuredi * ** 0
2.0
6
KO WT
in mitochondrial
n ageing and the abundance . We hypothe- WT KO WT KO 0 0
Creatinine (mg dl–1)
resistance. Basal IRI
–10 –5–4 0
–2 05 2 10 4 6 4
1.5
isome proliferatorThe matureactivated
renal tubule returnsreceptor
∼140 l per day gamma
of filtered plasma Mean expression diff. (log diff.
) NS
Mean expression (log )
s implicatewater NAM
1.0 2 2
back to the circulation
e by establishing energy-intensive electro-
g
Tran MT et* restores
al.,**Nature 2016
2
6
hed in renalchemicaltubules and important for stress
–log10P)
i 2.0
0.5
dependent stress gradients between the filtrateInjured
and vasculature. The kidney is Figure 1KO | NAMWT supplementation normal post-isch
6 0
only second to the heart in mitochondrial abundance4,7–11 . We hypothe- 0
l–1)
–4 −/−
–2 0 2 4 6 WT KO WT KOComment contourner l’effondrement de la voie métabolique de novo ?
Un peu d’histoire… Vitamine B3 (3è vitamine B découverte, en 1873) ou PP < NicoGne Prévient la pellagre (PP pour pellagra-prevenGng factor) NicoGnic ACid VitamIN / niacine (amide: nicoGnamide) ou NA NAD = nicoGnamide adénine dinucléoGde 1 nucléoGde de base nucléique = adénine 1 autre nucléoGde dont la base est le nicoGnamide
c 2.0 d 1.5
NAM
Creatinine (mg dl–1)
Veh.
Creatinine (mg dl–1)
** 1.5 NAM 1.0
1.0
0.5
0.5 P = 0.0011
0 0
MPN 0 12 24 48 72 Pre
Hours of reperfusion
f Control g
Tran MT et al., Nature 2016
*Mehr AP et al., Nat Med 2018
Comment contourner l’effondrement de la voie métabolique de novo ?
Nature 2018
Katsyuba E et al., Nature 2018
Quelle physiopathologie..? • Anomalies du cycle cellulaire épithélial • Anomalies métaboliques épithéliales • Epi-mutaGons dans les fibroblastes
XIXth century. Fixism is dead. Evolution happens.
Charles Darwin Jean-Baptiste de Lamarck
1809-1882 1744-1829
Organisms don’t adapt much Organisms adapt to their environment
Natural Selection (random mutations) Inheritance of acquired characteristics
Evolution is very slow Evolution can be fast« The Triple Helix »
Histone
Methylation Modifications
of Cytosine
Highly stable
Highly Dynamic433). Time will tell whether that potential is realized. This incarna
including th
Epigenetics and inheritance the transcrip
The Toadflax flower:
Should heritability onein agenome,
be mandatory contemporary view two phenotypes
of epigenetics? good measu
The requirement that epigenetic characters should be transmissible somes and th
that it bracke
a b in biology. It
Lcyc silencing
ing textbook
marks are sh
histone H2A
would qualif
but it is too t
Histone mod
with respect
histone acety
be viewed as
these histon
neither DNA
1744,
Wild typeLinnaeus, fixist 1742,
Peloric Ziöborg, student are not neces
Figure 1 | Frontal view of a wild-type toadflax flower and a peloric
gle histone m
or not epigen
Wild-type
epimutant. Peloric
a, The wild-type flower is dorsoventrally Epimutant
asymmetrical.
b, By contrast, the peloric flower is radially symmetrical with all petals Such a comp
Peloria
resembling the ventral petal of the wild-type : greek
flower. for
(Image « Monster »
reprinted, The issue
with permission, from ref. 4.) heritability.
Linnaeus: "This is certainly no less remarkable than if a cow were to give birth to a calf with a wolf's head,"Genome wide analysis of methylaCon profile in fibroblasts isolated
from normal vs fibroCc human kidneys
12 genes were found to be systemaGcally methylated in fibroGc kidneys
out of which 3 have orthologs in mice
e.g. RASAL1
RASAL1 is a GAP protein
Méthylation of RASAL1
In fibroblasts extracted Bechtel W et al, Nat Med 2010
from fibrotic kidneysRASAL1 promoter is methylated in myofibroblasts from injured kidneys
MeDIP
Captured (Me) DNA
Control for equal
loading in
immunoprecipitation
Bechtel W et al, Nat Med 2010RAS inhibitors are potentially anti-fibrotic drugs
Bechtel W et al, Nat Med 2010Tampe B et al., Kidney Int 2017
ssion basic res
Hydralazine (a demethylating agent) protects from AKI-induced CKD
Tampe B et al., Kidney Int 2017CONCLUSIONS Après un épisode d’AKI, l’épithélium tubulaire et les fibroblastes interstitiels ont un comportement fibrogénique (G2/M, FAO, RASAL1). 10 ans après: 15% des patients sont en dialyse L’AKI est un facteur de risque MAJEUR d’ESRD RAPIDE. Vitamine B3, hydralazine: de vieux traitements prometteurs
IdenAcal Twins, Roselle, Nj, 1967
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