Utility of Marginal Donors in Liver Transplantation MARGINAL OU ENXERTO LIMITROFE.pdf · Utility of...
Transcript of Utility of Marginal Donors in Liver Transplantation MARGINAL OU ENXERTO LIMITROFE.pdf · Utility of...
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Utility of Marginal Donors in
Liver Transplantation
HwanHyo, Lee
Department of Surgery, Samsung Medical Center,
Sungkyunkwan University School of Medicine,
Seoul, Korea
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Contents
� Review of Liver Transplantation(LT) Data
� Marginal Donors in LT
� Steatosis� Steatosis
� Small-for-Size(SFS) Graft
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Deceased & Living Donors1993 – 2002, UNOS
5,0005,0005,0005,000
6,0006,0006,0006,000
7,0007,0007,0007,000
Num
ber
of D
onor
sN
umbe
r of
Don
ors
Num
ber
of D
onor
sN
umbe
r of
Don
ors
0000
1,0001,0001,0001,000
2,0002,0002,0002,000
3,0003,0003,0003,000
4,0004,0004,0004,000
1993199319931993 1994199419941994 1995199519951995 1996199619961996 1997199719971997 1998199819981998 1999199919991999 2000200020002000 2001200120012001 2002200220022002YearYearYearYear
Num
ber
of D
onor
sN
umbe
r of
Don
ors
Num
ber
of D
onor
sN
umbe
r of
Don
ors
Deceased DonorDeceased DonorDeceased DonorDeceased DonorLiving DonorLiving DonorLiving DonorLiving Donor
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Deceased Donor Organs
Recovered 1993-2002, UNOS
6000
8000
10000
# o
f O
rgans R
ecovere
d
0
2000
4000
6000
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
# o
f O
rgans R
ecovere
d
Kidneys Livers Hearts Lungs Pancreas
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Waiting List at 1993-2002
UNOS
40,000
50,000
60,000
Num
ber
of R
egis
trations
0
10,000
20,000
30,000
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Year
Num
ber
of R
egis
trations
Kidney Liver
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Deaths on the Waiting List2000, 2001, 2002
Organ Type 2000 2001 2002
Kidney 3001 3119 3171Pancreas 15 40 27
193 221 201Kidney-Pancreas* 193 221 201Liver 1784 2012 1756Intestine* 23 45 52Heart 617 637 552Lung 492 491 468Heart-Lung 43 40 37Total * 6054 6455 6077* Total Unique Patient Deaths
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Waiting list in LT, KONOS
10001200
1400
0
200400
600800
2000 2001 2002 2003
Deceased donors Living donors Waiting
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Deceased donors in LTKONOS
50
6070
010
2030
4050
2000 2001 2002 2003
Deceased DDLT Discard
34.4 %34.4 %34.4 %34.4 %
13.8 %13.8 %13.8 %13.8 %
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Deceased and living donors in LT
KONOS
350400450500
050
100150200250300350
2000 2001 2002 2003
Deceased donors Living donors
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Liver Transplantation in SMC
Organ Transplantation Center (OTC)
60708090
0102030405060
1996 1997 1998 1999 2000 2001 2002 2003
Deceased Living Total
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Contents
� Review of Liver Transplantation(LT) Data
� Marginal Donors in LT
� Steatosis� Steatosis
� Small-for-Size(SFS) Graft
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Ideal Graft in LT
Deceased donor� Deceased donor
� Young adult age
� Enough graft size
� No steatosis
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What is the definition of
marginal liver donors ?
Donor with Potential Risk Factor
initial poor function (IPF) or
primary nonfunction (PNF)
� Increasing age
� Prolonged ischemia
� Hypotension
� Inotropic support
primary nonfunction (PNF)
� Steastosis
� Partial grafts
� Gender mismatch
� Non-heart beating donors
(NHBD)
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The limits of donor age
� Donor age of more than 70 years
� Associated with lower patient and graft survival
� Morphologic
changes
� Smaller and daker-
colored
� Fibrous thickening of
capsule
� Endothelial cell injury
during CIT
� Decreased ATP synthesis
after reperfusion
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Donor Age
UNOS
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Donor age in LT
SMC OTC
20
25
30
0
5
10
15
20
1996 1997 1998 1999 2000 2001 2002 2003
~ 29 30~ 39 40~ 49 50~
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Prolonged Cold Ischemia Time
(CIT)
� Independent risk factor for liver preservation
injury
� More than 14 hours : associated with a two-fold � More than 14 hours : associated with a two-fold
increase in preservation damage
� Prolonged postoperative course
� Biliary stricture
� Decreased graft survival
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Prolonged CIT
� Sinusoidal cell damage & Hypercoaguability
� Metabolic activity 10-fold
� Anaerobic metabolism and lactic acidosis
� Decrease of ATP & hypoxanthine
� Increase of reactive oxygen species
Ischemia-reperfusion(IR) injury
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Reperfusion –
insult on transplant liver
� Endothelial / Kupffer cell swelling
� Vasocontriction
� Leukocyte entrapment
interactions between different complex mechanisms
� Leukocyte entrapment
� Platelet aggregation within sinusoids
Failure of Microcirculation
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Endothelial & Kupffer Cell
Swelling
Failure of active transmembrane transport
Intracellular edema
Ischemia ReperfusionIschemia ReperfusionIschemia ReperfusionIschemia Reperfusion
Intracellular edema
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Vasocontriction Ischemia ReperfusionIschemia ReperfusionIschemia ReperfusionIschemia Reperfusion
Imbalance between nitric oxide(NO) and
endothelin(ET)
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1st Step of IR injury
� Liberation of endothelin-1(ET-1)
� Activation of Ito cells
� Constriction of hepatic sinusoids � Constriction of hepatic sinusoids
Reduced blood flow
� Activation of Kupffer cells
� Release of oxygen derived free
radicals (ODFR)
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1st Step of IR injury
ETETETET----1111Kupffer cellKupffer cellKupffer cellKupffer cell
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2nd Step of IR injury
� Up-regulation of adhesion molecules
� Activation of adhesion molecules (i.e., selectins,
integrins & Ig)
Liberation of chemokines from Kupffer cells� Liberation of chemokines from Kupffer cells
� Rolling and sticking Neutrophils to endothelial cells
Tissue injury
� Platelet aggregation
� Sinusoidal endothelial cell (SEC)
apoptosis
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2nd Step of IR injury
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Prevention of Preservation Injury
� Allows extended ischemia and
rewarming times
� Preventing organ damage during CITPreventing organ damage during CIT
� Prolonged storage
� University of Wiscosin(UW) solution
� Histidine-tryptophan-ketoglutarate
(HTK) or Bretschneider solution
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Contents
� Review of Liver Transplantation(LT) Data
� Marginal Donors in LT
� Steatosis� Steatosis
� Small-for-Size(SFS) Graft
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What is the role of Steatosis ?
� Macrosteatosis:macrovesicular fatty change
� Microsteatosis : small vacuole deposits
� Increase in cell volume: obstruction of
hepatic sinusoidal space
1% of steatosis* functional graft mass by 1%
* Marcos et al, Transpl 2000* Marcos et al, Transpl 2000* Marcos et al, Transpl 2000* Marcos et al, Transpl 2000
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Impact of Steatosis
on Graft Outcome
Severe (>60%) Mild (< 30%) Steatosis
� Primary nonfunction
� Early poor graft function
Graft Failure
good result
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Degree of Steatosis Acceptable for
LDLT
Microsteatosis : less injury and graft survival
rates similar to normal livers
� Macrosteatosis (< 30%): can be used
� Moderate macrosteatosis(<50%) : could be
used , if GV-to-SLV is more than 40%
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Accurate Detection of Steatosis
� Preoperative liver biopsy: standard method
Imaging studies : fatty infiltration findings� Imaging studies : fatty infiltration findings
� BMI(predictor of steatosis) > 25
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Photographs of Moderate Steatosis
� Macrovesicular steatosis: 5%, Microvesicular steatosis: 20%Macrovesicular steatosis: 5%, Microvesicular steatosis: 20%Macrovesicular steatosis: 5%, Microvesicular steatosis: 20%Macrovesicular steatosis: 5%, Microvesicular steatosis: 20%
ORO x 200ORO x 200ORO x 200ORO x 200 HE x 200HE x 200HE x 200HE x 200
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Photographs of Severe Steatosis
HE x 200HE x 200HE x 200HE x 200
� Macrovesicular steatosis: 20%, Microvesicular steatosis: 50%Macrovesicular steatosis: 20%, Microvesicular steatosis: 50%Macrovesicular steatosis: 20%, Microvesicular steatosis: 50%Macrovesicular steatosis: 20%, Microvesicular steatosis: 50%
ORO x 200ORO x 200ORO x 200ORO x 200
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Approach to Donors with Steatosis
� Recommendation
� Low calorie diet ( 25-30 Cal x ideal body
weight (kg) per day)
Aerobic exercise� Aerobic exercise
� Abstinence from alcohol
Overcome of Donor Shortage
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Contents
� Review of Liver Transplantation(LT) Data
� Marginal Donors in LT
� Steatosis� Steatosis
� Small-for-Size(SFS) Graft
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Optimal graft size in LT
� Standard liver volume (SLV) or Estimated
standard liver weight (ESLW)
� Liver volume optimal for the recipient’s
metabolic demands
* Urata et al, Hepatology 1995
� formula *
� SLV(ml) = 706.2 x BSA (m2) +2.4
metabolic demands
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Preoperative evaluation
of liver volume
� Liver CT (7.5mm slices)
RLV(ml):
� Graft-to-recipient’s weight ratio (GRWR)
� Graft volume to recipient’s SLV (GV/SLV)
� RLV(ml):
Sum of Areas x thickness (7.5)
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Volumetry Example
� Standard liver volume (SLV) of recipient
= 706.2 x (BSA) + 2.4 = 1204 cm3
Donor* Recipient
Volume % GRWR GV/SLV
Whole liver 1167cm3
Right lobe (excluding MHV) 705 cm3 60.4% 1.07%1.07% 58.6%58.6%
Left lobe (excluding MHV) 431 cm3 36.9%36.9% 0.65% 35.8 %
****CT volumetryCT volumetryCT volumetryCT volumetry
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What is the most important thing
in LDLT
Small-for-sizeLarge-for-size
Donor safety
� Primary nonfunction
� Early poor graft function
� Risk of rejection
Graft Failure
� Hepatic artery thrombosis
� Portal vein thrombosis
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Minimum Graft Size (?)
� Lo et al*, 40% or less of GV/SLV
� Kiuchi et al**, less than 1% of GRWR
� Kawasaki et al#, 30-40% of SLV or
* Lo et al, Transplantation 1996
** Kiuchi et al, Transplantion 1999
# Kawasaki et al, Ann Surg 1998
� Kawasaki et al#, 30-40% of SLV or
0.8~1.0% of GRWR
Lower graft survival
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Gra
ft Su
rviv
al R
ate
(%)
100
80
60
Graft Survival According to GRWR : 1.0, OTC in SMC
GRWR >= 1.0GRWR >= 1.0GRWR >= 1.0GRWR >= 1.0GRWR < 1.0GRWR < 1.0GRWR < 1.0GRWR < 1.0
Follow- up (year)
3210
Gra
ft Su
rviv
al R
ate
(%)
40
20
0Log rank=.8981Log rank=.8981Log rank=.8981Log rank=.8981
* From June 1997 to June 2002 , 79patients received adult LDLT* From June 1997 to June 2002 , 79patients received adult LDLT
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Gra
ft Su
rvival
Rat
e (%
)100
80
60
Graft Survival According to GRWR : 0.9, OTC in SMC
GRWR >= 0.9GRWR >= 0.9GRWR >= 0.9GRWR >= 0.9
GRWR < 0.9GRWR < 0.9GRWR < 0.9GRWR < 0.9
Follow- up (years)
3210
Gra
ft Su
rvival
Rat
e (%
)
40
20
0
GRWR < 0.9GRWR < 0.9GRWR < 0.9GRWR < 0.9
Log rank=.1825Log rank=.1825Log rank=.1825Log rank=.1825
* From June 1997 to June 2002 , 79patients received adult LDLT* From June 1997 to June 2002 , 79patients received adult LDLT
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Graft Survival According to GRWR : 0.8, OTC in SMC
Gra
ft Su
rvival
Rat
e (%
)100
80
60
GRWR >= 0.8GRWR >= 0.8GRWR >= 0.8GRWR >= 0.8
Follow- up (year)
3210
Gra
ft Su
rvival
Rat
e (%
)
40
20
0
GRWR < 0.8GRWR < 0.8GRWR < 0.8GRWR < 0.8
Log rank=.0256Log rank=.0256Log rank=.0256Log rank=.0256
* From June 1997 to June 2002 , 79patients received adult LDLT* From June 1997 to June 2002 , 79patients received adult LDLT
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Marginal- or Small-for-size
grafts
� Graft weight: less than 30% of SLV or 0.8% of
GRWR
� Kiuchi: 28% GW of recipient SLV, successful
transplantation - primary biliary cirrhosis
� Lo: 25% GW of recipient SLV, successful
transplantation – fulminant hepatic failure
biliary cirrhosis
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Small-For-Size(SFS) syndrome
� Graft weight: less than 30% of SLV or 0.8% of GRWR
� Graft weight, greater than 40% of SLV or 1.0% of
GRWR; associated with severe portal hypertension or
relative impedence to hepatic venous drainagerelative impedence to hepatic venous drainage
� Poor bile production
� Delayed synthetic function;coagulopathy
� Prolonged cholestasis
� Intractable ascites
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Mechanism of SFS syndrome
� Graft inflow : portal venous flow (PVF)
� PVF increase
� high cardiac output
� low peripheral vascular resistance
� reduced hepatic arterial flow
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Mechanism of SFS syndrome
� Persistent portal hypertension
� Portal venous hyperperfusion
Main factorsMain factorsMain factorsMain factors
� Portal venous hyperperfusion
SFSSReduced hepatic
arterial flow
� Preoperative conditions(UNOS status, ascites, bilirunin )
� Small functional graft mass
� Postoperative variables (sepsis, bile leak, renal failure)
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Histologic changes of graft in
SFSS
� Hepatocyte ballooning
� Centrolobular necrosis Reversible change
� Parenchymal cholestasis
� Graft regeneration : not affected
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Prevention of SFS syndrome
� Hepatic venous drainage (S5,S8)- Rt lobe graft
� Extended right-lobe graft including MHV
� Dual left lobe graft� Dual left lobe graft
� Auxiliary Partial Orthotorpic transplantation
� Splenic artery ligation
� Portosystemic shunt
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Hepatic venous drainage
- Rt lobe graft
� Hepatic venous drainage: S5, S8, RIHV
IVCIVCIVCIVC
RIHVRIHVRIHVRIHV
V5V5V5V5
IVCIVCIVCIVC
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Extended right-lobe graft
including MHV
� Increased risk of donor safety
� Extremely limited
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Dual left lobe graft
� Left lobe grafts from two donors
Lee et al, Surgery 2001Lee et al, Surgery 2001Lee et al, Surgery 2001Lee et al, Surgery 2001
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Auxiliary Partial Orthotopic Liver
Transplantation (APOLT)
� Concept: native liver support graft function
� Fulminant hepatic failure, metabolic disorders
� Inomata et al, 20 recipients � Inomata et al, 20 recipients
� Aid for a SFS graft
Inomata et al, Transplantation 1999Inomata et al, Transplantation 1999Inomata et al, Transplantation 1999Inomata et al, Transplantation 1999
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APOLT in SMC
� 29/ F(168 cm, 56kg), fulminant hepatitis; Lt
hemihepatectomy
� Donor : 21/M, her brother, extend left lateral
segment; 259 gm GRWR: 0.46 %segment; 259 gm GRWR: 0.46 %
graftgraftgraftgraft
Original Original Original Original liverliverliverliver
Postop 6 monthsPostop 6 monthsPostop 6 monthsPostop 6 months
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Management of Portal
Hyperperfusion
� SFS (GRWR<0.8%), associated with
excessive PVF (>250 ml/min/100 gm GW)
� Poor graft survivalPoor graft survival
� Splenic artery ligation (Troisi et al)
� to resolve ascites
� to increase HAF
� to prevent thrombocytopeniaTroisi et al, Ann Surg 2003
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Management of Portal Hypertension
� Portosystemic shunt; RPV – IVC (end-to-side)
� Nishizaki et al; taken down after reperfusion
� Takada et al; sustained opening���� portal � Takada et al; sustained opening���� portal
hypoperfusion / hyperammonemia
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Experimental studies for the
manipulation of marginal donors
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Upregulation of Heme Oxygenase System
•Heme Oxygenase-1 (HO-1): hsp32, potent cytoprotective effects
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Conclusions
� We should try and develop various clinical or
experimental modalities that can be manage
marginal donors.marginal donors.
Overcome of Donor Shortage