Machine preservation of the liver
Peter J Friend
University of Oxford
Disclosure
I am co-founder and medical director of the
Oxford University spin-out company, OrganOx,
that has been set up to develop
normothermic organ preservation.
Liver transplant survival – UK
From transplantation
Centre G
Centre D
Centre E
Centre B
Centre F
Centre C
Centre A
Liver transplant survival – UK
From listing
From transplantation
Centre G
Centre G
Centre D
Centre E
Centre B
Centre F
Centre C
Centre A
Centre B
Centre F
Centre D
Centre E
Centre A
Centre C
Patients more likely to die on waiting list than postoperatively
Trends in liver transplantation
• Increasing organ donation, but mostly in high
risk donors
• Increasing incidence of liver disease
• Waiting lists increasing faster than transplants
• Long waiting lists, restricted access, mortality
The challenge – to transplant greater numbers
of higher risk organs without compromising the
outcome
Utilisation of donor livers
DBD
DCD
Total
Consent for donation
763
1071
1834
Consent for liver
735
981
1716
Livers offered
725
868
1593
Livers accepted
673
274
947
Livers retrieved
640
185
825
Livers transplanted
582
136
718
45% livers offered are accepted
76% livers accepted are transplanted (50% of DCD)
Limitations of static cold storage
•
Cooling
Loss of cell membrane functions
•
No oxygen delivery
Anaerobic metabolism
•
Accumulation of metabolites
Ischaemia-reperfusion
•
Limited viability assessment
Injury occurs at time of reperfusion
Acceptable for high quality, but not marginal organs
DCD liver transplants have
poorer outcomes
Primary non-function
Ischaemic cholangiopathy
Inferior outcomes - graft failure &
biliary complications
Patient
P<0.01
Graft
P<0.001
Foley. D’Alessandro et al et al 2011
Ischaemic cholangiopathy after DCD liver
transplantation
Success has been achieved at the price of selectivity
11 studies
• Unrandomised control groups
• 489 DCD (Maastricht 3)
• 4455 DBD controls
• Isch. cholangiopathy 16% vs. 3%
(O/R 10.8)
• Biliary complications 29% vs.
17% (O/R 2.4)
• Retransplant (O/R 2.6)
• Primary non-function (O/R 3.6)
Jay, Skaro et al (2011),
Northwestern, Chicago
• Internalisation of membrane
proteins during ATP depletion
to reduce energy demand
• Structural but lack of functional
recovery after energy
restoration (unlike renal
tubular cells)
Hepatology 2000, 31(5): 1045-54
Liver preservation – the key issues
• Oxygen delivery
• Machine perfusion (versus static)
• Temperature
Oxygen delivery
Am J Trans 2011, 11:2627-34
• Oxygen insufflation via IVC, exit via pin-pricks in capsule
• Superior function; survival; transaminase release
(Rat liver reperfusion model)
Trans Int 2010, 23: 944-50
Machine perfusion
Hypothermic
Normothermic
Pig DCD liver transplant model (60 min WI)
7 hr cold storage versus 6 hr CS + 1 hr HOPE
Ann Surg 2009, 250 (5): 674-83
• 90 min warm ischaemia
• 4 hours CS or HMP
• Liver transplantation
• Better immediate function
with HMP
• Progressive cellular injury
• 20% survival
Transplantation 2012, 94 (1): 22-29
Columbia University, New York
Am J Trans 2010, 10: 372-381
• Low risk donors
– <65 yr, <25% steatosis, DBD
• 20 HMP preserved organs (3-7
hr), matched controls
• No difference in early
histological appearances
• Lower transaminase & lower
cytokine expression in HMP
Larger-scale clinical trial in progress
Normothermic machine perfusion
Recreate physiological environment
Deliver oxygen
Physiological
temperature
Provide nutrients
Allow normal metabolic activity
Avoid ischaemia-reperfusion
Assess viability
1.0
20hr s w ar m ( n=7)
pr opor tional s ur v iv al
0.9
20hr s c old ( n=7)
0.8
0.7
p=0.0268
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
24
48
72
hour s
96
120
Survival after normothermic preservation
DBD vs. DCD (40 min)
DBD
1
% Survival
0.8
DCD
0.6
0.4
HBD
0.2
NHBD
0
0
24
48
Time Hours
72
p=NS
96
120
Normothermic DBD vs. DCD (40 min)
ALT release
120
100
nhb40
20hrs warm (n=6)
DCD (n=6)
hb
20hrs
warm (n=7)
DBD
(n=7)
80
U/l
ALT
60
40
P=NS
20
0
no
do
r
re
i
cip
t
en
tic
pa
e
h
an
in
5m
in
m
10
in
m
30
in
m
60
rs
2h
rs
3h
rs
4h
rs
6h
time
rs
8h
s
hr
12
s
hr
16
s
hr
20
s
hr
24
s
ay
2d
s
ay
3d
s
ay
4d
s
ay
5d
Viability assessment – Base excess
BE Perfusion
HB
5hrs
DBD
5 hours
DBD
20 hours
HB
20hrs
NHBD40
20hrs
DCD (40) 20
hours
DCD (60) 20
hours
NHBD60
20hrs
10
5
16
12
8
6
4
3
2
1
m
in
30
m
in
10
-5
5m
in
Pr
im
e
0
* p<0.05
-10
*
-15
*
-20
time
*
*
•
•
•
•
•
Pig liver transplant model
90 minutes warm ischaemia
60 min normothermic recirculation (ECMO)
4 hours normothermic preservation
100% survival
Preservation or reconditioning?
Re-conditioning
Transplant
Organ retrieval
Recirculation
Preservation
Must the perfusion machine be transportable?
60 mins
warm
ischemia
Liver
retrieval
4 hr UW 20 hours NP
24 hours NP
Reperfuse
24 hr
Bile output
AST levels
Base excess
After 60 minutes warm
ischaemia, 4 hours cold
storage causes significant
damage
Reddy et al 2004
• Pig liver DCD model
• ATP levels
– 30% after 60 min WI
– 0% after 2 hr CS
– 80% after 4 hr NMP
J Surg Res 2011, 173: 83-88
From laboratory to clinic
Commercial perfusion systems
Product specification: What matters?
• Physical parameters: weight, size, materials
• Usability: transportability, automation, ease of setup
• Functionality (what features are essential?):
– Blood or oxygen carrier?
– In-line or off-line blood gas analysis?
– Gas bottles or on-board gas production?
– Mains power/DC power/battery power?
– Parameters measured and displayed to the user?
• Regulatory compliance
• Cost
Hypothermic or normothermic?
Cooling
Energy
depletion
Metabolite
accumulation
Viability testing
Therapeutic
delivery
Static cold
Hypothermic
machine
Normothermic
machine
-
-
+
+/-
+
+
+
+/-
+
+/-
+
-
Organ Recovery Systems
Hypothermic machine perfusion
Organ Assist – liver perfusion
OrganOx metra
Automated, transportable, self-contained
The OrganOx metra™ - start of perfusion
Start
After 10
secs
Clinical trial in progress
After 60 secs
Where will we be in 5 years?
• Routine machine perfusion of all/most livers
• Cold or warm?
• Portable or static?
• Logistic demands – retrieval teams
• Cost implications
• More donors and increased utilisation
Conclusions
• Static cold preservation does not meet the
challenges of marginal donor organs
• Hypothermic machine perfusion
– Benefits in pig model
– Clinical studies in progress
• Normothermic machine perfusion
– Resuscitation, prolonged preservation & viability
assessment (in pig models)
– Cold preservation must be avoided (even in transit)
– Clinical trials in progress
Machine perfusion …. not whether, but how?