Transplants from Obese Pancreas
Donors
IPTR UNOS
/
American Journal of Transplantation 2004; 4: 605-610
IPTR UNOS
/
Pancreas from donor with BMI=35
IPTR UNOS
/
Pancreas from donor with BMI=26
IPTR UNOS
/
Complications after cadaveric
pancreas transplant by donor BMI
BMI <25
BMI 25-30
BMI >30
p
Thrombosis
4.8%
12.2%
14.8%
0.03
Deep Infections
11.7%
13.3%
21.0%
0.07
Wound Infections
9.1%
9.7%
9.9%
0.96
Leaks
5.0%
6.1%
4.9%
0.84
Bleeding
18.3%
14.8%
13.6%
0.39
Relaparotomy
20.6%
21.9%
24.7%
0.69
Complications
IPTR UNOS
/
Are Obese Donors Suitable
for
Islet Isolation?
IPTR UNOS
/
Transplantation 2004; 78: in press
IPTR UNOS
/
YES, OBESE DONORS ARE
GOOD FOR ISLET ISOLATION
Islet Yield
(IEQ)
BMI >30
BMI <30
After
Digestion
After
Purification
443,000
290,000
319,000
216,000
>300,000
37%
16%
IPTR UNOS
/
Minneapolis: The City of Lakes
IPTR UNOS
/
Unique Aspects UMN Pancreas
and Islet Transplant Program
• Largest program in world, >2000 total since
1966, ~100/YR since 1997
• Equal emphasis all categories: SPK & PAK in
uremic and PTA in nonurremic diabetics
• Do segmental grafts from living donors
(laparoscopic) in all categories, which for SPK
allows no wait to correct both uremia and
diabetes with one operation
• Steroid-free and calcineurin-inhibitor-free
maintenance immunosuppression with
Campath—non-nephrotoxic as well as nonIPTR /UNOS
diabetogenic (since 2003)
Key Drug is Gancyclovir (Valcyte)
-CMV incidence <10%% in our
Campath trials
The agent that allows us to use
immunosuppressive doses by
nearly any protocol to achieve
low-rejection episode rate
IPTR UNOS
/
The Campath/MMF
maintenance protocol has
been associated with the
same rejection and infection
rates as our old protocol.
Difference is in renal allograft
function (lower creatinines
early and long-term).
IPTR UNOS
/
-Completely non-diabetogenic
(and non-nephrotoxic)
immunsuppression can prevent
rejection of P,K transplants.
-Should be tried in islet allograft
recipients to eliminate need for
re-transplants (multiple donors) or
highly selective donor and
recipient criteria
IPTR UNOS
/
Pancreas Transplants by Category
PTA = 414 (53 LRD)
PAK = 564 (31 LRD, 1 LURD)
SPK = 598 (30 LRD, 6 LURD)
SPL = 1
TOTAL = 1576
73
19
78
19
80
19
82
19
84
19
86
19
88
19
90
19
92
19
94
19
96
19
98
20
00
20
02
160
140
120
100
80
60
40
20
0
12/66 –12/31/2002
66
-
Number
Pancreas Transplants, U of MN
Year
IPTR UNOS
/
IPTR UNOS
/
LIVING DONOR
SEGMENTAL PANCREAS
OR
ISLET TRANSPLANTS
IPTR UNOS
/
History of living donor segmental
islet and pancreas transplant
• First two living donor islet allografts at U
Minnesota 1977 and 1978
• Preceded by successful islet autografts
• Insulin-independence not achieved in the first
two LD islet allografts
• First LD seg px tx at U MN1979, insulinindependence achieved. >140 cases since.
• First LD islet allograft with insulin
independence achieved Jan 19, 2005, Kyoto
IPTR UNOS
/
Auto-islet experience has
implications for living donor
islet allografts.
IPTR UNOS
/
IPTR UNOS
/
IPTR UNOS
/
IPTR UNOS
/
Living donor
segmental pancreas
transplant experience
IPTR UNOS
/
History of living donor segmental
islet and pancreas transplant
• First two living donor islet allografts at U
Minnesota 1977 and 1978
• Preceded by successful islet autografts
• Insulin-independence not achieved in the first
two LD islet allografts
• First LD seg px tx at U MN1979, insulinindependence achieved. >140 cases since.
• First LD islet allograft with insulin
independence achieved Jan 19, 2005, Kyoto
IPTR UNOS
/
MN Criteria for LD Segmental
Pancreas Donor
• BMI <28
• First phase insulin release during IVGTT or
arginine stimulation increased three-fold
above baseline
• No other family members diabetic other than
recipient
• When criteria met, diabetes risk in donor very
low (1%), but of ~40 who did not meet criteria,
6 became diabetic. Overall incidence of
postdonation diabetes ~4%
IPTR UNOS
/
IPTR UNOS
/
Since 1999 we have
done living donor
segmental
pancreatectomy by the
hand-assisted
laparoscopic technique
IPTR UNOS
/
Living donor segmental
pancreas transplant in
recipient has been done with
duct-injection, bladder- or
enteric-drainage.
IPTR UNOS
/
IPTR UNOS
/
Patient and Full Graft Survival
of 35 LD SPK Transplants
UNIVERSITY
OF
MINNESOTA
,
1/1994
-
7/2001
100
% Survival
80
60
40
20
1-Yr.Surv
Patient
100%
Kidney
100%
Pancreas
86%
0
0
12
24
36
48
Months after Transplant
60
IPTR UNOS
/
The Islet Transplant
IPTR UNOS
/
What about current islet
allograft outcomes with
deceased donors?
IPTR UNOS
/
Human Islet Allotransplantation
Daclizumab; 5 injections over 10 wks
Sirolimus + Low-dose tacrolimus
Transplant
#1
Day 0
Transplant
#2
10-12 KIE/kg
Day 70
IPTR /UNOS
Shapiro AMJ et al., NEJM 2000;343:230-8
Edmonton Protocol for Islet
Transplantation
• Isolate islets from deceased donor
pancreases by the standard Ricordi chamber
collagenase digestion-ficoll seperation
technique
• Standard intraportal islet infusion
• Dicluzamab induction and
tacrolimus/siroliumus steroid-free
maintenance immunosuppression
• Keep retransplanting to get enough betacells to achieve insulin-independence
(multiple donors)
IPTR UNOS
/
Critique of Edmonton Protocol
• Requires multiple donors (retransplants) to
achieve insulin-independence in most
recipients
• Even though steroid-free, the
immunosuppression is still diabetogenic—
both tacrolimus and sirolimus—and may be
responsible for the need for retransplants
• Non-diabetogenic immunosuppression is now
available—used in pancreas, not yet widely
applied in islets
IPTR UNOS
/
Main value of the original Edmonton
Protocol:
It showed that insulin-independence
could be achieved if enough islets
(beta-cells) were transplanted
Long-term functional survival is still a
problem (compared to pancreas
transplants)
IPTR UNOS
/
100
1:1 transplants
80
2-3:1 transplants
60
40
20
ila
M
R
91
-
96
n
G
89
ie
-9
ss
5
en
Ed
m
92
on
-9
to
5
n
99
-0
0
0
IT
% insulin-independent at 1 yr
Success rates of islet transplants for T1D
IPTR UNOS
/
% Insulin Independence
Insulin-independent islet allograft survival
Edmonton – Miami - Minnesota
100
80
n= 118
1-yr survival: 80-85 %
60
40
20
0
0
2
4
6
8
10
1
12
0.8
100
Probability off Insulin
% Insulin Independence
Months Post First Transplant
80
60
40
20
0.6
Ce
Pro
0.4
0.2
0
0
0
3
6
9
Months Posttransplant
12
0
100
200
300
400
Days Posttransplant
IPTR UNOS
/
Kaplan-Meier Survival Curves (Insulin Independence)
From time of first transplant
100
80% Fresh
Survival (%)
80
72% Cultured
60
40
Fresh
Cultured
20
Log Rank Statistic: 1.6
P-Value: 0.2
0
0
2
4
6
8
10
Time in Months Post First Transplant
12
IPTR UNOS
/
Five Year Kaplan-Meier Survival Curves
(Insulin Independence from time of first transplant)
100
Fresh (N=25)
Cultured (N=22)
Survival (%)
80
Log Rank Statistic: 1.6
P-Value: 0.2
60
40
24%
21%
20
0
0
12
24
36
48
60
Time in Months Post First Transplant
72
IPTR UNOS
/
Decay in islet function over time
Reasoning
• Do kinetics of decay in function, and absence
of auto- and alloantibodies in recipients with
failing grafts suggest that immunity is not
primary reason for graft failure?
• Chronic rejection? Autoimmune recurrence?
• Islet precursor cells missing?
• Does immunosuppression interfere
with islet replication/neogenesis?
• Serial systematic graft biopsies?
IPTR UNOS
/
Single-Donor Islet Transplantation
at U Minnesota
Transplantation of Cultured Islets from Two-Layer
Preserved Pancreases in Type 1 Diabetes with
Anti-CD3 Antibody
u
u
4 of 6 recipients achieved insulin independence after
single-donor islet transplantation
Induction immunotherapy with the anti-CD3 mAb
hOKT3g1 (Ala-Ala) may facilitate minimization of
maintenance immunosuppression
Am J Transplantation 2004
IPTR UNOS
/
Insulin (Units/day)
Stable insulin independence after single-donor
islet transplantation for >3, >4, >4 yrs
70
Subject #001-002
Subject #001-003
Subject #001-006
35
0
0
400
800
1200
1600
Days Posttransplant
IPTR UNOS
/
Stable insulin independence after single-donor
islet transplantation for >3, >4, >4 yrs
HbA1c (%)
10
8
6
4
Subject #001-002
Subject #001-003
Subject #001-006
2
0
400
800
1200
1600
Days Posttransplant
IPTR UNOS
/
Islet Transplant Protocol #2
Tacrolimus
MMF
Sirolimus
Etanercept
Heparin IV
Insulin IV
SC
SC
Daclizumab
Rabbit Anti-thymocyte Globulin
TLP -2
-1
Donor Islet
Isolation
0
+1
+2
+7 +10
+28
Days after transplant
Islet Transplant
Islet
Culture
7,271 ± 1,035 IE/kg
IPTR UNOS
/
Single-Donor Islet Transplantation
Feb 16, 2005
IPTR UNOS
/
Current Protocol (#3)
Cyclosporine
Everolimus
Etanercept
Heparin IV
Insulin IV
SC
SC
Rabbit Anti-thymocyte Globulin
TLP -2
-1
Donor Islet
Isolation
0
+1
+2
+7 +10
+28
Days after transplant
Islet Transplant
Islet
Culture
IPTR UNOS
/
100
1:1 transplants
80
2-3:1 transplants
60
40
20
ila
M
R
91
-
96
n
G
89
ie
-9
ss
5
en
Ed
m
92
on
-9
to
5
M
n
in
99
ne
-0
so
0
ta
00
-0
3
0
IT
% insulin-independent at 1 yr
Success rates of islet transplants for T1D
IPTR UNOS
/
Single-donor: 7 strategies
16 of 18 insulin-free with 1:1 transplant
•
•
•
•
•
•
•
Young, LARGE donors
Short cold storage
High islet graft potency
Pretransplant islet culture
Potent immunosuppression
Posttransplant insulin treatment
Minimizing diabetogenic side effects
Am J Transplantation 2004, and JAMA 2005
IPTR UNOS
/
With the advances in islet preparation, LD
islet transplantation can be revived
• Fresh, unpurified islets probably superior to
purified deceased donor islets
• Can help alleviate the eventual shortage of
deceased donor pancreases
• Right now waiting time still short in US
because so few listed relative to number of
donors
• In countries in which deceased donors are in
short supply, living donors could play a bigger
role
• Question is if success will be as good as with
LD segmental pancreas transplants
IPTR UNOS
/
History of living donor segmental
islet and pancreas transplant
• First two living donor islet allografts at U
Minnesota 1977 and 1978
• Preceded by successful islet autografts
• Insulin-independence not achieved in the first
two LD islet allografts
• First LD seg px tx at U MN1979, insulinindependence achieved. >140 cases since.
• First LD islet allograft with insulin
independence achieved Jan 19, 2005, Kyoto
IPTR UNOS
/
Human Studies
in Islet Transplantation
Living donor islet transplant
performed in Kyoto, Japan
on Jan 19, 2005
by Drs. Matsumoto and colleagues
IPTR UNOS
/
Islet Mass Sufficient?
No brain death
No cold storage
Reduced immune response
IPTR UNOS
/
Emerging Opportunities
1. Costimulation blockade: IL-2R Ab + LEA29Y + SRL
2. FTY720: IL-2R Ab + FTY720 + RAD
IPTR UNOS
/
Notable characteristics of islet
xenografts
• Islet xenografts are primarily avascular and
become revascularized by host endothelium
Korsgren 1997
• The gal-1,3-gal (Gal) epitope is not
expressed on adult pig islet endocrine cells
Bennet et al. 2000; Rayat et al., 2003
IPTR UNOS
/
Pig-to-NHP islet xenotransplantation
BSM+FTY720+RAD+ABI793+LFM
BSM+FTY720+RAD+ABI793
BSM+FTY720+RAD
University of Minnesota
IPTR UNOS
/
600
5.0
500
4.0
400
3.0
300
200
2.0
100
1.0
0
0.0
-30
0
30
60
90
120 150 180
Exogenous Insulin [U/kg/day]
Blood Glucose [mg/dL]
6.0
Days Posttransplant
IPTR UNOS
/
Histology day +187
Insulin
85 islets on 10 sections
57/85 w/o infiltrate
24/85 with periislet infiltrate
IPTR UNOS
/
Evolution of islet replacement
Human Pancreas
Human Islets
Porcine Islets
Precursor Cell
Derived islets
Islet Regeneration
in Native Pancreas
2000
200?
20??
IPTR UNOS
/
Meanwhile, back to the
present.
What to do?
IPTR UNOS
/
b-cell replacement therapy
• Growing demands
• Islet transplant –
preferable approach
– Eliminate surgical risks
– Less long-term
complications
Islet Transplant Registry
140
120
100
80
60
40
20
02
01
20
00
20
99
20
98
19
97
19
96
19
95
19
94
19
93
19
92
19
19
19
19
DIIT, University of Minnesota
91
0
90
Number of Transplants
• Xenogeneic islet
transplants could meet
the demand of donor
shortage
International pancreas transplant registry (IPTR), Bretzel RG, 2004
IPTR UNOS
/
Allocation of Available
Organs
• Use techniques that allows the
maximal number of recipients to
become insulin-independent
while minimizing the magnitude
of the surgery in as many as
possible
IPTR UNOS
/
Allocation
• Until we have an unlimited source of islets (e.g,
xenografts are succesful), or until islet and
pancreas allo-transplantation have equal
efficiency in inducing insulin-independence in
the recipients, we must link organ allocation
to the two BCR techniques by an algorithm
that allows the maximum number of recipients
to become insulin-independent while
minimizing the magnitude of the surgery in as
many as possible.
IPTR UNOS
/
Should Have a Common Waiting List
for Pancreas and Islet Transplant
Candidates
• Stratified according to insulin requirements
– Examples:
• Pancreas from a large donor, allocate first for
islet transplantation to candidates with low insulin
requirements
• Small or normal size donors allocate first for
Immediately-vascularized organ transplantation
to candidates with normal or high insulin
requirements who have no contraindications to
major surgery
• Candidates could be ranked by wait time, match,
medical urgency, etc.
IPTR UNOS
/
Bottom Line
• Do Islet Txs in Beta Cell Replacement
candidates who would predictably become
insulin-independent with a single donor using
state-of-the-art isolation
• Do Px Txs in those who would predictably
require re-transplants (multiple donors) for
islets, unless candidate is willing to have long
interval to achieve insulin-independence
• Do Px Txs in diabetics with exocrine
deficiency who want this condition also
corrected
IPTR UNOS
/
IPTR UNOS
/