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IPTR UNOS
/
BETA CELL REPLACEMENT
(PANCREAS AND ISLET
TRANSPLANTATION)
FOR
THE TREATMENT
OF
DIABETES MELLITUS
IPTR UNOS
/
IPTR UNOS
/
IPTR UNOS
/
BETA-CELL REPLACEMENT THERAPY
IN DIABETES MELLITUS
Diabetes mellitus is a disease of absolute or relative
deficiency of insulin-producing beta cells, in the islets of
Langerhans within the pancreas, relative to insulin needs,
whether the Type 1 or 2.
Pancreas transplantation is an islet transplant—just a big
islet.
The difference: pancreas transplantation, although highly
effective, is major surgery with significant complications,
while islet transplantation is the prototype of minimally
invasive surgery with few complications; but it is relatively
inefficient in terms of utilization of a scarce resource—
deceased donors.
The immunosuppression needed to prevent rejection is of the
same magnitude for either approach.
IPTR UNOS
/
BETA-CELL REPLACEMENT THERAPY
IN DIABETES MELLITUS
Diabetes mellitus is a disease
of absolute or relative
deficiency of insulin-producing
beta cells, in the islets of
Langerhans within the
pancreas, relative to insulin
needs, whether Type 1 or 2.
IPTR UNOS
/
BETA-CELL REPLACEMENT THERAPY
IN DIABETES MELLITUS
Pancreas
transplantation is an
islet transplant—
just a
big islet.
/
IPTR UNOS
BETA-CELL REPLACEMENT THERAPY
IN DIABETES MELLITUS
The difference: pancreas transplantation,
although highly effective, is major
surgery with significant complications,
while islet transplantation is the
prototype of minimally invasive surgery
with few complications; but it is relatively
inefficient in terms of utilization of a
scarce resource—deceased donors.
IPTR UNOS
/
BETA-CELL REPLACEMENT THERAPY
IN DIABETES MELLITUS
The immunosuppression
needed to prevent
rejection is of the same
magnitude for either
approach.
IPTR UNOS
/
BETA-CELL REPLACEMENT THERAPY
IN DIABETES MELLITUS
Diabetes mellitus is a disease of absolute or relative
deficiency of insulin-producing beta cells, in the islets of
Langerhans within the pancreas, relative to insulin needs,
whether the Type 1 or 2.
Pancreas transplantation is an islet transplant—just a big
islet.
The difference: pancreas transplantation, although highly
effective, is major surgery with significant complications,
while islet transplantation is the prototype of minimally
invasive surgery with few complications; but it is relatively
inefficient in terms of utilization of a scarce resource—
deceased donors.
The immunosuppression needed to prevent rejection is of the
same magnitude for either approach.
IPTR UNOS
/
Beta-cell replacement therapy
• WHEN: 1. Insulin-treated diabetic patients obligated to
immunosuppression: renal allograft recipients.
2. Labile diabetics—insulin-reactions with hypoglycemic
unawareness.
• HOW: Pancreas transplant if high and islet transplant if
low insulin requirements.
• WHICH WAY TO TAKE: Minimally invasive surgery
(islets) whenever possible, but depends on increasing
efficiency.
• As islet preparations improve, a single donor will suffice
for candidates with higher and higher insulin
requirements, and the proportion who need a pancreas
to avoid need for retransplant will progressively decrease.
• Do not inefficiently allocate a scarce resource (donor
pancreas).
IPTR UNOS
/
Beta-cell replacement therapy
• WHEN: 1. Insulin-treated
diabetic patients obligated to
immunosuppression: renal
allograft recipients.
• 2. Labile diabetics—insulinreactions with hypoglycemic
unawareness.
IPTR UNOS
/
Beta-cell replacement therapy
•HOW: Pancreas
transplant if high
and islet transplant
if low insulin
requirements.
IPTR UNOS
/
Beta-cell replacement therapy
• WHICH WAY TO TAKE: Minimally
invasive surgery (islets) whenever
possible, but depends on increasing
efficiency.
• As islet preparations improve, a single
donor will suffice for candidates with
higher and higher insulin requirements,
and the proportion who need a pancreas
to avoid need for retransplant will
progressively decrease.
• Do not inefficiently allocate a scarce
resource (donor pancreas).
IPTR /UNOS
Beta-cell replacement therapy
• WHEN: 1. Insulin-treated diabetic patients obligated to
immunosuppression: renal allograft recipients.
2. Labile diabetics—insulin-reactions with hypoglycemic
unawareness.
• HOW: Pancreas transplant if high and islet transplant if
low insulin requirements.
• WHICH WAY TO TAKE: Minimally invasive surgery
(islets) whenever possible, but depends on increasing
efficiency.
• As islet preparations improve, a single donor will suffice
for candidates with higher and higher insulin
requirements, and the proportion who need a pancreas
to avoid need for retransplant will progressively decrease.
• Do not inefficiently allocate a scarce resource (donor
pancreas).
IPTR UNOS
/
Beta-cell Replacement Therapy
for Diabetes:
An Integrated
Approach with Pancreas and Islet
Transplantation
IPTR UNOS
/
THREE BROAD CATEGORIES OF B-CELL
REPLACEMENT
in
PANCREAS (P) or ISLET (I) TRANSPLANT (T)
RECIPIENTS
-Simultaneous(S) kidney (K) transplant
SBK (SPK or SIK)
-After(A) kidney transplant
BAK (PAK or IAK)
-B-cell transplant alone
BTA (PTA or ITA)
IPTR UNOS
/
Pancreas Transplants Worldwide
5,260
59
17,399
29
2
156
144
8/04
IPTR UNOS
/
Islet transplant activity
Edmonton (67)
Miami (30)
(1999-2004)
Milan (35)
Minneapolis (20)
Philadelphia (12)
Brussels (35)
Giessen (27)
Vancouver (12)
Geneva/GRAGIL (28)
Nordic Network (24)
Leuven (20)
Innsbruck (11)
Zurich (10)
Houston (11)
Harvard (10)
Northwestern (8)
St Louis (8)
NIH (6)
Cincinnati (6)
Seattle (6)
Emory (6)
City of Hope CA (5)
Memphis (3)
UCSF (2)
U Mass (2)
U. Maryland (1)
Columbia NY (1)
Carolina Med Ctr (1)
Sydney (6)
Kyoto (5)
Budapest (4)
Kings (UK) (2)
Sao Paulo (2)
Chiba (1)
Tokyo (1)
Shanghai (1)
35 institutions
~ 430 patients
Red = ITA
Blue= ITA and SIK/IAK
Black= SIK/IAK
IPTR UNOS
/
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
/
Minimally invasive surgery is
desirable.
For BCR, the proportion of cases
done by the two techniques
(pancreas vs. islet
transplantation) is influenced by
their relative efficiency.
Currently pancreas is dominant.
IPTR UNOS
/
IPTR UNOS
/
Pancreas Transplants Worldwide
Number of Transplants
2000
1800
Total:
n = 23,051
1600
Non USA: n =
1400
USA:
5,924
n = 17,127
1200
1000
800
600
400
200
1//05
20
03
20
01
19
99
19
97
19
95
19
93
19
91
19
89
19
87
19
85
19
83
19
81
19
79
pre
78
0
IPTR UNOS
/
Number of Tx Centers and Number of Txs
USA Pancreas Transplants 1/1/1988  12/31/2004
Centers
140
120
100
Transplants
# Centers
1400
# of Txs
1200
1000
80
800
60
600
40
400
20
200
0
0
1988 1990 1992 1994 1996 1998 2000 2002 2004
1/05
IPTR UNOS
/
Pancreas Transplant Categories
USA SPK, PAK and PTA Transplants
Number of Transplants
1200
PTA
PAK
SPK
1000
800
600
400
200
0
02
20
00
20
98
19
96
19
94
19
92
19
90
19
88
19
8/04
IPTR UNOS
/
Living Donor Kidneys in PAK
USA Pancreas Transplants 1/1/1988  12/31/2003
%
100
80
60
40
20
0
1988
8/04
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
Recipient Age
USA Pancreas Transplants 1/1/1988  12/31/2003

PAK
PTA
SPK





Recipient Age [Yrs]
60






















40


20


1994
1996

1988
1990
1992




1998

2000
2002
Transplant Year
IPTR UNOS
/
Patients with Type II Diabetes
USA Pancreas Transplants 1/1/1994  12/31/2003
%
10
8
6
4
PAK
PTA
SPK
2
0
1994
1/05
1996
1998
2000
2002
IPTR UNOS
/
Recipient Gender
USA Pancreas Transplants 1/1/1988  12/31/2003
% Male
70
60
50
40
30
PAK
PTA
SPK
20
10
0
1988
1/05
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
Duct Management Technique
USA Pancreas Transplants 1/1/1988  12/31/2003
% enteric drained
90
80
70
60
50
40
30
20
10
0
1988
8/04
PAK
PTA
SPK
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
IPTR UNOS
/
IPTR UNOS
/
Portal Drainage in ED Txs
USA DD Primary Pancreas Transplants, 1/1/1988  12/31/2003
%
PAK
PTA
SPK
60
50
40
30
20
10
0
1996
8/04
1998
2000
2002
IPTR UNOS
/
IPTR UNOS
/
Improvements
in
Outcomes
by
Eras
IPTR UNOS
/
1-Year Patient Survival
USA DD Primary Pancreas Transplants, 1/1/1988  12/31/2003
%
100
90
80
PAK
PTA
SPK
70
60
1988
8/04
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
1-Year Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1988  12/31/2003
%
100
80
60
PAK
PTA
SPK Px
SPK Kd
40
20
1988
8/04
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
SPK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987  6/ 6/2004
%
Year HL[mos]
100
1988 154
1990 160
80
1992 158
1994 161
60
1996 165
1998 170
40
20
0
0
12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Months Posttransplant
8/04
IPTR UNOS
/
PAK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 1/1/1988  6/ 6/2004
%
100
Year HL[mos]
80
1988 59
1990 69
60
1992 78
40
1994 85
1996 95
20
1998 105
0
0
12
24
36
48
60
72
84
Months Posttransplant
8/04
96
108 120
IPTR UNOS
/
PTA Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987  6/ 6/2004
%
100
Year HL[mos]
1988 68
1990 78
1992 81
1994 88
1996 105
1998 121
80
60
40
20
0
0
12
24
36
48
60
72
84
96
108
120
Months Posttransplant
8/04
IPTR UNOS
/
Early Technical Pancreas Graft Failures
USA DD Primary Pancreas Transplants, 1/1/1988  12/31/2003
%
40
PAK
PTA
SPK
30
20
10
0
1988
8/04
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
1-Year Immunological Graft Loss
USA DD Primary Pancreas Transplants, 10/1/1988  12/31/2003
%
40
PAK
PTA
SPK
35
30
25
20
15
10
5
0
1988
8/04
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
Anti-T-Cell Induction
USA Pancreas Transplants 1/1/1988  12/31/2003
%
90
80
70
60
50
40
30
20
10
0
1988
8/04
PAK
PTA
SPK
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
5-Year Immunological Graft Loss
USA DD Primary Pancreas Transplants, 10/1/1988  12/31/2003
%
80
PAK
PTA
SPK
70
60
50
40
30
20
10
0
1988
8/04
1990
1992
1994
1996
1998
2000
2002
IPTR UNOS
/
- Recently, the indication for
solitary PaTxs has been
questioned because of
reportedly higher mortality
rates for transplanted vs.
for wait-listed patients.
(Venstrom et al. JAMA, 2003;
290: 2817 - 2833)
IPTR UNOS
/
We redid the analysis of mortality risk of
pancreas transplant candidates vs recipients
Am J Transp 2004; 4:2018-26
• Differences: Venstrom counted patients listed
at more than one center twice. We corrected.
• Some patients had been wrongly categorized
in the SPK, PTA and PAK groups. We
reclassified.
• We updated the Social Security Master Death
File and found many more deaths on the wait
list
• We corrected for serum creatinines that had
not been updated after a kidney transplant so
no patients were excluded
IPTR UNOS
/
Mortality risk
of
pancreas transplantation
vs.
remaining on the waiting list*
*Gruessner et al. Am J Transpl 2004; 4:
2018-26
IPTR UNOS
/
Patient Survival from Time of Listing
UNOS Pancreas Waiting List 1/1/1995  5/31/2003
100
%
80
60
40
Survival
Cat.
n
1Yr
4Yrs
■ SPK 6995 97.5% 90.7%
Wait 5536 87.2% 46.0%
20
0
0
12
24
Months Waiting
2/04
36
48
IPTR UNOS
/
Patient Survival from Time of Listing
UNOS Pancreas Waiting List 1/1/1995  5/31/2003
100
%
80
60
40
Survival
Cat.
n
1Yr
4Yrs
■ PAK 1714 97.3% 88.4%
Wait 1228 94.7% 74.5%
20
0
0
12
24
Months Waiting
2/04
36
48
IPTR UNOS
/
Patient Survival from Time of Listing
UNOS Pancreas Waiting List 1/1/1995  5/31/2003
100
%
80
60
40
Cat.
■ PTA
Wait
20
Survival
n
1Yr
4Yrs
647 98.7% 89.4%
485 94.1% 83.0%
0
0
12
24
Months Waiting
2/04
36
48
IPTR UNOS
/
Relative Hazard Ratios
UNOS Pancreas Waiting List 1/1/1995  5/31/2003
Relative Hazard Ratio
5
PAK
PTA
SPK
4
3
2
1
equal risk
Wait-Listed Patients
0
0
50
100
150
200
250
300
Days since Transplantation
8/04
350
400
IPTR UNOS
/
Pancreas Transplant
Outcome for
Contemporary Cases
(2000 - 2004)
IPTR UNOS
/
Patient Survival
USA DD Primary Pancreas Transplants 1/1/2000  6/6/2004
100
%
90
80
70
Cat.
PAK
PTA 429
SPK
60
n
1,112
1Yr Surv.
95%
98%
3,842
95%
p ≤ 0.05
50
0
6
12
18
24
Months Posttransplant
8/04
30
36
IPTR UNOS
/
Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000  6/6/2004
%
100
80
60
40
Cat.
PAK
PTA
SPK
20
n
1,109
429
3,841
1Yr Fxn
78%
76%
85%
p < 0.0001
0
0
8/04
6
12
18
24
Months Posttransplant
30
36
IPTR UNOS
/
Time between Kidney and Pancreas Tx
USA DD Primary PAK Transplants 1/1/2000  6/6/2004
Number of Transplants
400
300
200
100
0
30
60
90
120
150
180
210
240
270
Time between Kidney and PancreasTransplant [Mos]
IPTR UNOS
/
Major Immunosuppressive Protocols
USA Primary DD Pancreas Transplants 1/1/2000  6/ 6/2004
80
%
60
TAC/AZA
CsA/MMF
TAC/MMF
TAC
SIR based
40
20
0
PAK
8/04
PTA
SPK
IPTR UNOS
/
Antibody Therapy
USA DD Primary Pancreas Transplants 1/1/2000  6/6/2004
%
60
50
No ABs
40
Depl. AB
NonDepl. AB
30
Both ABs
20
10
0
PAK
8/04
PTA
SPK
IPTR UNOS
/
Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000  6/6/2004
%
Anti-T-Cell Therapy & TAC & MMF
100
80
60
40
Cat.
PAK
PTA
SPK
20
n
568
233
1915
1Yr Surv.
83%
80%
88%
p < 0.0001
0
0
8/04
6
12
18
24
Months Posttransplant
30
36
IPTR UNOS
/
Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000  6/6/2004
%
Anti T-Cell Therapy & Sirolimus & TAC
100
80
60
40
Cat.
PAK
PTA
SPK
20
n
131
53
399
1Yr Surv.
83%
83%
87%
0
0
8/04
6
12
18
24
Months Posttransplant
30
36
IPTR UNOS
/
Pancreas Graft Loss due to Chronic
Rejection
USA DD TS Primary Pancreas Transplants, 1/1/2000  6/ 2004
%
40
Cat.
PTA
PAK
SPK
30
n
378
1,001
3,539
2Yr Loss
10.3%
5.7%
1.5%
P < 0.0001
20
10
0
0
6
12
18
Months Posttransplant
4/05
24
30
IPTR UNOS
/
Organ Allocation for Beta-cell
Replacement Therapy:
islet versus whole pancreas
IPTR UNOS
/
Method of Beta-cell Replacement
-Pancreas Transplant—Highly
efficient but major surgery
-Islet Transplant—Minimally invasive
but less efficient
-Integration—Select donors(large)
most likely to give high yields for
islet tx to recipients with low insulin
requirements. Use all other donors
for pancreas transplants to the
remaining diabetic candidates
IPTR UNOS
/
Most deceased donor pancreases that
are suitable for beta-cell replacement
are currently used as a solid organ
immediately vascularized graft.
The reason: Islet isolation yield is
variable and the incidence of being
insufficient to induce insulinindependence is higher than the
incidence of technical failure of a
pancreas allograft.
IPTR UNOS
/
Discard and/or technical
failure rate after pancreas
procurement is higher with
islet than with pancreas
transplantation.
Thus the need for
retransplantation is higher
after a primary islet than after
a pancreas transplant.
IPTR UNOS
/
It may require multiple donors
(retransplants) to achieve a
sufficient beta cell mass for insulinindependence with the islet
transplant technique for BCR.
With the pancreas transplant
technique, the need for more than
one donor (a retransplant) is much
lower and solely a factor of the
technical failure and rejection loss
rates.
IPTR /UNOS
The degree of immunosuppression
used for anti-rejection prophylaxis
is similar for pancreas and islet
transplantation, or even higher in
solitary islet recipients(ITA, DD
IAK) because of the inability to
have a good marker to detect
rejection episodes while in a
reversible stage.
IPTR UNOS
/
With solitary pancreas transplants,
elevations of serum amylase and
lipase can be used as a marker for
rejection, as can a decrease in the
urine amylase for bladder drained
grafts, with biopsy confirmation
possible.
In SD SPK and SIK recipients, an
increase in serum creatinine is a
marker, and a kidney biopsy can be
confirmatory.
IPTR UNOS
/
Nevertheless, there are donor
pancreases that are suitable
for islet isolation while at
higher than average risk for TF
if used as an immediately
vascularized, solid organ
graft, .e.g., obese (BMI>30) or
older (>50 years) with
atherosclerois
I T
/
P R UNOS
Thus, allocation schemes
have been devised for
rationale distribution of
deceased donor pancreses to
islet and pancreas transplant
candidates on a common list
for Beta-cell Replacement
Therapy:
IPTR UNOS
/
LIFESOURCE OPO (MN, ND, SD)
Pancreas offered to an SPK or SIK
candidate if ranked 1 or 2 on the
combined kidney waiting list (includes
KTA candidates).
If no high ranked SPK or SIK candidate,
then offered to highest ranked solitary
pancreas or islet candidate on the
combined BCR waiting list, and
preferentially to islet candidates if donor
BMI >28 (regardless of age) or >50 Iy/o.
PTR /UNOS
All donors with BMI >28 are first
offered to islet candidates ranked
highest on the combined BCR list,
and then to pancreas recipients
IPTR UNOS
/
Rationale for this
pancreas allocation
approach is based on
pancreas and islet
transplant outcome and
utilization data
IPTR UNOS
/
Donor Age
US CD Pancreas Transplants 1/1/1988
5/31/2003
-
3.4%
IPTR UNOS
/
Technical Failure Rate
USA DD Primary Pancreas Transplants 1/1/2000  6/ 6/2004
%
20
P = 0.009
Donor Cause of Death
15
Trauma
CCV +/- 50 years
10
5
0
SPK
PAK
PTA
IPTR UNOS
/
1-Year Pancreas Technical Failure Rate
USA DD Primary Pancreas Transplants 1/1/2000  6/ 6/2004
%
SPK
PAK
PTA
25
20
15
10
5
0
0- 9
10 - 19
20 - 29
30 - 39
Donor Age
8/04
40 - 49
50 - 59
60 - 69
IPTR UNOS
/
1-Year Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000  6/ 6/2004
%
SPK
PAK
PTA
100
90
80
70
60
50
0- 9
10 - 19
20 - 29
30 - 39 40 - 49
Donor Age
8/04
50 - 59
60 - 69
IPTR UNOS
/