IPTR /UNOS
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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—insulin-reactions 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
inPANCREAS (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
8/04
17,399
144
2
5,26059
156
29
IPTR /UNOS
Sydney (6)
Islet transplant activity(1999-2004)Edmonton (67)
Miami (30)
Minneapolis (20)
NIH (6)
Northwestern (8)
Philadelphia (12)
Harvard (10)
Houston (11)
St Louis (8)
Geneva/GRAGIL (28)
Milan (35)
Zurich (10)
Giessen (27)
Cincinnati (6)
U. Maryland (1)
Seattle (6)
U Mass (2)
Memphis (3)
Kings (UK) (2)
Nordic Network (24)
Innsbruck (11)
Red = ITABlue= ITA and SIK/IAKBlack= SIK/IAK
Emory (6)
Vancouver (12)
35 institutions~ 430 patientsCarolina Med Ctr (1)
City of Hope CA (5)
Brussels (35)
Leuven (20)
Kyoto (5)
Chiba (1)Sao Paulo (2)
Columbia NY (1)
Shanghai (1)
Tokyo (1)
Budapest (4)
UCSF (2)
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 beta-cells 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
1//05
0
200
400
600
800
1000
1200
1400
1600
1800
2000
Num
ber
of T
rans
plan
ts
Total: n = 23,051
Non USA: n = 5,924
USA: n = 17,127
IPTR /UNOS
0
20
40
60
80
100
120
140
1988 1990 1992 1994 1996 1998 2000 2002 2004
Centers
0
200
400
600
800
1000
1200
1400# Centers
# of Txs
Number of Tx Centers and Number of Txs
1/05
Transplants
–
IPTR /UNOS
Pancreas Transplant Categories
8/04
0
200
400
600
800
1000
1200
Nu
mb
er
of
Tra
ns
pla
nts PTA
PAK
SPK
IPTR /UNOS
Living Donor Kidneys in PAK
0
20
40
60
80
100
1988 1990 1992 1994 1996 1998 2000 2002
%
8/04
–
IPTR /UNOS
Recipient Age
PAK
PTASPK
1988 1990 1992 1994 1996 1998 2000 2002
Transplant Year
20
40
60
–
IPTR /UNOS
Patients with Type II Diabetes –
1/05
0
2
4
6
8
10
1994 1996 1998 2000 2002
%
PAK
PTA
SPK
IPTR /UNOS
Recipient Gender–
1/05
0
10
20
30
40
50
60
70
1988 1990 1992 1994 1996 1998 2000 2002
PAK
PTA
SPK
% Male
IPTR /UNOS
Duct Management Technique–
8/04
010203040
5060708090
1988 1990 1992 1994 1996 1998 2000 2002
PAK
PTA
SPK
% enteric drained
IPTR /UNOS
IPTR /UNOS
IPTR /UNOS
Portal Drainage in ED Txs–
8/04
0
10
20
30
40
50
60
1996 1998 2000 2002
% PAK
PTA
SPK
IPTR /UNOS
IPTR /UNOS
Improvements in
Outcomes by Eras
IPTR /UNOS
1-Year Patient Survival–
8/04
60
70
80
90
100
1988 1990 1992 1994 1996 1998 2000 2002
%
PAK
PTA
SPK
IPTR /UNOS
1-Year Pancreas Graft Function–
8/04
20
40
60
80
100
1988 1990 1992 1994 1996 1998 2000 2002
%
PAK
PTA
SPK Px
SPK Kd
IPTR /UNOS
SPK Pancreas Graft Function–
8/04
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Months Posttransplant
%
1988 154
1990 160
1992 158
1994 161
1996 165
1998 170
Year HL[mos]
IPTR /UNOS
PAK Pancreas Graft Function–
8/04
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96 108 120
Months Posttransplant
%
1988 59
1990 69
1992 78
1994 85
1996 95
1998 105
Year HL[mos]
IPTR /UNOS
PTA Pancreas Graft Function–
8/04
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96 108 120
Months Posttransplant
%
1988 681990 781992 811994 881996 1051998 121
Year HL[mos]
IPTR /UNOS
Early Technical Pancreas Graft Failures
–
8/04
0
10
20
30
40
1988 1990 1992 1994 1996 1998 2000 2002
%
PAK
PTA
SPK
IPTR /UNOS
1-Year Immunological Graft Loss–
8/04
0
5
10
15
20
25
30
35
40
1988 1990 1992 1994 1996 1998 2000 2002
%
PAK
PTA
SPK
IPTR /UNOS
Anti-T-Cell Induction–
8/04
0102030405060708090
1988 1990 1992 1994 1996 1998 2000 2002
%
PAK
PTA
SPK
IPTR /UNOS
5-Year Immunological Graft Loss–
8/04
0
10
20
30
40
50
60
70
80
1988 1990 1992 1994 1996 1998 2000 2002
%
PAK
PTA
SPK
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
0
20
40
60
80
100
0 12 24 36 48
Months Waiting
%
SurvivalCat. n 1Yr 4Yrs ■ SPK 6995 97.5% 90.7% Wait 5536 87.2% 46.0%
Patient Survival from Time of Listing–
2/04
IPTR /UNOS
0
20
40
60
80
100
0 12 24 36 48
Months Waiting
%
SurvivalCat. n 1Yr 4Yrs ■ PAK 1714 97.3% 88.4% Wait 1228 94.7% 74.5%
Patient Survival from Time of Listing–
2/04
IPTR /UNOS
0
20
40
60
80
100
0 12 24 36 48
Months Waiting
%
SurvivalCat. n 1Yr 4Yrs ■ PTA 647 98.7% 89.4% Wait 485 94.1% 83.0%
Patient Survival from Time of Listing–
2/04
IPTR /UNOS
0
1
2
3
4
5
0 50 100 150 200 250 300 350 400
Days since Transplantation
Rel
ativ
e H
azar
d R
atio
PAKPTASPK
Relative Hazard Ratios–
8/04
Wait-Listed Patients
equal risk
IPTR /UNOS
Pancreas Transplant Outcome for
Contemporary Cases(2000 - 2004)
IPTR /UNOS
50
60
70
80
90
100
0 6 12 18 24 30 36
Months Posttransplant
%
Patient Survival–
Cat. n 1Yr Surv.PAK 1,112 95% PTA 429 98% SPK 3,842 95% p ≤ 0.05
8/04
IPTR /UNOS
0
20
40
60
80
100
0 6 12 18 24 30 36
Months Posttransplant
%
Pancreas Graft Function–
Cat. n 1Yr Fxn PAK 1,109 78% PTA 429 76% SPK 3,841 85%
p < 0.0001
8/04
IPTR /UNOS
0 30 60 90 120 150 180 210 240 270
Time between Kidney and PancreasTransplant [Mos]
100
200
300
400
Time between Kidney and Pancreas Tx–
IPTR /UNOS
0
20
40
60
80
PAK PTA SPK
%
TAC/AZA
CsA/MMF
TAC/MMF
TAC
SIR based
Major Immunosuppressive Protocols–
8/04
IPTR /UNOS
0
10
20
30
40
50
60
PAK PTA SPK
%
Antibody Therapy–
No ABs
Depl. AB
NonDepl. AB
Both ABs
8/04
IPTR /UNOS
0
20
40
60
80
100
0 6 12 18 24 30 36
Months Posttransplant
%
Pancreas Graft Function–
Cat. n 1Yr Surv. PAK 568 83% PTA 233 80% SPK 1915 88%
p < 0.0001
8/04
Anti-T-Cell Therapy & TAC & MMF
IPTR /UNOS
0
20
40
60
80
100
0 6 12 18 24 30 36
Months Posttransplant
%
Pancreas Graft Function–
Cat. n 1Yr Surv. PAK 131 83% PTA 53 83% SPK 399 87%
8/04
Anti T-Cell Therapy & Sirolimus & TAC
IPTR /UNOS
Pancreas Graft Loss due to Chronic Rejection
–
4/05
0
10
20
30
40
0 6 12 18 24 30
Months Posttransplant
%
Cat. n 2Yr Loss PTA 378 10.3% PAK 1,001 5.7% SPK 3,539 1.5%
P < 0.0001
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 insulin-independence 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 insulin-independence 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
IPTR /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 y/o.
IPTR /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
3.4%
IPTR /UNOS
Technical Failure Rate
0
5
10
15
20
SPK PAK PTA
%
Trauma
CCV +/- 50 years
–
P = 0.009Donor Cause of Death
IPTR /UNOS
1-Year Pancreas Technical Failure Rate–
8/04
0
5
10
15
20
25
0 - 9 10 - 19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69
Donor Age
% SPK
PAK
PTA
IPTR /UNOS
1-Year Pancreas Graft Function–
8/04
50
60
70
80
90
100
0 - 9 10 - 19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69
Donor Age
% SPK
PAK
PTA