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BETA CELL REPLACEMENT(PANCREAS AND ISLET
TRANSPLANTATION) FOR THE TREATMENT OF
DIABETES MELLITUS
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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
  transplantjust 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 resourcedeceased donors.
• The immunosuppression needed to prevent rejection
  is of the same magnitude for either approach.

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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.

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BETA-CELL REPLACEMENT THERAPY IN DIABETES
MELLITUS

• Pancreas transplantation is an islet transplant
• just a
• big islet.

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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 resourcedeceased donors.

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BETA-CELL REPLACEMENT THERAPY IN DIABETES
MELLITUS

• The immunosuppression needed to prevent rejection
  is of the same magnitude for either approach.

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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
  transplantjust 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 resourcedeceased donors.
• The immunosuppression needed to prevent rejection
  is of the same magnitude for either approach.

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Beta-cell replacement therapy

• WHEN 1. Insulin-treated diabetic patients
  obligated to immunosuppression renal allograft
  recipients.
  2. Labile diabeticsinsulin-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).

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Beta-cell replacement therapy

• WHEN 1. Insulin-treated diabetic patients
  obligated to immunosuppression renal allograft
  recipients.
  
• 2. Labile diabeticsinsulin-reactions with
  hypoglycemic unawareness.

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Beta-cell replacement therapy

• HOW Pancreas transplant if high and islet
  transplant if low insulin requirements.

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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).

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Beta-cell replacement therapy

• WHEN 1. Insulin-treated diabetic patients
  obligated to immunosuppression renal allograft
  recipients.
  2. Labile diabeticsinsulin-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).

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Beta-cell Replacement Therapy for Diabetes
An Integrated Approach with Pancreas and
Islet Transplantation
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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)

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Pancreas Transplants Worldwide
5,260
59
17,399
29
2
156
144
8/04
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Islet transplant activity (1999-2004)
Edmonton (67)
Miami (30)
Milan (35)
Minneapolis (20)
Brussels (35)
Philadelphia (12)
Giessen (27)
Vancouver (12)
Geneva/GRAGIL (28)
Houston (11)
Nordic Network (24)
Harvard (10)
Leuven (20)
Northwestern (8)
Innsbruck (11)
St Louis (8)
Zurich (10)
NIH (6)
Sydney (6)
Cincinnati (6)
Kyoto (5)
Seattle (6)
Budapest (4)
Emory (6)
Kings (UK) (2)
City of Hope CA (5)
Chiba (1)
Memphis (3)
Sao Paulo (2)
Tokyo (1)
UCSF (2)
U Mass (2)
Shanghai (1)
35 institutions 430 patients
U. Maryland (1)
Red ITA Blue ITA and SIK/IAK Black SIK/IAK
Columbia NY (1)
Carolina Med Ctr (1)
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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)

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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.
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Pancreas Transplants Worldwide
Total n 23,051 ? Non USA n 5,924 ?
USA n 17,127
1//05
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Number of Tx Centers and Number of Txs
USA Pancreas Transplants 1/1/1988 12/31/2004
Transplants
1/05
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Pancreas Transplant Categories
USA SPK, PAK and PTA Transplants
8/04
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Living Donor Kidneys in PAK
USA Pancreas Transplants 1/1/1988 12/31/2003
8/04
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Recipient Age
USA Pancreas Transplants 1/1/1988 12/31/2003
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Patients with Type II Diabetes
USA Pancreas Transplants 1/1/1994 12/31/2003
1/05
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Recipient Gender
USA Pancreas Transplants 1/1/1988 12/31/2003
Male
1/05
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Duct Management Technique
USA Pancreas Transplants 1/1/1988 12/31/2003
enteric drained
8/04
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Portal Drainage in ED Txs
USA DD Primary Pancreas Transplants, 1/1/1988
12/31/2003
8/04
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Improvements in Outcomes by Eras
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1-Year Patient Survival
USA DD Primary Pancreas Transplants, 1/1/1988
12/31/2003
8/04
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1-Year Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1988
12/31/2003
8/04
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SPK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987
6/ 6/2004
Year HLmos
8/04
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PAK Pancreas Graft Function
USA DD Primary Pancreas Transplants, 1/1/1988
6/ 6/2004
Year HLmos
8/04
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PTA Pancreas Graft Function
USA DD Primary Pancreas Transplants, 10/1/1987
6/ 6/2004
Year HLmos
8/04
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Early Technical Pancreas Graft Failures
USA DD Primary Pancreas Transplants, 1/1/1988
12/31/2003
8/04
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1-Year Immunological Graft Loss
USA DD Primary Pancreas Transplants, 10/1/1988
12/31/2003
8/04
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Anti-T-Cell Induction
USA Pancreas Transplants 1/1/1988 12/31/2003
8/04
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5-Year Immunological Graft Loss
USA DD Primary Pancreas Transplants, 10/1/1988
12/31/2003
8/04
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• 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)

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We redid the analysis of mortality risk of
pancreas transplant candidates vs recipientsAm
J Transp 2004 42018-26

• 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

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Mortality risk of pancreas transplantation
vs. remaining on the waiting listGruessner
et al. Am J Transpl 2004 4 2018-26
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Patient Survival from Time of Listing
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Survival Cat. n 1Y
r 4Yrs SPK 6995 97.5 90.7 ?
Wait 5536 87.2 46.0
2/04
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Patient Survival from Time of Listing
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Survival Cat. n 1Y
r 4Yrs PAK 1714 97.3 88.4 ?
Wait 1228 94.7 74.5
2/04
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Patient Survival from Time of Listing
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Survival Cat. n 1Y
r 4Yrs PTA 647 98.7 89.4 ?
Wait 485 94.1 83.0
2/04
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Relative Hazard Ratios
UNOS Pancreas Waiting List 1/1/1995 5/31/2003
Wait-Listed Patients
equal risk
8/04
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Pancreas Transplant Outcome forContemporary
Cases(2000 - 2004)
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Patient Survival
USA DD Primary Pancreas Transplants 1/1/2000
6/6/2004
Cat. n 1Yr Surv. PAK 1,112 95 PTA
429 98 SPK 3,842 95
p 0.05
8/04
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Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000
6/6/2004
Cat. n 1Yr Fxn PAK 1,109 78 PTA 429 76
SPK 3,841 85
p lt 0.0001
8/04
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Time between Kidney and Pancreas Tx
USA DD Primary PAK Transplants 1/1/2000 6/6/2004
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Major Immunosuppressive Protocols
USA Primary DD Pancreas Transplants 1/1/2000
6/ 6/2004
8/04
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Antibody Therapy
USA DD Primary Pancreas Transplants 1/1/2000
6/6/2004
? No ABs ? Depl. AB ? NonDepl. AB ? Both ABs
8/04
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Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000
6/6/2004
Anti-T-Cell Therapy TAC MMF
Cat. n 1Yr Surv. PAK 568 83 PTA 233 80
SPK 1915 88
p lt 0.0001
8/04
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Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000
6/6/2004
Anti T-Cell Therapy Sirolimus TAC
Cat. n 1Yr Surv. PAK 131 83 PTA 53 83
SPK 399 87
8/04
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Pancreas Graft Loss due to Chronic Rejection
USA DD TS Primary Pancreas Transplants, 1/1/2000
6/ 2004
Cat. n 2Yr Loss PTA 378 10.3
PAK 1,001 5.7 SPK 3,539 1.5
P lt 0.0001
4/05
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Organ Allocation for Beta-cell Replacement
Therapyislet versus whole pancreas
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Method of Beta-cell Replacement

• -Pancreas TransplantHighly efficient but major
  surgery
• -Islet TransplantMinimally invasive but less
  efficient
• -IntegrationSelect 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

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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.
64
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.

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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.
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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.
67
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.
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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
(BMIgt30) or older (gt50 years) with atherosclerois

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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
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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 gt28 (regardless of
age) or gt50 y/o.
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All donors with BMI gt28 are first offered to
islet candidates ranked highest on the combined
BCR list, and then to pancreas recipients
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Rationale for this pancreas allocation approach
is based on pancreas and islet transplant outcome
and utilization data
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Donor Age
USA CAD Pancreas Transplants 1/1/1988 - 5/31/2003
3.4
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Technical Failure Rate
USA DD Primary Pancreas Transplants 1/1/2000 6/
6/2004
P 0.009
Donor Cause of Death
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1-Year Pancreas Technical Failure Rate
USA DD Primary Pancreas Transplants 1/1/2000 6/
6/2004
8/04
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1-Year Pancreas Graft Function
USA DD Primary Pancreas Transplants 1/1/2000 6/
6/2004
8/04
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Transplants from Obese Pancreas Donors

•  

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American Journal of Transplantation 2004 4
605-610
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Pancreas from donor with BMI35
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Pancreas from donor with BMI26
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Complications after cadaveric pancreas transplant
by donor BMI
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Are Obese Donors SuitableforIslet Isolation?
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Transplantation 2004 78 in press
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YES, OBESE DONORS ARE GOOD FOR ISLET ISOLATION
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Minneapolis The City of Lakes
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Unique Aspects UMN Pancreas and Islet Transplant
Program

• Largest program in world, gt2000 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
  Campathnon-nephrotoxic as well as
  non-diabetogenic (since 2003)

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Key Drug is Gancyclovir (Valcyte)-CMV incidence
lt10 in our Campath trialsThe agent that
allows us to use immunosuppressive doses by
nearly any protocol to achieve low-rejection
episode rate
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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).
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-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
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Pancreas Transplants by Category
Pancreas Transplants, U of MN 12/66 12/31/2002
PTA 414 (53 LRD)
PAK 564 (31 LRD, 1 LURD)
SPK 598 (30 LRD, 6 LURD)
SPL 1
TOTAL 1576
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LIVING DONOR SEGMENTAL PANCREAS OR ISLET
TRANSPLANTS
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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,
  insulin-independence achieved. gt140 cases since.
• First LD islet allograft with insulin
  independence achieved Jan 19, 2005, Kyoto

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Auto-islet experience has implications for living
donor islet allografts.
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Living donor segmental pancreas transplant
experience
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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,
  insulin-independence achieved. gt140 cases since.
• First LD islet allograft with insulin
  independence achieved Jan 19, 2005, Kyoto

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MN Criteria for LD Segmental Pancreas Donor

• BMI lt28
• 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

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Since 1999 we have done living donor segmental
pancreatectomy by the hand-assisted laparoscopic
technique
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Living donor segmental pancreas transplant in
recipient has been done with duct-injection,
bladder- or enteric-drainage.
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Patient and Full Graft Survival of 35 LD SPK
Transplants
UNIVERSITY OF MINNESOTA , 1/1994 - 7/2001
1-Yr.Surv Patient 100 Kidney
100 Pancreas 86
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The Islet Transplant
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What about current islet allograft outcomes with
deceased donors?
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Human Islet Allotransplantation
10-12 KIE/kg
Shapiro AMJ et al., NEJM 2000343230-8
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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)

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Critique of Edmonton Protocol

• Requires multiple donors (retransplants) to
  achieve insulin-independence in most recipients
• Even though steroid-free, the immunosuppression
  is still diabetogenicboth tacrolimus and
  sirolimusand may be responsible for the need for
  retransplants
• Non-diabetogenic immunosuppression is now
  availableused in pancreas, not yet widely
  applied in islets

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Main value of the original Edmonton ProtocolIt
showed that insulin-independence could be
achieved if enough islets (beta-cells) were
transplantedLong-term functional survival is
still a problem (compared to pancreas transplants)
112
Success rates of islet transplants for T1D
insulin-independent at 1 yr
113
Insulin-independent islet allograft
survivalEdmonton Miami - Minnesota
n 118 1-yr survival 80-85
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Kaplan-Meier Survival Curves (Insulin
Independence) From time of first transplant
80 Fresh
72 Cultured
Survival ()
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Five Year Kaplan-Meier Survival Curves (Insulin
Independence from time of first transplant)
Survival ()
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Decay in islet function over timeReasoning

• 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?

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Single-Donor Islet Transplantation
at U Minnesota
Transplantation of Cultured Islets from
Two-Layer Preserved Pancreases in Type 1 Diabetes
with Anti-CD3 Antibody

• 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
118
Stable insulin independence after
single-donor islet transplantation for gt3, gt4, gt4
yrs
119
Stable insulin independence after
single-donor islet transplantation for gt3, gt4, gt4
yrs
120
Islet Transplant Protocol 2
TLP
Donor Islet Isolation
7,271 1,035 IE/kg
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Single-Donor Islet Transplantation
Feb 16, 2005
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Current Protocol (3)
Cyclosporine
TLP
Donor Islet Isolation
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Success rates of islet transplants for T1D
insulin-independent at 1 yr
124
Single-donor 7 strategies16 of 18 insulin-free
with 11 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
125
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

126
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,
  insulin-independence achieved. gt140 cases since.
• First LD islet allograft with insulin
  independence achieved Jan 19, 2005, Kyoto

127
Human Studies in Islet Transplantation
Living donor islet transplant performed in
Kyoto, Japan on Jan 19, 2005 by Drs. Matsumoto
and colleagues
128
Islet Mass Sufficient?
No brain death
No cold storage
Reduced immune response
129
Emerging Opportunities
1. Costimulation blockade IL-2R Ab LEA29Y SRL
2. FTY720 IL-2R Ab FTY720 RAD
130
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

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Pig-to-NHP islet xenotransplantation
BSMFTY720RADABI793LFM
BSMFTY720RADABI793
BSMFTY720RAD
University of Minnesota
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Insulin
Histology day 187
85 islets on 10 sections 57/85 w/o
infiltrate 24/85 with periislet infiltrate
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Evolution of islet replacement
2000 200?
20??
135
Meanwhile, back to the present.What to do?
136
b-cell replacement therapy

• Growing demands
• Islet transplant preferable approach
• Eliminate surgical risks
• Less long-term complications
• Xenogeneic islet transplants could meet the
  demand of donor shortage

DIIT, University of Minnesota
International pancreas transplant registry
(IPTR), Bretzel RG, 2004
137
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

138
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.

139
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.

140
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

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