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Let’s get started. BETA CELL REPLACEMENT ( PANCREAS AND ISLET TRANSPLANTATION ) FOR THE TREATMENT OF DIABETES MELLITUS. BETA-CELL REPLACEMENT THERAPY IN DIABETES MELLITUS. - PowerPoint PPT Presentation
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I P T R / UNOS Let’s get started
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Page 1: Let’s get started

IPTR /UNOS

Let’s get started

Page 2: Let’s get started

IPTR /UNOS

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 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.

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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.

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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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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.

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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 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.

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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).

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Beta-cell replacement therapy• WHEN: 1. Insulin-treated

diabetic patients obligated to immunosuppression: renal allograft recipients.

• 2. Labile diabetics—insulin-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 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).

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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

8/04

17,399

144

2

5,26059

156

29

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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)

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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

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

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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

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Pancreas Transplant Categories

8/04

0

200

400

600

800

1000

1200

Nu

mb

er

of

Tra

ns

pla

nts PTA

PAK

SPK

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Living Donor Kidneys in PAK

0

20

40

60

80

100

1988 1990 1992 1994 1996 1998 2000 2002

%

8/04

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Recipient Age

PAK

PTASPK

1988 1990 1992 1994 1996 1998 2000 2002

Transplant Year

20

40

60

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Patients with Type II Diabetes –

1/05

0

2

4

6

8

10

1994 1996 1998 2000 2002

%

PAK

PTA

SPK

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Recipient Gender–

1/05

0

10

20

30

40

50

60

70

1988 1990 1992 1994 1996 1998 2000 2002

PAK

PTA

SPK

% Male

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Duct Management Technique–

8/04

010203040

5060708090

1988 1990 1992 1994 1996 1998 2000 2002

PAK

PTA

SPK

% enteric drained

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Portal Drainage in ED Txs–

8/04

0

10

20

30

40

50

60

1996 1998 2000 2002

% PAK

PTA

SPK

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Improvements in

Outcomes by Eras

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1-Year Patient Survival–

8/04

60

70

80

90

100

1988 1990 1992 1994 1996 1998 2000 2002

%

PAK

PTA

SPK

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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

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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]

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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]

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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]

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Early Technical Pancreas Graft Failures

8/04

0

10

20

30

40

1988 1990 1992 1994 1996 1998 2000 2002

%

PAK

PTA

SPK

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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

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Anti-T-Cell Induction–

8/04

0102030405060708090

1988 1990 1992 1994 1996 1998 2000 2002

%

PAK

PTA

SPK

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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

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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 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

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Mortality risk of

pancreas transplantation vs.

remaining on the waiting list*

*Gruessner et al. Am J Transpl 2004; 4: 2018-26

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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

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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

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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

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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

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Pancreas Transplant Outcome for

Contemporary Cases(2000 - 2004)

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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

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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

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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–

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0

20

40

60

80

PAK PTA SPK

%

TAC/AZA

CsA/MMF

TAC/MMF

TAC

SIR based

Major Immunosuppressive Protocols–

8/04

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0

10

20

30

40

50

60

PAK PTA SPK

%

Antibody Therapy–

No ABs

Depl. AB

NonDepl. AB

Both ABs

8/04

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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

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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

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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

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Organ Allocation for Beta-cell Replacement Therapy:

islet versus whole pancreas

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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

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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.

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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.

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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 (BMI>30) or older (>50 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 >28 (regardless of age) or >50 y/o.

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All donors with BMI >28 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

3.4%

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Technical Failure Rate

0

5

10

15

20

SPK PAK PTA

%

Trauma

CCV +/- 50 years

P = 0.009Donor Cause of Death

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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

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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


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