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BETA CELL REPLACEMENT (PANCREAS AND ISLET TRANSPLANTATION) FOR THE TREATMENT OF DIABETES MELLITUS

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.

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.

BETA-CELL REPLACEMENT THERAPY IN DIABETES MELLITUS Pancreas transplantation is an islet transplant— just a big islet.

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.

BETA-CELL REPLACEMENT THERAPY IN DIABETES MELLITUS The immunosuppression needed to prevent rejection is of the same magnitude for either approach.

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.

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).

Beta-cell replacement therapy WHEN: 1. Insulin-treated diabetic patients obligated to immunosuppression: renal allograft recipients. 2. Labile diabetics—insulin- reactions with hypoglycemic unawareness.

Beta-cell replacement therapy HOW: Pancreas transplant if high and islet transplant if low insulin requirements.

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).

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).

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

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)

Pancreas Transplants Worldwide 8/04 17, ,

Sydney (6) Islet transplant activity ( ) 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 = ITA Blue= ITA and SIK/IAK Black= SIK/IAK Emory (6) Vancouver (12) 35 institutions ~ 430 patients Carolina 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)

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)

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.

Pancreas Transplants Worldwide 1//05 Total: n = 23,051 Non USA:n = 5,924 USA: n = 17,127

Number of Tx Centers and Number of Txs 1/05 Transplants  – 

Pancreas Transplant Categories  8/04

Living Donor Kidneys in PAK 8/04  – 

Recipient Age  – 

Patients with Type II Diabetes  –  1/05

Recipient Gender  –  1/05 % Male

Duct Management Technique  –  8/04 % enteric drained

Portal Drainage in ED Txs  –  8/04

Improvements in Outcomes by Eras

1-Year Patient Survival  –  8/04

1-Year Pancreas Graft Function  –  8/04

SPK Pancreas Graft Function  –  8/04 Year HL[mos]

PAK Pancreas Graft Function  –  8/04 Year HL[mos ]

PTA Pancreas Graft Function  –  8/04 Year HL[mos ]

Early Technical Pancreas Graft Failures  –  8/04

1-Year Immunological Graft Loss  –  8/04

Anti-T-Cell Induction  –  8/04

5-Year Immunological Graft Loss  –  8/04

-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: )

We redid the analysis of mortality risk of pancreas transplant candidates vs recipients Am J Transp 2004; 4: 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

Mortality risk of pancreas transplantation vs. remaining on the waiting list* *Gruessner et al. Am J Transpl 2004; 4:

Survival Cat.n1Yr4Yrs ■ SPK % 90.7%  Wait %46.0% Patient Survival from Time of Listing  –  2/04

Survival Cat.n1Yr4Yrs ■ PAK % 88.4%  Wait %74.5% Patient Survival from Time of Listing  –  2/04

Survival Cat.n1Yr4Yrs ■ PTA % 89.4%  Wait %83.0% Patient Survival from Time of Listing  –  2/04

Relative Hazard Ratios  –  8/04 Wait-Listed Patients equal risk

Pancreas Transplant Outcome for Contemporary Cases ( )

Patient Survival  –  Cat.n 1Yr Surv. PAK1,112 95% PTA 42998% SPK3,842 95% p ≤ /04

Pancreas Graft Function  –  Cat. n1Yr Fxn PAK1,10978% PTA42976% SPK 3,841 85% p < /04

Time between Kidney and Pancreas Tx  – 

Major Immunosuppressive Protocols  –  8/04

Antibody Therapy  –  No ABs Depl. AB NonDepl. AB Both ABs 8/04

Pancreas Graft Function  –  Cat. n1Yr Surv. PAK56883% PTA23380% SPK % p < /04 Anti-T-Cell Therapy & TAC & MMF

Pancreas Graft Function  –  Cat. n1Yr Surv. PAK13183% PTA5383% SPK % 8/04 Anti T-Cell Therapy & Sirolimus & TAC

Pancreas Graft Loss due to Chronic Rejection  –  4/05 Cat. n2Yr Loss PTA % PAK1,0015.7% SPK 3, % P <

Organ Allocation for Beta-cell Replacement Therapy: islet versus whole pancreas

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

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.

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.

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.

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.

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.

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

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:

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.

All donors with BMI >28 are first offered to islet candidates ranked highest on the combined BCR list, and then to pancreas recipients

Rationale for this pancreas allocation approach is based on pancreas and islet transplant outcome and utilization data

Donor Age USA CAD Pancreas Transplants 1/1/ /31/ %

Technical Failure Rate  –  P = Donor Cause of Death

1-Year Pancreas Technical Failure Rate  –  8/04

1-Year Pancreas Graft Function  –  8/04