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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.

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  1. Let’s get started

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

  3. 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 inefficientin terms of utilization of a scarce resource—deceased donors. The immunosuppression needed to prevent rejection is of the same magnitude for either approach.

  4. 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.

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

  6. 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 inefficientin terms of utilization of a scarce resource—deceased donors.

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

  8. 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 inefficientin terms of utilization of a scarce resource—deceased donors. The immunosuppression needed to prevent rejection is of the same magnitude for either approach.

  9. 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).

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

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

  12. 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).

  13. 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).

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

  15. 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)

  16. Pancreas Transplants Worldwide 5,260 59 17,399 29 2 156 144 8/04

  17. 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) UCSF (2) Sao Paulo (2) Tokyo (1) 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)

  18. 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)

  19. 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.

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

  21. Number of Tx Centers and Number of Txs USA Pancreas Transplants 1/1/1988 – 12/31/2004 Transplants 1/05

  22. Pancreas Transplant Categories USA SPK, PAK and PTA Transplants 8/04

  23. Living Donor Kidneys in PAK USA Pancreas Transplants 1/1/1988 – 12/31/2003 8/04

  24. Recipient Age USA Pancreas Transplants 1/1/1988 – 12/31/2003

  25. Patients with Type II Diabetes USA Pancreas Transplants 1/1/1994 – 12/31/2003 1/05

  26. Recipient Gender USA Pancreas Transplants 1/1/1988 – 12/31/2003 % Male 1/05

  27. Duct Management Technique USA Pancreas Transplants 1/1/1988 – 12/31/2003 % enteric drained 8/04

  28. Portal Drainage in ED Txs USA DD Primary Pancreas Transplants, 1/1/1988 – 12/31/2003 8/04

  29. Improvements in Outcomes by Eras

  30. 1-Year Patient Survival USA DD Primary Pancreas Transplants, 1/1/1988 – 12/31/2003 8/04

  31. 1-Year Pancreas Graft Function USA DD Primary Pancreas Transplants, 10/1/1988 – 12/31/2003 8/04

  32. SPK Pancreas Graft Function USA DD Primary Pancreas Transplants, 10/1/1987 – 6/ 6/2004 Year HL[mos] 8/04

  33. PAK Pancreas Graft Function USA DD Primary Pancreas Transplants, 1/1/1988 – 6/ 6/2004 Year HL[mos] 8/04

  34. PTA Pancreas Graft Function USA DD Primary Pancreas Transplants, 10/1/1987 – 6/ 6/2004 Year HL[mos] 8/04

  35. Early Technical Pancreas Graft Failures USA DD Primary Pancreas Transplants, 1/1/1988 – 12/31/2003 8/04

  36. 1-Year Immunological Graft Loss USA DD Primary Pancreas Transplants, 10/1/1988 – 12/31/2003 8/04

  37. Anti-T-Cell Induction USA Pancreas Transplants 1/1/1988 – 12/31/2003 8/04

  38. 5-Year Immunological Graft Loss USA DD Primary Pancreas Transplants, 10/1/1988 – 12/31/2003 8/04

  39. 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)

  40. We redid the analysis of mortality risk of pancreas transplant candidates vs recipientsAm 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

  41. Mortality risk of pancreas transplantation vs. remaining on the waiting list**Gruessner et al. Am J Transpl 2004; 4: 2018-26

  42. Patient Survival from Time of Listing UNOS Pancreas Waiting List 1/1/1995 – 5/31/2003 Survival Cat. n 1Yr 4Yrs ■ SPK 6995 97.5% 90.7%  Wait 5536 87.2% 46.0% 2/04

  43. Patient Survival from Time of Listing UNOS Pancreas Waiting List 1/1/1995 – 5/31/2003 Survival Cat. n 1Yr 4Yrs ■ PAK 1714 97.3% 88.4%  Wait 1228 94.7% 74.5% 2/04

  44. Patient Survival from Time of Listing UNOS Pancreas Waiting List 1/1/1995 – 5/31/2003 Survival Cat. n 1Yr 4Yrs ■ PTA 647 98.7% 89.4%  Wait 485 94.1% 83.0% 2/04

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