Let’s get started 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—insulinreactions 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 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) IPTR UNOS / Pancreas Transplants Worldwide 5,260 59 17,399 29 2 156 144 8/04 IPTR UNOS / Islet transplant activity Edmonton (67) Miami (30) (1999-2004) Milan (35) Minneapolis (20) Philadelphia (12) Brussels (35) Giessen (27) Vancouver (12) Geneva/GRAGIL (28) Nordic Network (24) Leuven (20) Innsbruck (11) Zurich (10) Houston (11) Harvard (10) Northwestern (8) St Louis (8) NIH (6) Cincinnati (6) Seattle (6) Emory (6) City of Hope CA (5) Memphis (3) UCSF (2) U Mass (2) U. Maryland (1) Columbia NY (1) Carolina Med Ctr (1) Sydney (6) Kyoto (5) Budapest (4) Kings (UK) (2) Sao Paulo (2) Chiba (1) Tokyo (1) Shanghai (1) 35 institutions ~ 430 patients Red = ITA Blue= ITA and SIK/IAK Black= SIK/IAK 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 betacells 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 Number of Transplants 2000 1800 Total: n = 23,051 1600 Non USA: n = 1400 USA: 5,924 n = 17,127 1200 1000 800 600 400 200 1//05 20 03 20 01 19 99 19 97 19 95 19 93 19 91 19 89 19 87 19 85 19 83 19 81 19 79 pre 78 0 IPTR UNOS / Number of Tx Centers and Number of Txs USA Pancreas Transplants 1/1/1988 12/31/2004 Centers 140 120 100 Transplants # Centers 1400 # of Txs 1200 1000 80 800 60 600 40 400 20 200 0 0 1988 1990 1992 1994 1996 1998 2000 2002 2004 1/05 IPTR UNOS / Pancreas Transplant Categories USA SPK, PAK and PTA Transplants Number of Transplants 1200 PTA PAK SPK 1000 800 600 400 200 0 02 20 00 20 98 19 96 19 94 19 92 19 90 19 88 19 8/04 IPTR UNOS / Living Donor Kidneys in PAK USA Pancreas Transplants 1/1/1988 12/31/2003 % 100 80 60 40 20 0 1988 8/04 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / Recipient Age USA Pancreas Transplants 1/1/1988 12/31/2003 PAK PTA SPK Recipient Age [Yrs] 60 40 20 1994 1996 1988 1990 1992 1998 2000 2002 Transplant Year IPTR UNOS / Patients with Type II Diabetes USA Pancreas Transplants 1/1/1994 12/31/2003 % 10 8 6 4 PAK PTA SPK 2 0 1994 1/05 1996 1998 2000 2002 IPTR UNOS / Recipient Gender USA Pancreas Transplants 1/1/1988 12/31/2003 % Male 70 60 50 40 30 PAK PTA SPK 20 10 0 1988 1/05 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / Duct Management Technique USA Pancreas Transplants 1/1/1988 12/31/2003 % enteric drained 90 80 70 60 50 40 30 20 10 0 1988 8/04 PAK PTA SPK 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / IPTR UNOS / IPTR UNOS / Portal Drainage in ED Txs USA DD Primary Pancreas Transplants, 1/1/1988 12/31/2003 % PAK PTA SPK 60 50 40 30 20 10 0 1996 8/04 1998 2000 2002 IPTR UNOS / IPTR UNOS / Improvements in Outcomes by Eras IPTR UNOS / 1-Year Patient Survival USA DD Primary Pancreas Transplants, 1/1/1988 12/31/2003 % 100 90 80 PAK PTA SPK 70 60 1988 8/04 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / 1-Year Pancreas Graft Function USA DD Primary Pancreas Transplants, 10/1/1988 12/31/2003 % 100 80 60 PAK PTA SPK Px SPK Kd 40 20 1988 8/04 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / SPK Pancreas Graft Function USA DD Primary Pancreas Transplants, 10/1/1987 6/ 6/2004 % Year HL[mos] 100 1988 154 1990 160 80 1992 158 1994 161 60 1996 165 1998 170 40 20 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 Months Posttransplant 8/04 IPTR UNOS / PAK Pancreas Graft Function USA DD Primary Pancreas Transplants, 1/1/1988 6/ 6/2004 % 100 Year HL[mos] 80 1988 59 1990 69 60 1992 78 40 1994 85 1996 95 20 1998 105 0 0 12 24 36 48 60 72 84 Months Posttransplant 8/04 96 108 120 IPTR UNOS / PTA Pancreas Graft Function USA DD Primary Pancreas Transplants, 10/1/1987 6/ 6/2004 % 100 Year HL[mos] 1988 68 1990 78 1992 81 1994 88 1996 105 1998 121 80 60 40 20 0 0 12 24 36 48 60 72 84 96 108 120 Months Posttransplant 8/04 IPTR UNOS / Early Technical Pancreas Graft Failures USA DD Primary Pancreas Transplants, 1/1/1988 12/31/2003 % 40 PAK PTA SPK 30 20 10 0 1988 8/04 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / 1-Year Immunological Graft Loss USA DD Primary Pancreas Transplants, 10/1/1988 12/31/2003 % 40 PAK PTA SPK 35 30 25 20 15 10 5 0 1988 8/04 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / Anti-T-Cell Induction USA Pancreas Transplants 1/1/1988 12/31/2003 % 90 80 70 60 50 40 30 20 10 0 1988 8/04 PAK PTA SPK 1990 1992 1994 1996 1998 2000 2002 IPTR UNOS / 5-Year Immunological Graft Loss USA DD Primary Pancreas Transplants, 10/1/1988 12/31/2003 % 80 PAK PTA SPK 70 60 50 40 30 20 10 0 1988 8/04 1990 1992 1994 1996 1998 2000 2002 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 / Patient Survival from Time of Listing UNOS Pancreas Waiting List 1/1/1995 5/31/2003 100 % 80 60 40 Survival Cat. n 1Yr 4Yrs ■ SPK 6995 97.5% 90.7% Wait 5536 87.2% 46.0% 20 0 0 12 24 Months Waiting 2/04 36 48 IPTR UNOS / Patient Survival from Time of Listing UNOS Pancreas Waiting List 1/1/1995 5/31/2003 100 % 80 60 40 Survival Cat. n 1Yr 4Yrs ■ PAK 1714 97.3% 88.4% Wait 1228 94.7% 74.5% 20 0 0 12 24 Months Waiting 2/04 36 48 IPTR UNOS / Patient Survival from Time of Listing UNOS Pancreas Waiting List 1/1/1995 5/31/2003 100 % 80 60 40 Cat. ■ PTA Wait 20 Survival n 1Yr 4Yrs 647 98.7% 89.4% 485 94.1% 83.0% 0 0 12 24 Months Waiting 2/04 36 48 IPTR UNOS / Relative Hazard Ratios UNOS Pancreas Waiting List 1/1/1995 5/31/2003 Relative Hazard Ratio 5 PAK PTA SPK 4 3 2 1 equal risk Wait-Listed Patients 0 0 50 100 150 200 250 300 Days since Transplantation 8/04 350 400 IPTR UNOS / Pancreas Transplant Outcome for Contemporary Cases (2000 - 2004) IPTR UNOS / Patient Survival USA DD Primary Pancreas Transplants 1/1/2000 6/6/2004 100 % 90 80 70 Cat. PAK PTA 429 SPK 60 n 1,112 1Yr Surv. 95% 98% 3,842 95% p ≤ 0.05 50 0 6 12 18 24 Months Posttransplant 8/04 30 36 IPTR UNOS / Pancreas Graft Function USA DD Primary Pancreas Transplants 1/1/2000 6/6/2004 % 100 80 60 40 Cat. PAK PTA SPK 20 n 1,109 429 3,841 1Yr Fxn 78% 76% 85% p < 0.0001 0 0 8/04 6 12 18 24 Months Posttransplant 30 36 IPTR UNOS / Time between Kidney and Pancreas Tx USA DD Primary PAK Transplants 1/1/2000 6/6/2004 Number of Transplants 400 300 200 100 0 30 60 90 120 150 180 210 240 270 Time between Kidney and PancreasTransplant [Mos] IPTR UNOS / Major Immunosuppressive Protocols USA Primary DD Pancreas Transplants 1/1/2000 6/ 6/2004 80 % 60 TAC/AZA CsA/MMF TAC/MMF TAC SIR based 40 20 0 PAK 8/04 PTA SPK IPTR UNOS / Antibody Therapy USA DD Primary Pancreas Transplants 1/1/2000 6/6/2004 % 60 50 No ABs 40 Depl. AB NonDepl. AB 30 Both ABs 20 10 0 PAK 8/04 PTA SPK IPTR UNOS / Pancreas Graft Function USA DD Primary Pancreas Transplants 1/1/2000 6/6/2004 % Anti-T-Cell Therapy & TAC & MMF 100 80 60 40 Cat. PAK PTA SPK 20 n 568 233 1915 1Yr Surv. 83% 80% 88% p < 0.0001 0 0 8/04 6 12 18 24 Months Posttransplant 30 36 IPTR UNOS / Pancreas Graft Function USA DD Primary Pancreas Transplants 1/1/2000 6/6/2004 % Anti T-Cell Therapy & Sirolimus & TAC 100 80 60 40 Cat. PAK PTA SPK 20 n 131 53 399 1Yr Surv. 83% 83% 87% 0 0 8/04 6 12 18 24 Months Posttransplant 30 36 IPTR UNOS / Pancreas Graft Loss due to Chronic Rejection USA DD TS Primary Pancreas Transplants, 1/1/2000 6/ 2004 % 40 Cat. PTA PAK SPK 30 n 378 1,001 3,539 2Yr Loss 10.3% 5.7% 1.5% P < 0.0001 20 10 0 0 6 12 18 Months Posttransplant 4/05 24 30 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 insulinindependence 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 insulinindependence 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 I T / P R 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 Iy/o. PTR /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 US CD Pancreas Transplants 1/1/1988 5/31/2003 - 3.4% IPTR UNOS / Technical Failure Rate USA DD Primary Pancreas Transplants 1/1/2000 6/ 6/2004 % 20 P = 0.009 Donor Cause of Death 15 Trauma CCV +/- 50 years 10 5 0 SPK PAK PTA IPTR UNOS / 1-Year Pancreas Technical Failure Rate USA DD Primary Pancreas Transplants 1/1/2000 6/ 6/2004 % SPK PAK PTA 25 20 15 10 5 0 0- 9 10 - 19 20 - 29 30 - 39 Donor Age 8/04 40 - 49 50 - 59 60 - 69 IPTR UNOS / 1-Year Pancreas Graft Function USA DD Primary Pancreas Transplants 1/1/2000 6/ 6/2004 % SPK PAK PTA 100 90 80 70 60 50 0- 9 10 - 19 20 - 29 30 - 39 40 - 49 Donor Age 8/04 50 - 59 60 - 69 IPTR UNOS /