1. Transplantation in the Diabetic Patient The Status of Pancreas transplantation A. Osama Gaber Professor of Surgery Director of the Transplant Institute, Memphis

2. Diabetes Mellitus in the U.S. 15 million people are diabetic 800,000 new cases per year 7 th leading cause of death (heart disease most common) Leading cause of ESRD DM – related health care costs : 15% of total US budget

3. Diabetic Nephropathy 1. Renal hypertrophy and hyper function 2. Intermittent microalbuminuria 3. Incipient nephropathy 4. Symptomatic nephropathy 5. End stage renal disease Early persistent albuminuria Late + Hypertension + Renal structural damage

4. Incidence and Prevalence of ESRD according to underlying Disease Incidence%Prevalence%Deaths% Diabetes38,16043114,4783429,09943 HTN23,1662677,9782318,05427 GN8,038953,994165,3118 Polycystic KD2,096214,85441,1912 Urologic Dis.1,59026,63521,1082 Other15,0741772,3222112,20118 Total88,091100340,26110066,964100 USRDS 2001

5. No of Kidney Tx by Disease [1999] CADLDTotal% Diabetes2,5238533,37625 Glom. Disease1,8851,2543,13924 Hypertension1,6415812,22217 Polycystic KD7153281,0438 Others2,1751,4633,63827 Total8,9394,47913,418100 UNOS 2000 * * * Includes kidney transplants in SPK recipients

7. Impact of Renal Function on Mortality

8. Projected Years of Life With and Without Kidney Transplantation Years

9. Time-dependent 5-yr Mortality Risk in SKPT Recipients Relative to Patients with Type I DM Awaiting Transplantation Ojo AO et al;Transplantation.2001 Jan 15;71(1):82-90

10. Evolution of Diabetes Treatment by Transplantation Pancreas transplantation for patients obligated to immunesupression Pancreas transplantation for serious complications Islet Transplantation for prevention of secondary complications Treatment of Diabetes By Transplantation Early DM LateIntrermed

11. IPTR Report August 2005 As of December 2004 –23,000 pancreas transplants 17,00 in US Significant improvements in Pancres graft survival –SPK From 75% 1988/89 to 85% 2002/03 –PAK 55% 78% –PTA 45% 77%

12. IPTR Data August 2005 1988/892002/03 SPK12%6% PAK13%8% PTA24%7% Technical failure rates 1988/892002/03 SPK7%2% PAK28%7% PTA38%8% Immunologic failure rates

13. IPTR Data August 2005 Enteric drainage Most common –81% of SPK –67% of PAK –56% of PTA Portal venous drainage –20% of SPK –23% of PAK –35% 0f PTA Technical failure rates higher in SPK ED Immunologic graft loss rate higher in ED vs. BD (15% vs. 5% at I year)

14. USA CAD Primary Pancreas Transplants 10/1/1987 – 5/15/2003 Yearsn1Yr Surv 87 – 92193491% 93 – 95228893% 96 – 98260694% 99 – 001845 95% 01 – 03193795% P = 0.0001 6/03 SPK Patient Survival by Era

15. Patient Survival while Waiting UNOS Pancreas Waiting List 1/1/1995 – 5/20/2003 Survival Cat.n1Yr4Yrs PAK312298%90% PTA113797% 94% SPK 1171593%65% 6/03

16. USA CAD Primary Pancreas Transplants 10/1/1987 - 5/15/2003 P = 0.0001 Yearsn1Yr Surv 87 – 92192183% 93 – 95227387% 96 – 98256691% 99 – 001789 93% 01 – 03183892% 6/03 SPK Kidney Graft Function by Era

17. USA CAD Primary Pancreas Transplants 10/1/1987 - 5/15/2003 P = 0.0001 Yearsn1Yr Surv 87 – 92193476% 93 – 95228880% 96 – 98260384% 99 – 001845 84% 01 – 03193085% 6/03 SPK Pancreas Graft Function by Era

18. Diastolic Dysfunction in Diabetic Uremia

19. Normalization of Diastolic Function after SPK Transplantation

20. Reversal Of Diastolic Dysfunction

21. Regression of left Ventricular Hypertrophy

23. Urinary Albumin Excretion Rate A Hall mark of Diabetic Nephropathy Recent confirmation by; Copelli A,et al Diabetes Care. 2005 Jun;28(6):1366-70

24. Randomized immunosuppression Trials AuthorComparatorConcomitantFindings Bechstein WO Transplantation 77:1221,2004 TAC vs. CYAPoly Ab, MMF, ST Panc survival 91% vs74% Rejection rate 27%nvs 38% Burke GW Transplantation 77:1221,2004 Ab vs. No IndTAC, MMF, St Kid 92% vs 82% CMV in Ab grp Stratta RJ Transplantation75:1260, 2003 Dacluzimab dosing TAC,MMF, ST2 mg dosing--- less rejection Saudek F Transplantation proc.37,1663 2005 Rapa vs. MMFAb, Tac, STMMF 87% vs. Rapa 81%

25. SPK Transplants in Type I and Type II Diabetics With ESRD: Similar 10-Year Outcomes J.A. Light and D.Y. Barhyte Transplantation Proceedings, 37, 1283–1284 (2005)

26. Early Transplantation Improves Patient and Graft Outcomes P<0.042 Israni AK,FeldmanHI,PropertKJ,LeonardM,MangeKC Am J Transplant 2005 Feb;5(2):374-82

27. Patient Survival while Waiting UNOS Pancreas Waiting List 1/1/1995 – 5/20/2003 Survival Cat.n1Yr4Yrs PAK312298%90% PTA113797% 94% SPK 1171593%65% 6/03

28. Patient Survival after Tx UNOS Pancreas Waiting List 1/1/1995 – 5/20/2003 Survival Cat.n1Yr4Yrs PAK168295%85% PTA61397% 86% SPK 677595%88% 6/03

29. PAK Pancreas Graft Function by Era USA CAD Primary Pancreas Transplants 10/1/1987 - 5/15/2003 P < 0.0001 Yearsn1Yr Surv 87 – 9213657% 93 – 9513264% 96 – 9828472% 99 – 00371 77% 01 – 0358079% 6/03

30. Survival After Pancreas Transplantation VenstrumJM et al;JAMA 2004Apr7:291(13):1566

31. Chronic Kidney Disease StageDefinition 1GFR<90 ml/min/1.73m2 with evidence of renal damage 2GFR60-98 ml/min/1.73m2 with evidence of renal damage 3GFR30-59 ml/min/1.73m2 4GFR15-29 ml/min/1.73m2 5GFR<15 ml/min/1.73m2 Each 10ml/min/1.73m2 decline in GFR Increases CV event risk in patients 45-64 by 1.05 Renal Dysfunction increases risk of operative mortality S Cr >177umol(2mg/dl) 7fold increase in op mortality S Cr 130-270 umol(1.5-3) 40% increase in op mortality S Cr >130umol(1.5 mg/dl) increased risk of cardiac arrest and MI Browner et al JAMA 1992;268:228-232 O’Brian et al Kid International2002 ;62:585-592

32. PTA Patient Survival by Era USA CAD Primary Pancreas Transplants 10/1/1987 – 5/15/2003 Yearsn1Yr Surv 87 – 9210294% 93 – 959489% 96 – 9814296% 99 – 00173 99% 01 – 0323197% Wilcoxon:p=0.04 Log-Rank:p=0.09 6/03

33. PTA Graft Function by Era USA CAD Primary Pancreas Transplants 10/1/1987 - 5/15/2003 P < 0.0001 Yearsn1Yr Surv 87 – 9210255% 93 – 959454% 96 – 9814176% 99 – 00173 79% 01 – 0323076% 6/03

34. PTA Graft Loss due to Rejection p < 0.0001 Yearsn1Yr Loss 87 – 927528% 93 – 957128% 96 – 981158% 99 – 00143 7% 01 – 032057% USA TS CAD Primary Pancreas Transplants 10/1/1987– 5/15/2003 6/03

35. Actuarial Patient Survival by Decade for Recipients of Primary Living Donor Kidney Transplants Matas et al: Annals of surgery; vol 234, No2, 149-164

36. PTA Pancreas Graft Rejection by Vasc.Mgmt USA TS CAD Primary ED Pancreas Transplants 1/1/1999 – 5/15/2003 Vsc. Mgmt n1Yr Surv. Systemic9111% Portal 78 7% 6/03 P  0.07

37. Calcineurin and Steroid Free Pancreas Transplants Rainer W. G. Gruessner, Raja Kandaswamy, Abhinav Humar, Angelika C. Gruessner, and David E. R. Sutherland; Transplantation 2005;79: 1184–1189 6 Months graft survival

38. Calcineurin and Steroid Free Pancreas Transplants The rate of pancreas graft loss from rejection at 6 months SPK recipients 0% (vs. 0%; P0.99); for PAK recipients, 0% (vs. 4%;P0.99) PTA recipients, 15% (vs. 3%; P0.06). Rainer W. G. Gruessner, Raja Kandaswamy, Abhinav Humar, Angelika C. Gruessner, and David E. R. Sutherland; Transplantation 2005;79: 1184–1189

39. Mortality Assessment for Pancreas Transplants Multiple listings excluded SSDMF used to verify all death UNOS kidney database used to verify data Multivariate analysis: overall mortality not increased In any of the categories Gruessner RW,Sutherland DE,Grussner AC Am J Transplant 2004 Dec;4(12):2018-26

40. Ninety-Five Percent Insulin Independence 3 Years After PTA With Portal-Enteric Drainage U. Boggi, F. Mosca, F. Vistoli, S. Signori,et alTransplantation Proceedings, 37, 1274–1277 (2005)

41. Conclusions and Summary Diabetic patients are at significant disadvantage on dialysis Diabetic patients benefit the most from transplantation Earlier transplantation in Diabetics achieves the best risk benefit ratio Type II diabetics represent significant challenges in post transplant rehab