1. The Role of Pancreas Transplantation in the Long Term Management of Diabetes Christopher Johnson MD Professor of Surgery Division of Transplant Surgery Medical College of Wisconsin

2. Learning objectives: 1. This talk will increase your understanding about the rationale (including risk/benefit assessment) for pancreas transplantation in the management of diabetes. 2. This talk will allow you to better appreciate some of technical and immunological challenges associated with pancreas transplantation 3. This talk will help you to better anticipate therapy options for diabetic patients who have chronic kidney disease.

3. no disclosures

4. Tight control reduces end organ damage but increases the risk (2-3 fold) of severe hypoglycemic episodes (1). 1 DCCT. The Diabetes Control and Complications Trial Research Group The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin- Dependent Diabetes Mellitus. N Engl J Med 1993; 329: 977–986. 1 DCCT. The Diabetes Control and Complications Trial Research Group The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin- Dependent Diabetes Mellitus. N Engl J Med 1993; 329: 977–986. 1

5. DCCT trial (1441 patients randomized to intensive insulin vs. conventional insulin) designed to examine the effect of tight control on 2 ° complications (followed > 6yrs) Retinopathy Retinopathy Neuropathy Neuropathy Incidence progression Prevalence of neuropathy

6. A successful pancreas transplant completely normalizes blood sugar control However, it requires life long immunosuppression

7. Types of pancreas transplants: Kidney/Pancreas (pts undergoing kidney transplantation) Pancreas after kidney (already on IS) Pancreas transplant alone (severe life- threatening complications of DM) Islet after kidney (no surgical procedure) Islet transplant (no surgical procedure but requires IS)

8. Combined kidney/pancreas transplant is the most common scenario for pancreas transplantation:

9. Indications for Simultaneous Kidney and Pancreas Transplant: Presence of ESRD (or eGFR < 20 ml/min) Presence of ESRD (or eGFR < 20 ml/min) Presence of diabetes: type 1 or 2 (meeting age (< 55) and BMI criteria (<30) Presence of diabetes: type 1 or 2 (meeting age (< 55) and BMI criteria (<30) Lack of major complications and/or severe cardiovascular disease which limits life expectancy Lack of major complications and/or severe cardiovascular disease which limits life expectancy

10. Figure 13: Unadjusted 1-year, 3-year, 5-year and 10-year pancreas graft survival by transplant type

11. Reversal of Lesions of Diabetic Nephropathy after Pancreas Transplantation Fioretto, Paola; Steffes, Michael W.; Sutherland, David E.R.; Goetz, Frederick C.; Mauer, Michael. NEJM 339:69-75 July 9, 1998 Number 2

12. Survival estimates for patients with kidney graft function at 1 year. Abbreviations: LD, living donor; CAD, cadaveric. Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure Am J Kid Disease 41:464-470. 2003

13. Figure 2: Waiting list death rates by diagnosis, 1999–2008.

14. Diabetics who receive k/p gain more life- years than k-alone or non-diabetics :

15. k/p transplants are equally successful for type 1 and type 2 diabetes: data from SRTR 2010

16. What is the role of pancreas transplant in type 2 diabetes? Diabetes affects 10% of the population Diabetes affects 10% of the population 90-95% is type 2 90-95% is type 2 Distinction between type 1 and 2 not always clear cut Distinction between type 1 and 2 not always clear cut c C –peptide is not accurate in renal failure

17. suggested criteria: suggested criteria:

19. Organ Procurement: Simultaneous Liver and Pancreas Removal

20. Back table dissection:

21. More back table dissection…

22. Back table Reconstruction of Pancreatic Allograft

23. Arterial “Y” Graft of Donor Iliac Artery Portal Vein Mobilization

24. Bladder Drainage with Systemic Venous Anastomosis Enteric Drainage with Portal Venous Anastomosis

25. Trends in maintenance immunosuppression therapy prior to discharge for simultaneous kidney-pancreas transplantation 1994-2003 American Journal of Transplantation 2005;5(Part 2):874-886

26. Incidence of rejection during first year among simultaneous kidney-pancreas recipients American Journal of Transplantation 2005;5(Part 2):874-886

27. ADVANCES IN PANCREAS TRANSPLANTATION. Transplantation. 77(9) Supplement:S62-S67, May 15, 2004. Burke G, Ciancio G, Sollinger H

28. Post-Transplant Complications Early post-operative complications (Bleeding, infection) Venous Thrombosis Reperfusion pancreatitis Pancreas is a relatively low-flow organ Unrecognized inherited hypercoagulable state in the recipient Transplant Pancreatitis Mild - transient amylase elevation for 48-96h Severe – fat necrosis, infected peripancreatic fluid Kidney (urine leak, ureteral stricture) Surgical Aspects of Pancreas Transplantation:

29. Radiologic tools for transplant evaluation:

30. Splenic vein thrombosis:

31. Fluid collection on CT:

32. Drachenberg CB, Papadimitriou JC, Klassen DK, et.al: Evaluation of pancreas transplant needle biopsy. Reproducibility and revision of histologic grading system. Transplantation 1997;63(11):1579-1586.Transplantation 1997;63(11):1579-1586 Drachenberg C, Klassen D, Bartlett S, Hoehn-Saric E, Schweitzer E, Johnson L, Weir J and Papadimitriou J: Histologic grading of pancreas acute allograft rejection in percutaneous needle biopsies. Transplant Proc 1996;28(1):512-513Transplant Proc 1996;28(1):512-513 Diagnosis of Pancreatic Allograft Rejection (is difficult)

34. PAK and PTA have higher rate of immunologic graft loss after 1 year

35. Indications for isolated pancreas transplant (PAK or PTA): Frequent and/or severe hypoglycemic events consistent failure of insulin-based management to prevent acute and chronic complications (poor control). clinical and/or emotional problems associated with the use of exogenous insulin therapy that are so severe as to be incapacitating

36. Isolated Pancreas Transplant : Recipient Selection Criteria  IDDM, age > 18 years with an upper age limit of ?  Ability to withstand surgery and immunosuppression  Psychosocial stability/ social support/ compliance/  commitment to long-term follow-up  Diabetic secondary complications  Hyper-lability/ Hypoglycemic Unawareness  Financial resources (USA)  Absence of any exclusionary criteria: - renal function - coronary disease

37. Mortality risk/benefit of PAK and PTA: American Journal of Transplantation 2004; 4: 2018–2026 Mortality on waiting list: Mortality after transplant: spk SPK

38. Islet Isolation 1. Organ Procurement 2. Distension with Collagenase 3. Digestion & Mechanical Separation 4. Purification of Islets 5. Quantification

44. The “Edmonton Protocol” Efficient Isolation Procedure Efficient Isolation Procedure Reliable Collagenase Reliable Collagenase Steroid Free Immunosuppressive Protocol Steroid Free Immunosuppressive Protocol IL-2R Blockade IL-2R Blockade Tacrolimus Tacrolimus Sirolimus Sirolimus

45. Only 31% remained insulin independent at 2 years N Engl J Med 2006;355:1318-30.

46. Failed islet transplants are associated with sensitization to HLA antigens:

47. Whole Pancreas Transplantation ++ Pancreatic Islet Cell Transplantation

49. Successful islet transplants decrease progression of nephropathy and retinopathy Preservation of renal function Decreased progression of retinopathy

50. Conclusions: Pancreas transplants when successful, normalize glucose metabolism and increase quality (and quantity) of life. “Good risk” diabetics (type 1 or 2) with renal failure should receive either a living donor kidney transplant or a combined kidney/pancreas transplant

51. Conclusions: “Good risk” diabetics with a functioning kidney transplant (and problematic BS control) should be considered for pancreas after kidney “Better risk” diabetics without kidney disease, but with life threatening manifestations should be considered for pancreas transplant alone “Good” = age < 55, BMI < 30, insulin use < 1U/kg/day, no or minimal CAD, PVD