1. UCHSC Renal and Islet Transplantation in Diabetes Alex Wiseman, M.D. Director, Renal Transplant Clinic University of Colorado Health Sciences Center

2. UCHSC Objectives  Compare treatment options of dialysis vs. kidney transplantation in patients with diabetes and renal failure  Understand the importance of early kidney transplantation in patients with diabetes  Define current success rates of islet transplantation  List commonly encountered side effects following islet transplantation  Describe future directions for islet transplantation

3. UCHSC Diabetes 50.1% Hypertension 27% Glomerulonephritis 13% Other 10% United States Renal Data System. Annual Data Report. 2000. No. of patients Projection 95% CI 1984 1988 1992 1996 2000 2004 2008 0 100 200 300 400 500 600 700 r 2 =99.8% 243,524 281,355 520,240 No. of dialysis patients (thousands) DM in Renal Failure: A growing epidemic

4. UCHSC Incident dialysis patients; adjusted for age, gender, race, & primary diagnosis. All ESRD patients, 1996, used as reference cohort. Modality determined on first ESRD service date; excludes patients transplanted or dying during the first 90 days. Adjusted five-year survival, by modality: incident patients Figure 6.34, USRDS 2004

5. UCHSC Incident dialysis patients & patients receiving a first transplant in the calendar year. All probabilities are adjusted for age, gender, & race; overall probabilities are also adjusted for primary diagnosis. All ESRD patients, 1996, used as reference cohort. Modality determined on first ESRD service date; excludes patients transplanted or dying during the first 90 days. Adjusted survival: 1993-1997 incident patients Figure 6.5 USRDS 2004

6. UCHSC Expected remaining lifetimes (years) of dialysis & transplant patients DialysisTransplant MF 39.5 40.2 35.6 36.5 31.6 32.5 27.4 28.6 23.8 25.2 20.6 22.2 17.6 19.4 14.9 16.9 12.6 14.6 10.5 12.5 8.5 10.5 6.9 8.9 5.9 7.8 Age 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 MF 16.815.4 14.213.1 11.910.9 9.89.2 8.38.0 7.26.9 6.26.0 5.35.1 4.5 3.8 3.2 2.7 2.4 2.0 62.5 57.7 53.0 48.2 43.5 38.8 34.3 29.8 25.5 21.5 17.7 14.3 11.2 General Population

7. UCHSC How much does a transplant benefit the patient?  Comparison of outcomes of patients receiving a transplant vs. those on the waiting list:  Projected Survival: Age with transplant without transplant  0-19 y39y26y  20-3931y14y  40-59 22y11y  60-7410y6y Wolfe RA et al, NEJM 1999;341:1725

8. UCHSC In patients with diabetes, dramatic survival benefit with transplant  Comparison of outcomes of patients with diabetes receiving a transplant vs. those on the waiting list:  Projected Survival: Age with transplant without transplant  20-3925y8y  40-59 22y8y  60-748y5y Wolfe RA et al, NEJM 1999;341:1725

9. UCHSC High demand for kidneys!

10. UCHSC Average wait time:  By Blood group:  Type O1469 days  Type B1815 days  Type A740 days  Type AB396 days  By Age:  6-17400 days  18-34987 days  35-491134 days  50-641328 days  65+1599 days

11. UCHSC Living donation has increased while deceased donation has remained stable 1990-2002 # Transplants by donor type Year OPTN/SRTR 2003 Annual Report 300% increase 12% increase

12. UCHSC Unrelated/spouse donation has resulted in the increase in living donors

13. UCHSC HUMAN ISLET TRANSPLANTATION

14. UCHSC General Principle:  Normalization of blood glucose (not merely control of blood glucose) will lead to improvements in: n Survival n Quality of life n Protection from heart disease, kidney disease, retinopathy, and nerve injury  The only method that normalizes blood glucose in patients with diabetes is treatment with insulin- producing cells

15. UCHSC Methods to treat with insulin-producing cells  Pancreas transplant  Pancreas obtained from cadaver donors, transplanted surgically within 12 hours  Surgical procedure involves general anesthesia, abdominal surgery, and a 7-10 day hospitalization  Complications: n Thrombosis of pancreatic vessels n Pancreatic leak n Infection  Islet Cell Transplant  Islet tissue obtained from cadaver organs by collagenase digestion of the pancreas and purification of islets via density gradients  Islets injected into portal vein for liver implantation, performed by interventional radiology, followed by a 1-2 day hospitalization  Complications: n Bleeding n Thrombosis

16. UCHSC Pancreatic Duct Cannulation

17. UCHSC Final islet prep

18. UCHSC “Insulin independence after solitary islet transplantation in type 1 diabetic patients using steroid-free immunosuppression”  7 consecutive patients achieved euglycemia during a mean follow-up of 11 months, with normal HgbA1c and GTT  6/7 patients required >1 donor (>1 transplant) a median of 29 days from the first procedure  Mean islet equivalents =11,400/kg required to achieve euglycemia  Cadaveric pancreata from older donors >45 yo (70% would have been discarded) Shapiro AMJ et al, NEJM 2000; 343:230

19. UCHSC 600 500 400 300 200 100 2 4 6 81010 1212 2 46 810 600 500 400 300 200 100 0 1212 a.m.p.m. Post-transplant Pre-transplant Time of day Blood glucose (mg/dl) Shapiro et al. N Engl J Med 2000; 343:230-238

20. UCHSC The Edmonton Protocol: update and follow-up  65 patients treated with islet transplantation:  44 completed therapy (defined by insulin independence)  Median duration of insulin independence =15 months  Mean islets transplanted=799,912  128 procedures:  Bleeding in 15, portal vein thrombosis in 5  2+ antihypertensive meds in 42% (6% at entry)  Statin use 83% (23% at entry) Ryan EA, et al, Diabetes 2005; 54:2060

21. UCHSC At 5 years, c-peptide secretion preserved but only 11% maintain insulin independence

22. UCHSC HgbA1c remains improved despite return to insulin use Insulin-free Lost function Primary nonftn

23. UCHSC University of Miami-Insulin independence in 14 of 16 subjects

24. UCHSC Copyright restrictions may apply. Hering, B. J. et al. JAMA 2005;293:830-835. Islet University of Minnesota-single donor islet transplantation

25. UCHSC ITN Multicenter Trial 9 centers enrolled 3-5 patients to replicate Edmonton trial 16/36 patients rendered insulin- independent at one year following final infusion Data presented by AMJ Shapiro at the ATC 2004 Center

26. UCHSC Success rates: pancreas vs. islet transplantation  Transplant:1998-002001-03  Kidney/Pancreas (SPK) 82%86%  Pancreas after kidney (PAK) 74%79%  Pancreas alone (PTA) 76%76%  Islet Transplant1990-962000-3  Combined data8%58%*  *data from 12 participating centers, up to 3 infusions One-year Graft Survival: Source: SRTR and CITR

27. UCHSC 5-year graft survival-all organs  Kidney66%  Pancreas (PTA)47%  Liver66%  Heart71%  Lung45% Source: Scientific Registry of Transplant Recipients Annual Report 2004

28. UCHSC Islet Cell Resources (ICR) Funded by the NIH to provide islets for use in clinical protocols and establish and improve isolation procedures and shipping of islets to outside centers

29. UCHSC Components of an Islet Transplant Program  Laboratory:cleanroom specifications, technical support (4-5 on call at all times), in-process environmental monitoring, post-isolation quality control testing  Clinical:recipient eval and post-transplant follow-up, OPO training/cooperation for organ allocation, transplant procedural coverage, inpatient care,immune/metabolic monitoring  Regulatory:IND for cellular therapy with FDA, annual reports to FDA and NIH, standard operating procedures for islet isolation/transplant, training documentation and equipment validation, UNOS certification and reporting, CITR reporting, DSMB reporting  Finance:NIH, UCH, GCRC, UCHSC, Barbara Davis Center

30. UCHSC

33. Clinical Outcomes  fasting pre-tx post-tx Pt Infusion IEQ/kg c-peptide insulin (u/d) insulin (u/d) HgbA1c  1 3 19.5K 2.045 78.2 -> 6.0  2 2 8.8K 1.942 126.7 -> 5.2  3 1 5.0K 0.643 257.6 -> 5.6  4 2 17.5K 1.724 67.0 -> 4.8  All patients have eliminated life-threatening hypoglycemia unawareness

34. UCHSC The future of islet transplantation

35. UCHSC Islets Possible Reasons for Islet Graft Failure Allograft rejection Disease recurrence Insufficient islet mass Poor quality of islets Toxicity of anti- rejection drugs Failure to engraft Insulin resistance

36. UCHSC OBSTACLES TO SUCCESSFUL ISLET TRANSPLANTATION: Low engraftment of islets  The transplanted  cell mass is ~50% of the mass present in a normal individual  The engrafted  cell mass is ~30% of the transplanted  cell mass  Islet engraftment takes weeks before revascularization is completed, rendering islets susceptible to: Hypoxic injury Nonspecific cell-mediated injury: “IBMIR”, cytokine release, reactive oxygen intermediates elaborated during postoperative healing/wound reaction

37. UCHSC Is islet transplantation safe?  Acute complications:  Bleeding ~10-15%  Thrombosis~5%  Transaminitis~50%  Long-term complications:  Renal function  Hypertension  Hyperlipidemia  Mouth ulcers  Risk of sensitization  Risk of infection (CMV)

38. UCHSC Is islet transplantation safe? SAE Report CITR June 2005  150 participants:  N=98no SAE  N=251  N=162  N=63  N=44  N=2>4  52 pts had 102 SAE’s  N=22life-threatening  N=61 hospitalization  N=18 prolonged hosp stay  Most common SAE types:  N=26GI disorder  N=17Blood/lymph  N=11Infection

39. UCHSC Adverse events:  Patient 1:  mouth ulcers, diarrhea, depression  Patient 2:  mouth ulcers, abd pain (SAE), hyperlipidemia, neutropenia, life-threatening clostridia septicum infection (withdrawl from trial)  Patient 3:  mouth ulcers, abd pain (SAE), hyperlipidemia, rash  Patient 4:  mouth ulcers, hypertension, liver hemorrhage (SAE), Cr 1.2 to 1.4 (off tacrolimus)

40. UCHSC Hepatic Steatosis following islet transplantation

41. UCHSC In an era of scarce resources, should one patient population receive special consideration?  Type 1 diabetic patients with life-threatening hypoglycemia? Pro: Normoglycemia may be life-saving Con: Immunosuppression risk/side effects  Diabetic patients with renal failure? Pro: Immunosuppression not a factor Con: Benefit of normoglycemia may not significantly impact survival  Diabetic patients with early signs of organ damage? Pro: Early intervention may prevent costly, life threatening complications Con: Enormous patient population

42. UCHSC Supply and Demand (2003 data):  5908 deceased donors  1372 for pancreas tx  ~4500 pancreata available for islet isolation  ~2000 adequate yield  ~1000 patients transplanted  One million type 1 diabetic patients in the U.S. transplant.1% of patients  ~5000 Type 1 diabetic patients with ESRD on tx list transplant 20% of patients

43. UCHSC CONCLUSIONS:  Successful islet cell transplantation is now possible Less invasive but less durable than pancreas transplants Innovations in inhibiting early inflammation, reducing toxicity of meds needed  Kidney transplantation is of paramount importance in the patient with diabetes and renal failure Early referral (GFR 20-30 ml/min) Evaluation of living donors  Organ allocation, patient selection, and payment for islet transplantation will remain controversial topics during the “growth” phase of development of islet transplant programs