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

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

UCHSC Diabetes 50.1% Hypertension 27% Glomerulonephritis 13% Other 10% United States Renal Data System. Annual Data Report No. of patients Projection 95% CI r 2 =99.8% 243, , ,240 No. of dialysis patients (thousands) DM in Renal Failure: A growing epidemic

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

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: incident patients Figure 6.5 USRDS 2004

UCHSC Expected remaining lifetimes (years) of dialysis & transplant patients DialysisTransplant MF Age MF General Population

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  y14y  y11y  y6y Wolfe RA et al, NEJM 1999;341:1725

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  y8y  y8y  y5y Wolfe RA et al, NEJM 1999;341:1725

UCHSC High demand for kidneys!

UCHSC Average wait time:  By Blood group:  Type O1469 days  Type B1815 days  Type A740 days  Type AB396 days  By Age:  days  days  days  days  days

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

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

UCHSC HUMAN ISLET TRANSPLANTATION

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

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

UCHSC Pancreatic Duct Cannulation

UCHSC Final islet prep

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

UCHSC a.m.p.m. Post-transplant Pre-transplant Time of day Blood glucose (mg/dl) Shapiro et al. N Engl J Med 2000; 343:

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

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

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

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

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

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

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

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

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

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

UCHSC

Clinical Outcomes  fasting pre-tx post-tx Pt Infusion IEQ/kg c-peptide insulin (u/d) insulin (u/d) HgbA1c  K > 6.0  K > 5.2  K > 5.6  K > 4.8  All patients have eliminated life-threatening hypoglycemia unawareness

UCHSC The future of islet transplantation

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

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

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)

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

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)

UCHSC Hepatic Steatosis following islet transplantation

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

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

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 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