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A. Utility of Pancreas Transplantsnavigator

  1. Diabetes mellitus type 1
  2. Reversal of diabetic nephropathy requires >5 years [3]
  3. Combination transplant with kidney
    1. These patients usually do better than single organ/tissue transplants
    2. Renal function is maintained for prolonged periods with double transplants
    3. Pancreas transplant alone with good renal function may not improve outcomes over standard care with insulin and other agents [2]
  4. Islet cell transplants alone (portal vein infusion) are usually unsuccessful to date

B. Indications for Pancreas and Islet Cell Transplantationnavigator

  1. Mainly indicated for Diabetes Mellitus (DM) Type 1 Patients
    1. This is a disease of ß-islet cell destruction
    2. In most cases, patients eligible for transplants are those with DM and complications
  2. Diabetic nephropathy with creatinine clearance <40mL/min or dialysis dependence
  3. Renal transplant not done if creatnine clearance >55mL/min
  4. However, outcomes for pancreas transplant without renal transplant are worse than for no transplant at all [2]

C. Exclusion for Pancreas Transplantnavigator

  1. Significant Cardiovascular Disease (usually without reserve)
  2. Major psychiatric illness
  3. Active infection or malignancy
  4. Extreme obesity (>130% of ideal body weight)
  5. Lack of clear diabetic complications

D. Pancreas Transplant Protocol navigator

  1. Most procedures use whole-organ pancreas transplant with duodenal segment
    1. About 80% are combined pancreas-kidney transplantations
    2. Increased interest in purified islet cell transplants (see below)
  2. Organ Operation usually takes 3-5 hours
  3. Pancreas Placement
    1. Right Lower quadrant (pelvis)
    2. Right iliac artery and vein used for blood supply
    3. Duodenal segment is attached to bladder (ends are sewn shut)
  4. Kidney Placement
    1. Left lower quadrant (pelvis)
    2. Left iliac artery and vein used for blood supply
    3. Ureter enters bladder
  5. Native organs are not removed from recipient
  6. Successful Living Donor Transplant [4]
    1. Living donor (patient's mother) underwent distal pancreatectomy
    2. Islet transplant successful with insulin independence achieved on day 22 post-transplant
  7. Immunosuppression
    1. Induction (pre-transplant) of recipient previously with OKT3 monoclonal antibody
    2. Combination of sirolimus and tacrolimus 7 days prior to transplant continued throughout
    3. Adding basiliximab (anti-IL2R antibody) 4 days before and day of transplant
    4. Infliximab (anti-TNFa antibody) may be added on day before transplant
    5. Traditionally cyclosporine, prednisone and azathioprine were used
    6. These agents cause significant hyperglycemia and may be islet-cell toxic
    7. Sirolimus, tacrolimus, mycophenolate increasingly used

E. Outcomesnavigator

  1. Overal patient survival is ~90% at 1 year (55% at 4 years)
  2. Graft Survival [8]
    1. Pancreas Alone: Year 1: 77%; Year 5: 41%; Year 10: 20%
    2. Pancreas + Kidney: Year 1: 85%; Year 5: 70%; Year 10: 47%
  3. Majority of patients are insulin independent
  4. Early studies suggest that transplantation improves late diabetic complications
  5. Effect on Diabetic Nephropathy [3]
    1. Most currently used immunosuppressives worsen glycemic control
    2. Mesangial proliferation is major component with resultant albuminuria
    3. Reversal of diabetic renal pathology requires 5-10 years

F. Complicationsnavigator

  1. Immunosuppression
    1. Infection
    2. Nephropathy from cyclosporine, tacrolimus, sirolimus
    3. Cushing's - mainly due to glucocorticoids
  2. Surgical Complications
  3. Cystitis - chemical (pancreatic enzymes), infection, combination
  4. Pancreatic excretion of bicarbonate and consequent metabolic acidosis
  5. Graft Failure
  6. Hyperinsulinemia - questionable effects

G. Islet Cell Transplantation [1,5,6] navigator

  1. Human islet cells can now be isolated efficiently from pancreas
  2. Cells can be infused into portal vein and functionally lodge in the liver
    1. Initially, a non-specific (nitric oxide dependent) inflammation occurs
    2. This limits early islet cell function and may reduce number of grafted cells
    3. This problem, called primary nonfunction, is under intense study
  3. Matching Islet Transplants
    1. Blood type match required
    2. Cross match for lymphocytotoxic antibodies
    3. HLA match not required
    4. Single donor, marginal dose islet transplantation has been successful in 8 of 8 patients [9]
  4. Immunosuppressive agents are generally needed in high doses
    1. Glucocorticoids substantially worsen diabetes
    2. Cyclosporine and tacrolimus are toxic to ß-islet cells
    3. Therefore, the high doses of these agents substantially impair ß-cell function
    4. Novel regimens have now been identified with some efficacy
    5. Induction with antithymocyte globulin, daclizumab and etanercept followed by maintenance with mycophenolate, sirolimus and no or low dose tacrolimus has been effective [9]
  5. Glucocorticoid-Free Immunosuppression [5,9,10]
    1. Also called "Edmonton Protocol"
    2. Low dose tacrolimus combined with sirolimus (rapamycin)
    3. Glucocortoids replaced with daclizumab (Zenapax®), an IL2-receptor blocking antibody
    4. Two or more pancreas-equivalents of islet cells required for transplant to achieve insulin independence
    5. Led to 7 of 7 patients with insulin independence after transplant in initial study [5]
    6. Etanercept (Embrel®), a TNFa blocker, added for maintenance with good effect [9]
    7. Followup of ~1 year had HbA1c levels <6% (normal range)
    8. In larger multinational study, 44% of 36 subjects were insulin independent at 1 year [10]
    9. Even in patients without complete insulin indendence, islet transplants provided reduced hypoglycemic effects and improved HbA1c [10]
    10. Therefore, islet cell transplantation appears to be achievable in a minority of patients
  6. Largest Clinical Report [7]
    1. Thirty subjects received 50 islet transplant procedures
    2. Islet cell infusions 9000 islets/kg into the portal vein
    3. Of 15 patients followed for 1 year, 80% were insulin independent
    4. Hypertension, hypercholesterolemia, infection were most important complications

References navigator

  1. Ricordi C. 1996. Diabetes Rev. 4(3):356
  2. Venstrom JM, McBride MA, Rother KI, et al. 2003. JAMA. 290(21):2817 abstract
  3. Fioretto P, Steffes MW, Sutherland DE, et al. 1998. NEJM. 339(2):69 abstract
  4. Matsumoto S, Okitsu T, Iwanaga Y, et al. 2005. Lancet. 365:1642 abstract
  5. Shapiro AM, Lakey JR, Ryan EA, et al. 2000. NEJM. 343(4):230 abstract
  6. Robertson RP. 2004. NEJM. 350(7):694 abstract
  7. Ryan EA, Lakey JR, Paty BW, et al. 2002. Diabetes. 51(7):2148 abstract
  8. Sayegh MH and Carpenter CB. 2004. NEJM. 351(26):2761 abstract
  9. Hering BJ, Kandaswamy R, Ansite JD, et al. 2005. JAMA. 293(7):830 abstract
  10. Shapiro AM, Ricordi C, Hering BJ, et al. 2006. NEJM. 355(19):1318