original articleT h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 355;13 www.nejm

ObjectiveTo determine outcome in diabetic pancreas transplant recipients according to risk factors and the surgical techniques and immunosuppressive protocols that evolved during a 33-year period at a single institution. Summary Background DataInsulin-dependent diabetes mellitus is associated with a high incidence of management problems and secondary complications. Clinical pancreas transplantation began at the University of Minnesota in 1966, initially with a high failure rate, but outcome improved in parallel with other organ transplants. The authors retrospectively analyzed the factors associated with the increased success rate of pancreas transplants. MethodsFrom December 16, 1966, to March 31, 2000, the authors performed 1,194 pancreas transplants (111 from living donors; 191 retransplants): 498 simultaneous pancreas-kidney (SPK) and 1 simultaneous pancreas-liver transplant; 404 pancreas after kidney (PAK) transplants; and 291 pancreas transplants alone (PTA). The analyses were divided into five eras: era 0, 1966 to 1973 (n ϭ 14), historical; era 1, 1978 to 1986 (n ϭ 148), transition to cyclosporine for immunosuppression, multiple duct management techniques, and only solitary (PAK and PTA) transplants; era 2, 1986 to 1994 (n ϭ 461), all categories (SPK, PAK, and PTA), predominately bladder drainage for graft duct management, and primarily triple therapy (cyclosporine, azathioprine, and prednisone) for maintenance immunosuppression; era 3, 1994 to 1998 (n ϭ 286), tacrolimus and mycophenolate mofetil used; and era 4, 1998 to 2000 (n ϭ 275), use of daclizumab for induction immunosuppression, primarily enteric drainage for SPK transplants, pretransplant immunosuppression in candidates awaiting PTA. ResultsPatient and primary cadaver pancreas graft functional (insulinindependence) survival rates at 1 year by category and era were as follows: SPK, era 2 (n ϭ 214) versus eras 3 and 4 combined (n ϭ 212), 85% and 64% versus 92% and 79%, respectively; PAK, era 1 (n ϭ 36) versus 2 (n ϭ 61) versus 3 (n ϭ 84) versus 4 (n ϭ 92), 86% and 17%, 98% and 59%, 98% and 76%, and 98% and 81%, respectively; in PTA, era 1 (n ϭ 36) versus 2 (n ϭ 72) versus 3 (n ϭ 30) versus 4 (n ϭ 40), 77% and 31%, 99% and 50%, 90% and 67%, and 100% and 88%, respectively. In eras 3 and 4 combined for primary cadaver SPK transplants, pancreas graft survival rates were significantly higher with bladder drainage (n ϭ 136) than enteric drainage (n ϭ 70), 82% versus 74% at 1 year (P ϭ .03). Increasing recipient age had an adverse effect on outcome only in SPK recipients. Vascular disease was common (in eras 3 and 4, 27% of SPK recipients had a pretransplant myocardial infarction and 40% had a coronary artery bypass); those with no vascular disease had significantly higher patient and graft survival rates in the SPK and PAK categories. Living donor segmental pancreas transplants were associated with higher technically successful graft survival rates in each era, predominately solitary (PAK and PTA) in eras 1 and 2 and SPK in eras 3 and 4. Diabetic seconda...

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (Group 1;n=29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (Group 2; n=20); CITR recipients given TCDAb without TNF-α-i (Group 3;n=43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (Group 4,n=177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (Group 5;n=677). 5-yr insulin independence rates in Group 1 (50%) and Group 2 (50%) were comparable to outcomes in PTA (Group 5: 52%; p>>0.05) but significantly higher than in Group 3 (0%; p=0.001) and Group 4 (20%; p=0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p=0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.

We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single-donor islet transplants. Islets were isolated from two-layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C-peptide-negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti-CD3 monoclonal antibody hOKT3c 1 (AlaAla) and sirolimus. Immunosuppression was maintained with sirolimus and reduced-dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post-transplant. The four insulin-independent patients showed prolonged CD4 + T-cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4 + CD25 + T cells. These cells suppressed the in-vitro proliferative response to donor cells and, to a lesser extent, to third-party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single-donor islet transplants.

TFs remain significant after pancreas transplants. In SPK recipients, TF represents the most common cause of pancreas graft loss. For isolated pancreas transplants, TF is second only to rejection as a cause of graft loss. Increased preservation times and donor or recipient obesity seem to be risk factors. Minimizing these risks factors would be important to try to decrease TF.