Mycophenolate mofetil in pancreas transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease the incidence of acute rejection episodes after kidney transplantation. The use of MMF along with tacrolimus for > or =1 year after pancreas transplantation has not been studied in a large single-center analysis. METHODS: Between July 1, 1995 and June 30, 1997, both MMF and tacrolimus were given to 120 pancreas transplant recipients. By category, 61 underwent simultaneous pancreas-kidney transplantation (SPK); 44 underwent pancreas transplantation after previous kidney transplantation (PAK); and 15 underwent pancreas transplantation alone (PTA). By donor source, 86% of the grafts were from a cadaver, and 14% were from a living-related donor. Induction therapy was with MMF, tacrolimus, prednisone, and antithymocyte globulin (n=109) or OKT3 (n=2). Until oral intake was resumed, recipients initially received intravenous azathioprine. Side effects were as follows: gastrointestinal (GI) toxicity in 53% of recipients receiving combined MMF and tacrolimus therapy; bone marrow toxicity in 24% of recipients receiving MMF alone; nephrotoxicity in 18% and neurotoxicity in 11% of recipients receiving tacrolimus alone. We did a matched-pair analysis to compare outcome in MMF versus azathioprine recipients, using the database of the International Pancreas Transplant Registry. Matching criteria included transplantation category, transplantation number, recipient and donor age, duct management, HLA typing, and transplantation year. RESULTS: One-year patient survival rates were 98% for SPK, 98% for PAK, and 100% for PTA (P=NS). For SPK recipients, 1-year pancreas graft survival rates were 86% with MMF versus 79% with azathioprine (P=NS); kidney graft survival rates were 96% with MMF versus 86% with azathioprine (P=NS). The incidence of first rejection episodes at 1 year was significantly lower for MMF recipients (15% with MMF versus 43% with azathioprine) (P = 0.0003). For recipients of solitary pancreas transplants (PTA and PAK), we found no difference in graft survival rates between MMF and azathioprine. The conversion rate from MMF to azathioprine at 1 year was 14% for SPK recipients, 26% for PAK, and 39% for PTA (P < 0.007). The most common reason for conversion was GI toxicity, in particular for nonuremic (PTA) or posturemic (PAK) recipients. The rates of posttransplant infection and lymphoproliferative disease were low for recipients on MMF and tacrolimus. CONCLUSIONS: The combination of MMF and tacrolimus after pancreas transplantation is highly effective and safe. For SPK recipients, the incidence of acute reversible rejection episodes was significantly lower with MMF than with azathioprine. The conversion rate from MMF to azathioprine because of GI toxicity was lowest for SPK and highest for PTA recipients.

A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation.

Between May 1, 1993 and April 5, 1995, 154 pancreas allograft recipients at 9 institutions were given FK506 posttransplant. Three groups were studied: (1) recipients given FK506 initially for induction and maintenance therapy (n = 82), (2) recipients switched to FK506 for antirejection or rescue therapy (n = 61), and (3) recipients converted to FK506 for other reasons (n = 11). Of 82 patients in the induction group, 7 (9%) had simultaneous bone marrow (BM) and pancreas-kidney (SPK-BM) transplants, 54 (66%) had SPK transplants without BM, 14 (17%) had pancreas transplants alone (PTA), and 7 (9%) had pancreas after previous kidney transplants (PAK). All but 1 recipient was given quadruple immunosuppression (anti-T cell agents plus azathioprine and prednisone) for induction. The median FK506 starting dose was 4 mg/day p.o.; the median average FK506 blood level, 12 ng/ml. The most common side effects were neurotoxicity (16%), nephrotoxicity (13%), and gastrointestinal toxicity (9%). New-onset diabetes mellitus requiring permanent insulin therapy did not occur. Of 61 transplants in the rescue group, 44 (72%) were SPK, 11 (18%) PTA, and 6 (10%) PAK. All but 3 (95%) of the recipients had been on cyclosporine-azathioprine-prednisone triple immunosuppression before substitution of FK506 for cyclosporine; 46% of the recipients had one, and 54% > or = 2, rejection episodes preconversion. The most common side effects were nephrotoxicity (25%), neurotoxicity (23%), and gastrointestinal toxicity (21%). Two recipients were reconverted to cyclosporine because of transient hyperglycemia, and one recipient is on insulin. In the induction group, patient survival at 6 months was 90% for SPK, 100% for PTA, and 100% for PAK. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 6 months was 87% for FK506 versus 70% for cyclosporine recipients (P = 0.04); for PTA recipients, 84% versus 66% (P = n.s.); and for PAK recipients, 80% versus 14% (P = 0.11). When technical failures and death with functioning grafts were censored, pancreas graft survival remained significantly better in the FK506 group. The incidence of first reversible rejection episodes by 6 months in FK506 recipients was 35% for SPK, 40% for PTA, and 20% for PAK. Of 75 pancreas grafts, 64 are currently functioning; in 5 recipients the pancreas failed (1 from rejection); 6 recipients died with a functioning pancreas graft. There were 3 posttransplant lymphomas (all EBV-positive); 2 recipients died and 1 is alive after subtotal colectomy and transplant pancreatectomy. In the antirejection rescue group, patient survival rates at 6 months were 91% for SPK, 100% for PTA, and 80% for PAK (P = n.s.). Pancreas graft survival rates at 6 months were 90% for SPK, 72% for PTA, and 40% for PAK. The incidence of first reversible rejection episodes after conversion to FK506 at 6 months was 44% in SPK, 54% in PTA, and 50% in PAK. Of 61 pancreas grafts, 51 are currently functioning; in 7 recipients the pancreas failed (5 from rejection); 3 recipients died with a functioning graft. There were no posttransplant lymphomas in the rescue group. This multicenter survey shows that FK506 in pancreas transplantation is associated with (1) a low rate of graft loss from rejection when used for induction therapy, (2) a high rate of graft salvage when used for rescue or rejection therapy, and (3) a very low rate of new-onset insulin-dependent diabetes mellitus. These encouraging results are tarnished by 3 posttransplant lymphomas in the induction group; a possible explanation is overimmunosuppression, but further (randomized) studies are necessary to analyze the long-term risk-benefit ratio of FK506 after pancreas transplantation.

Prolonged preservation increases surgical complications after pancreas transplants.

BACKGROUND: Prolonged preservation of the donor organ may result in delayed graft function or nonfunction after most organ transplants. We studied whether or not prolonged preservation increases surgical complications after pancreas transplants. METHODS: Between January 1, 1994, and September 30, 1998, a total of 294 recipients underwent cadaver pancreas transplants at our institution. Recipients were analyzed in 2 groups: those with pancreas preservation time < or = 20 hours (n = 211) versus > 20 hours (n = 83). RESULTS: Demographic data were similar between the 2 groups, except that mean donor age in the prolonged preservation group was significantly lower. Despite use of younger donors, prolonged preservation was associated with an increased incidence of surgical complications, most notably leaks, thrombosis, and wound infections. Grafts with prolonged preservation were more often noted by the transplant surgeon to be edematous after reperfusion, although the incidence of hyperamylasemia posttransplant did not differ between the 2 groups. Graft and patient survival rates also did not differ between the 2 groups. The incidence of early graft loss (< 3 months) was, however, higher in the prolonged preservation group (20.5% versus 9.0%, P = .04). CONCLUSIONS: Prolonged preservation of the donor organ increases the incidence of surgical complications after pancreas transplants. All attempts should be made to minimize preservation time, keeping it below 20 hours, if possible.

Surgical risks and outcome of pancreas retransplants.

BACKGROUND: The increased popularity of pancreas transplants has led to an increased number of potential candidates for retransplants after the initial graft has been lost to technical failure or rejection. We studied a group of recipients who underwent pancreas transplants at a single center to determine whether retransplant recipients were at higher risk of complications. METHODS: Between June 1, 1994, and Dec 31, 1997, a total of 213 pancreas transplants were performed at the University of Minnesota. Of these, 187 were primary transplants and 26 were retransplants. Demographically, the two groups were not significantly different. We analyzed and compared the two groups with respect to incidence of surgical complications, graft survival rates, and patient survival rates. RESULTS: Surgical complications such as bleeding and vascular thrombosis were slightly more common after retransplants, but this trend did not quite reach statistical significance. Infectious complications and leaks were equivalent between the two groups. The incidence of acute rejection was higher after retransplants (P =.02). At 3 years posttransplant, patient survival was no different between the two groups, but pancreas graft survival was lower after retransplants (P =.08). The incidence of early graft loss (by 6 months posttransplant) was significantly higher in retransplant recipients (27% vs 14%, P =.04). CONCLUSIONS: Pancreas retransplants can be performed with a minimal increase in surgical complications. However, graft survival after retransplants is slightly inferior to that after primary transplants, probably for both immunologic and nonimmunologic reasons. Retransplants can be offered to suitable candidates, but they may require more aggressive monitoring for rejection.

Use of FK 506 in pancreas transplantation.

Until recently, FK 506 was used only for rescue therapy after pancreas transplantation. We report our initial experience with FK 506 for 67 pancreas recipients (treated between 1 May 1993 and 30 April 1995). Of these recipients, 49 (73%) received FK 506 for induction and maintenance therapy, 12 (18%) for rescue or antirejection therapy, and 6 (9%) for reasons other than rescue or antirejection therapy. In our induction and maintenance therapy group, 32 recipients (65%) underwent a simultaneous pancreas-kidney transplant (SPK), 8 (16%) a pancreas transplant alone (PTA), and 9 (19%) a pancreas after previous kidney transplant (PAK). Quadruple immunosuppression was used for induction; the median FK 506 starting dose was 4 mg/day p.o. and target levels were 10-20 ng/ml. The most common side effects were nephrotoxicity (16%) and neurotoxicity (14%); transient episodes of hyperglycemia were also noted (12%), in particular in the presence of concurrent rejection and infection episodes. A matched-pair analysis was done to compare graft outcome with FK 506 versus cyclosporin A (CsA). For SPK recipients, pancreas graft survival at 6 months was 79% with FK 506 versus 65% with CsA (P = 0.04), for PTA, 100% versus 63% (P > 0.35), and for PAK, 88% versus 33% (P > 0.01). Pancreas graft loss due to rejection at 6 months posttransplant was lower with FK 506 versus CsA. Two FK 506 recipients died from B-cell lymphomas (Epstein-Barr virus positive) at 6 and 7 months posttransplant. In our rescue or anti-rejection group, 5 recipients underwent SPK, 3 PTA, and 4 PAK. The mean average FK 506 dose was 10 mg/day p.o. and the mean average FK 506 blood level was 11 ng/ml. The most common side effects were nephrotoxicity (33%) and neurotoxicity (16%). Two recipients developed hyperglycemic episodes, of whom 1 has remained on insulin with good exocrine pancreas graft function. Graft survival at 6 months after conversion was 75% for SPK, 67% for PTA, and 50% for PAK. Only one graft was lost due to chronic rejection. Our single-center experience shows that FK 506 after pancreas transplantation is associated with: (1) a low rate of graft loss due to rejection when used for induction, in particular for solitary pancreas transplants, (2) a high rate of graft salvage when used for rescue, (3) a 1% rate of new-onset insulin-dependent diabetes mellitus, and (4) a 3% rate of posttransplant lymphoma. Further studies are necessary to analyze the long-term impact of FK 506 on pancreas transplant outcome.

Steroid withdrawal in pancreas transplant recipients.

BACKGROUND: Numerous studies of steroid withdrawal have been carried out in kidney and liver transplant recipients, but only a few in pancreas transplant recipients. Yet, pancreas transplant recipients could have significant long-term benefits from steroid withdrawal. METHODS: We performed a retrospective analysis to determine the feasibility of steroid withdrawal in pancreas transplant recipients. RESULTS: Of 360 recipients who underwent a pancreas transplant between January 1, 1994 and June 30, 1998, 14 attempted steroid withdrawal (12 simultaneous pancreas-kidney [SPK]; 2 pancreas transplant alone [PTA]). Reasons for steroid withdrawal were bone fractures (n = 3), psychiatric disorders (n = 2), severe acne (n = 1), recurrent infections (n = 4), and problems with hypercholesterolemia or hypertension (n = 4). All 14 were maintained on tacrolimus and mycophenolate mofetil (MMF) immunosuppression, except for 1 who was on tacrolimus and azathioprine (AZA). Of the 14 recipients, 11 had no episodes of acute rejection before steroid withdrawal. The remaining 3 had one or more acute rejection episodes. Of the 14 recipients, 10 (72%) currently remain off steroids (mean follow-up 18 months, range 5-51 months). However, 4 recipients have resumed steroids: 2 after an acute rejection episode (at 2 and 21 months post-withdrawal) and 2 because of leukopenia (WBC < 3000) and an inability to tolerate full-dose MMF. Steroid withdrawal was unsuccessful in both PTA recipients and in 2 of the 12 SPK recipients. All 14 recipients currently have a functioning pancreas graft. However, 1 of the SPK recipients, in whom steroid withdrawal failed, has developed chronic kidney rejection and is now back on hemodialysis awaiting a retransplant. CONCLUSION: Steroid withdrawal is possible in up to 70% of pancreas transplant recipients. Further studies are necessary to define ideal candidates for steroid withdrawal. Based on the results of this analysis, we have launched a prospective, randomized trial of steroid withdrawal in pancreas transplant recipients.

Simultaneous pancreas-kidney transplantation from live donors.

OBJECTIVE: In this first report of a clinical series of simultaneous pancreas-kidney transplants (SPKs) from live donors, the authors assess donor and recipient outcome as well as the spectrum of surgical and metabolic complications. SUMMARY BACKGROUND DATA: The rationale for live (vs. cadaveric) donation includes an immunologic advantage (better matching, decreased drugs, and fewer rejection episodes) and elimination of waiting time. Only sequential kidney and pancreas or pancreas transplants alone from live donors had been done until the authors' current series. METHODS: Between March 15, 1994, and March 15, 1997, the authors performed 20 SPKs from live donors (6 human leukocyte antigen-identical siblings, 14 mismatched relatives [5 parents, 7 siblings, 1 daughter, 1 aunt]). Of the 20 donors, 13 were women, and 7 were men; median age was 43 years (range, 30-58 years). All donors underwent standardized metabolic workup, including oral glucose tolerance tests, determination of hemoglobin A1 c levels, and tests to study insulin secretion and functional insulin secretory reserve. Of the 20 recipients, 12 were women, and 8 were men; median age was 34 years (range, 14-50 years). Management of exocrine pancreatic secretions was with bladder drainage in 17 and duct injection in 3 recipients. Median follow-up was 9 months (range, 1-36 months). RESULTS: Currently, all 20 kidney grafts are functioning. Of the 20 pancreas grafts, 15 are functioning, 3 thrombosed, but 2 of those patients underwent immediate retransplantation from a cadaveric donor, and their grafts currently are functioning. Recipient complications included three anastomotic leaks and three intra-abdominal abscesses. Donor complications included four splenectomies, two peripancreatic fluid collections, one pseudocyst, and one intra-abdominal abscess; two donors underwent reoperation. Three donors had impaired glucose metabolism postdonation. Using tacrolimus and mycophenolate mofetil for mainstay immunosuppression, only 8 of 20 recipients experienced > or =1 rejection episode; only 1 pancreas graft was lost to rejection. Donor and recipient mortality was 0%. CONCLUSION: Simultaneous pancreas-kidney transplants from live donors can be done with no mortality and good graft outcome. With stringent donor criteria, this approach could become another surgical alternative for endocrine replacement therapy in selected patients with uremic type I diabetes.