Peter Schenker

Long-term results of pancreas transplantation in patients older than 50 years

Aging of the population and improvements in diabetes therapy have led to an increased number of older pancreas transplant candidates. The aim of our retrospective study was to evaluate pancreas transplantation (PT) outcomes in patients ≥50 years, as limited data exist in these patients. We analyzed 398 consecutive pancreas transplant patients from June 1994 to June 2009 for different outcomes (patient/graft survival, rejection rate, and surgical complications) between the age groups ≥50 years (n = 69) and <50 years (n = 329). Donor and recipient characteristics were similar except for recipient age (54.0 vs. 38.8 years), BMI (24.6 vs. 22.9 kg/m2), and duration of diabetes mellitus (36.0 vs. 27.7 years). One‐, 5‐, and 10‐year patient and graft (kidney/pancreas) survival were not significantly different between the groups with patient survival rates reaching 84% and pancreas graft survival up to 67% after 10 years. Surgical complications such as relaparotomy rate (34% vs. 33%) or pancreas graft thrombosis (14% vs. 11%) as well as 1‐year rejection rates (35% vs. 31%) were not significantly different. PT in selected patients aged ≥50 years resulted in survival comparable with that of younger patients. In conclusion, advanced age should no longer be considered as an exclusion criterion for PT. However, good medical assessment and careful patient selection are necessary.

Incidence of pancreas graft thrombosis using low-molecular-weight heparin

Abstract:  Introduction:  Simultaneous pancreas–kidney transplantation is the current treatment of choice for patients with type I diabetes and end stage renal disease. Vascular graft thrombosis (VGT) after pancreas transplantation is the main cause of early graft loss.

Long-Term Results After Simultaneous Pancreas-Kidney Transplantation Using Donors Aged 45 Years or Older

UNLABELLED With the shortage of organ donors, there is a critical need to use all available pancreas grafts for transplantation. METHODS From June 1994 to December 2006 we performed 340 pancreas transplantations (317 simultaneous pancreas-kidney 5 pancreas only, 18 pancreas after kidney) including 69 (20%) transplantations from donors aged 45 years or older. Pancreas grafts from older donors were analyzed for graft and patient survival as well as surgical complications, compared with results from younger donors. RESULTS Recipient characteristics were comparable in both groups. The older donor group mean age was 47.8 years (+/-2.1) versus 27.9 years (+/-10.3) for the younger group. Cumulative patient survival was 96% versus 98% after 1, 82% versus 91% after 5 and 82% versus 88% after 10 years with 1-5- and 10-year kidney graft survivals of 82%, 72%, 57% versus 93%, 83%, 73%, respectively. Pancreas transplant survival after 1, 5, and 10 years were 69%, 60%, 45% in older and 88%, 76%, and 72% in younger donor cohorts. There were 14 (20%) cases of venous thrombosis in the older group and 25 (9%) in the younger group (P = .012). CONCLUSION Our results demonstrated that utilization of pancreas grafts from donors over 45 years resulted in acceptable outcomes after simultaneous pancreas-kidney transplant and could expand the donor pool. Among the older donor group, patient survival was slightly lower than the younger group, whereas pancreas graft function was significantly inferior (P < .01). Since venous thrombosis was the main reason for pancreas graft loss in older group, anticoagulation is essential.

Preprocurement Pancreas Allocation Suitability Score Does Not Correlate With Long-Term Pancreas Graft Survival

BACKGROUND Within recent years, more marginal donors have been offered to Eurotransplant. To help identify suitable pancreas donors, the Eurotransplant Pancreas Advisory Committee introduced a donor score system (P-PASS). Little is known about the influence of P-PASS on long-term pancreas graft survival. METHODS From June 1994 to September 2009, we performed 405 pancreas transplantations. In a retrospective study we analyzed P-PASS in 318 cases. Pancreas grafts from donors with P-PASS < 17 (n = 146) analyzed for graft and patient survival as well as for surgical complications were compared with donors of a PASS > or = 17 (n = 172). The mean follow-up was 7.2 +/- 4.3 years. RESULTS Recipient characteristics were comparable in both groups. Mean P-PASS was 16.7 +/- 2.7 for both groups: 14.3 +/- 1.5 for P-PASS < 17 and 18.8 +/- 1.6 for P-PASS > or = 17. Pancreas graft survival rates for 1, 5, and 10 years were 85%, 77%, and 73% among P-PASS < 17 and 81%, 73%, and 64% among P-PASS > or = 17 groups (P = .12). There were 12 (8.2%) cases of venous thrombosis in the <17 group and 22 (12.7%) in the > or =17 group (P < .05). The relaparotomy rate was significant higher (38.7% vs 28.7%) and duration of hospital treatment longer (40.2 vs 32 days) in the P-PASS > or = 17 group (P < .05). There was no significant difference in patient or kidney graft survival between groups. CONCLUSIONS The data demonstrated that utilization of pancreas grafts from donors with a P-PASS > or = 17 resulted in good overall outcomes and could expand the organ donor pool. There was no correlation between P-PASS and long-term patient or graft outcome. Complications requiring relaparotomy were more frequent among patients after transplantation from donors with higher P-PASS.

125 Cases of duodenoduodenostomy in pancreas transplantation: a single-centre experience of an alternative enteric drainage.

Several exocrine drainage procedures have been successfully developed to perform pancreas transplantation (PT). Retroperitoneal graft placement allows exocrine drainage via direct duodenoduodenostomy (DD). This technique provides easy access for endoscopic surveillance and biopsy. A total of 241 PT procedures were performed in our centre between 2002 and 2012. DD was performed in 125 patients, and duodenojejunostomy (DJ) in 116 patients. We retrospectively compared our experience with these two types of enteric drainage, focusing on graft and patient survivals, as well as postoperative complications. With a mean follow‐up of 59 months, both groups demonstrated comparable patient and graft survivals. 14 (11%) of 125 cases in the DD group and 21 (18%) of 116 cases in the DJ group had pancreatic graft loss (P = 0.142). Graft thrombosis [5 (4%) vs. 18 (16%) P = 0.002], anastomotic insufficiency [2 (1.6%) vs. 8 (7%) P = 0.052] and relaparotomy [52 (41%) vs. 56 (48%) P = 0.29] occurred more frequently in the DJ group, whereas gastrointestinal bleeding [14 (11%) vs. 4 (3%) P = 0.026] occurred more often in the DD group. DD is a feasible and safe technique in PT, with no increase in enteric complications. It is equivalent to other established techniques and extends the feasibility of anastomotic sites, especially in recipients who have undergone a second transplantation.

En Bloc Retroperitoneal Pancreas-Kidney Transplantation With Duodenoduodenostomy Using Pediatric Organs

BACKGROUND Given the shortage of organ donors, there is a critical need to use all available pancreas grafts for transplantation. In the Eurotransplant region, only 26% of all offered pancreas grafts were transplanted during 2007. Pediatric donors are rarely used in pancreas transplantation. METHODS In this case report, we describe a retroperitoneal en bloc pancreas-kidney transplantation (SPK) with systemic venous anastomosis and duodenoduodenostomy using grafts from an 11-year-old child. The bloc was transplanted in a 42-year-old type I diabetic patient with end-stage renal disease. The proximal end of the aortic graft was closed. Arterial anastomosis was performed end-to-end between right internal iliac artery and the aortic graft because of severe atherosclerosis. Donor portal vein and donor renal vein were anastomosed separately end-to-side to recipient inferior vena cava. Exocrine drainage was carried out with a side-to-side duodenoduodenostomy. Both grafts were in the retroperitoneal position. RESULTS The pancreas graft functioned immediately, the kidney graft resumed function at 7 days posttransplantation. Graft function was excellent over a follow-up of 18 months. The patient had no episodes of acute rejection or graft dysfunction, no severe infections, and no additional morbidity from the modified technique of retroperitoneal pancreas transplantation using duodenoduodenostomy. CONCLUSIONS This case indicates that pediatric donors could be used more frequently in pancreas transplantation for adult recipients and could increase the organ donor pool. En bloc SPK is a feasible and safe technique. Further studies are required to confirm the benefits of a retroperitoneal SPK using duodenoduodenostomy.

Effects of Dopamine Donor Pretreatment on Graft Survival after Kidney Transplantation: A Randomized Trial

BACKGROUND AND OBJECTIVES Donor dopamine improves initial graft function after kidney transplantation due to antioxidant properties. We investigated if a 4 µg/kg per minute continuous dopamine infusion administered after brain-death confirmation affects long-term graft survival and examined the exposure-response relationship with treatment duration. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Five-year follow-up of 487 renal transplant patients from 60 European centers who had participated in the randomized, multicenter trial of dopamine donor pretreatment between 2004 and 2007 (ClinicalTrials.gov identifier: NCT00115115). RESULTS Follow-up was complete in 99.2%. Graft survival was 72.6% versus 68.7% (P=0.34), and 83.3% versus 80.4% (P=0.42) after death-censoring in treatment and control arms according to trial assignment. Although infusion times varied substantially in the treatment arm (range 0-32.2 hours), duration of the dopamine infusion and all-cause graft failure exhibited an exposure-response relationship (hazard ratio, 0.96; 95% confidence interval [95% CI], 0.92 to 1.00, per hour). Cumulative frequency curves of graft survival and exposure time of the dopamine infusion indicated a maximum response rate at 7.10 hours (95% CI, 6.99 to 7.21), which almost coincided with the optimum infusion time for improvement of early graft function (7.05 hours; 95% CI, 6.92 to 7.18). Taking infusion time of 7.1 hours as threshold in subsequent graft survival analyses indicated a relevant benefit: Overall, 81.5% versus 68.5%; P=0.03; and 90.3% versus 80.2%; P=0.04 after death-censoring. CONCLUSIONS We failed to show a significant graft survival advantage on intention-to-treat. Dopamine infusion time was very short in a considerable number of donors assigned to treatment. Our finding of a significant, nonlinear exposure-response relationship disclosed a threshold value of the dopamine infusion time that may improve long-term kidney graft survival.

Extended pancreas donor program - the EXPAND study rationale and study protocol.

AbstractBackgroundSimultaneous pancreas kidney transplantation (SPK), pancreas transplantation alone (PTA) or pancreas transplantation after kidney (PAK) are the only curative treatment options for patients with type 1 (juvenile) diabetes mellitus with or without impaired renal function. Unfortunately, transplant waiting lists for this indication are increasing because the current organ acceptability criteria are restrictive; morbidity and mortality significantly increase with time on the waitlist. Currently, only pancreas organs from donors younger than 50 years of age and with a body mass index (BMI) less than 30 are allocated for transplantation in the Eurotransplant (ET) area. To address this issue we designed a study to increase the available donor pool for these patients.Methods/DesignThis study is a prospective, multicenter (20 German centers), single blinded, non-randomized, two armed trial comparing outcome after SPK, PTA or PAK between organs with the currently allowed donor criteria versus selected organs from donors with extended criteria. Extended donor criteria are defined as organs procured from donors with a BMI of 30 to 34 or a donor age between 50 and 60 years. Immunosuppression is generally standardized using induction therapy with Myfortic, tacrolimus and low dose steroids. In principle, all patients on the waitlist for primary SPK, PTA or PAK are eligible for the clinical trial when they consent to possibly receiving an extended donor criteria organ. Patients receiving an organ meeting the current standard criteria for pancreas allocation (control arm) are compared to those receiving extended criteria organ (study arm); patients are blinded for a follow-up period of one year. The combined primary endpoint is survival of the pancreas allograft and pancreas allograft function after three months, as an early relevant outcome parameter for pancreas transplantation.DiscussionThe EXPAND Study has been initiated to investigate the hypothesis that locally allocated extended criteria organs can be transplanted with similar results compared to the currently allowed standard ET organ allocation. If our study shows a favorable comparison to standard organ allocation criteria, the morbidity and mortality for patients waiting for transplantation could be reduced in the future.Trial registrationTrial registered at: NCT01384006

Modified release tacrolimus in de novo immunosuppression after simultaneous pancreas-kidney transplantation--a first single-center experience.

BACKGROUND Modified release tacrolimus is a new, once-daily oral formulation of the established immunosuppressive agent tacrolimus. Little is known about de novo immunosuppression after simultaneous pancreas-kidney transplantation using modified release tacrolimus. METHODS To test the feasibility of modified release tacrolimus in simultaneous pancreas-kidney transplantation (SPK), we conducted a prospective study of 14 consecutive transplants using modified release tacrolimus (Advagraf, ADV), mycophenolate mofetil, and low-dose corticosteroids as the initial immunosuppressive regimen. Patient and graft survival, the rates of acute rejection, graft function as well as ADV dosages, and trough levels (C(min)) were investigated after a mean follow-up time of 11.0 +/- 3.1 months. RESULTS Overall patient, kidney, and pancreas graft survival were 100%, 100%, and 93%, respectively. One pancreas graft was lost owing to vascular graft thrombosis 2 days after transplantation. The incidence of rejection episodes at 11 months was 38%. ADV was well tolerated in the majority of patients. Only in 1 case tacrolimus (ADV) was stopped because of psychotic symptoms. In week 2 and 3 posttransplant, a significant adjustment in the ADV dosage was necessary to achieve sufficient tacrolimus trough levels. CONCLUSIONS The results of this case series report demonstrate that patients after SPK can be safely treated with modified release tacrolimus. Further studies are needed to investigate pharmacokinetic profiles of modified release tacrolimus after SPK.

Differential expression of cell-cycle regulators in human beta-cells derived from insulinoma tissue.

INTRODUCTION The low frequency of beta-cell replication in the adult human pancreas limits beta-cell regeneration. A better understanding of the regulation of human beta-cell proliferation is crucial to develop therapeutic strategies aiming to enhance beta-cell mass. METHODS To identify factors that control beta-cell proliferation, cell-cycle regulation was examined in human insulinomas as a model of increased beta-cell proliferation (n=11) and healthy pancreatic tissue from patients with benign pancreatic tumors (n=9). Tissue sections were co-stained for insulin and cell-cycle proteins. Transcript levels of selected cell-cycle factors in beta-cells were determined by qRT-PCR after performing laser-capture microdissection. RESULTS The frequency of beta-cell replication was 3.74±0.92% in the insulinomas and 0.11±0.04% in controls (p=0.0016). p21 expression was higher in insulinomas (p=0.0058), and Rb expression was higher by trend (p=0.085), whereas p16 (p<0.0001), Cyclin C (p<0.0001), and p57 (p=0.018) expression levels were lower. The abundance of Cyclin D3 (p=0.62) and p27 (p=0.68) was not different between the groups. The reduced expression of p16 (p<0.0001) and p57 (p=0.012) in insulinomas and the unchanged expression of Cyclin D3 (p=0.77) and p27 (p=0.55) were confirmed using qRT-PCR. CONCLUSIONS The expression of certain cell-cycle factors in beta-cells derived from insulinomas and healthy adults differs markedly. Targeting such differentially regulated cell-cycle proteins may evolve as a future strategy to enhance beta-cell regeneration.