key: cord-0022173-0elgrs2k authors: Boggi, Ugo; Vistoli, Fabio; Andres, Axel; Arbogast, Helmut P.; Badet, Lionel; Baronti, Walter; Bartlett, Stephen T.; Benedetti, Enrico; Branchereau, Julien; Burke, George W.; Buron, Fanny; Caldara, Rossana; Cardillo, Massimo; Casanova, Daniel; Cipriani, Federica; Cooper, Matthew; Cupisti, Adamasco; Davide, Josè; Drachenberg, Cinthia; de Koning, Eelco J. P.; Ettorre, Giuseppe Maria; Fernandez Cruz, Laureano; Fridell, Jonathan A.; Friend, Peter J.; Furian, Lucrezia; Gaber, Osama A.; Gruessner, Angelika C.; Gruessner, Rainer W.G.; Gunton, Jenny E.; Han, Duck‐Jong; Iacopi, Sara; Kauffmann, Emanuele Federico; Kaufman, Dixon; Kenmochi, Takashi; Khambalia, Hussein A.; Lai, Quirino; Langer, Robert M.; Maffi, Paola; Marselli, Lorella; Menichetti, Francesco; Miccoli, Mario; Mittal, Shruti; Morelon, Emmanuel; Napoli, Niccolò; Neri, Flavia; Oberholzer, Jose; Odorico, Jon S.; Öllinger, Robert; Oniscu, Gabriel; Orlando, Giuseppe; Ortenzi, Monica; Perosa, Marcelo; Perrone, Vittorio Grazio; Pleass, Henry; Redfield, Robert R.; Ricci, Claudio; Rigotti, Paolo; Paul Robertson, R.; Ross, Lainie F.; Rossi, Massimo; Saudek, Frantisek; Scalea, Joseph R.; Schenker, Peter; Secchi, Antonio; Socci, Carlo; Sousa Silva, Donzilia; Squifflet, Jean Paul; Stock, Peter G.; Stratta, Robert J.; Terrenzio, Chiara; Uva, Pablo; Watson, Christopher J.E.; White, Steven A.; Marchetti, Piero; Kandaswamy, Raja; Berney, Thierry title: First World Consensus Conference on pancreas transplantation: Part II – recommendations date: 2021-07-29 journal: Am J Transplant DOI: 10.1111/ajt.16750 sha: a930ca369e2f8d85902ac237f2f181ac2e1c83d4 doc_id: 22173 cord_uid: 0elgrs2k The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts’ recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas‐kidney transplantation (SPK) and pancreas transplantation alone can improve long‐term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long‐term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st‐world‐consensus‐conference‐of‐pancreas‐transplantation/246. Guidelines are available for transplantation of all solid organs but the pancreas and the intestine. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Unfortunately, pancreas transplantation is a relatively low volume but high complexity procedure that has never gained widespread acceptance. For instance, many of the medical protocols used in pancreas transplantation are borrowed from other types of transplantation, mostly from the kidney, and all immunosuppressive drugs are used off-label in pancreas transplantation. 14 In addition, because most pancreas transplants are performed as either simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplants, the majority of recipients suffer from advanced diabetic nephropathy, a condition that has been associated with an increase in all-cause mortality due to higher incidence of micro-and macrovascular complications of diabetes. 15 Few patients are referred for pancreas transplant alone (PTA) at a stage when extrarenal diabetic complications might be reversible. Although many uremic patients can still receive a pancreas transplant in conjunction with a kidney transplant, the high prevalence and severity of associated chronic complications of diabetes cause these recipients to be less likely to experience stabilization or reversal of progressive diabetic complications. 16, 17 In recent years, there has been a decline in the number of pancreas transplants in the United States, Europe, and the United Kingdom. [18] [19] [20] Although the reasons for this decline are multifactorial, the lack of objective assessment of the impact of pancreas transplantation on the treatment of diabetic patients and absence of validated practice guidelines may be among the contributing factors. In selected patients, pancreas transplantation provides dramatic improvements in quality of life [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] and may prolong survival. [33] [34] [35] [36] [37] [38] [39] Additionally, some traditional deterrents have been minimized because pancreas transplantation currently requires the same immunosuppression as kidney transplantation 40 and surgical complications are observed at lower rates. 41 We report herein the expert recommendations for the practice of pancreas transplantation developed during the First World Consensus Conference on Pancreas Transplantation held in Pisa, Italy, on October 17-19, 2019. We also report several additional deliberations on the impact of the different types of pancreas transplantation on the course of diabetes that were crafted by an independent jury following an exhaustive review and presentation of data from the literature and audience discussions with experts. The methods used to achieve the consensus were presented in detail in a dedicated manuscript. 42 Briefly, the steering committee defined 144 questions (grouped in 12 topics). The 12 topics were categorized into two key domains. The first domain (three topics-35 questions) included "nontechnical" issues related PAK was criticized due to possibly increased risks compared to continued insulin therapy. Indeed, in addition to the general concerns that apply to all types of pancreas transplantation, PAK transplant was associated with increased risk of renal graft loss. 66, 67 Jury deliberations indicate that PAK transplant increases the risk of mortality early after transplantation, but improves life expectancy thereafter. As already observed for the kidney, 68 higher early mortality is the consequence of the need for a major surgical procedure and administration of additional immunosuppression and should not discourage PAK transplantation. Indeed, after the early posttransplant period, the additional risk of mortality disappears while quality of life is greatly improved and renal graft function is better preserved. Considerations on quality of life and renal graft function apply well to patients with type 1 diabetes. In patient with type 2 diabetes, PAK transplant was deemed feasible but evidence on possible advantages was lacking. AJT BOGGI et al. Deliberations on PTA were truly important because they underscored the high value of this type of transplantation. Indeed, contrary to a landmark study, 69 the jury deliberated that PTA does not increase the long-term risk of death compared with people remaining on the waiting list. PTA might be actually associated with a long-term survival advantage in diabetic patients who have impaired hypoglycemia awareness. Although these deliberations are not based on new data, 27,39,70,71 they are key since they are provided by an independent jury and unambiguously debunk the myth of PTA recipients exposed to undue risks. A further concern with PTA is the risk of accelerated loss of renal function. [73] [74] [75] The jury deliberated that impaired pretransplant renal function is a risk factor for accelerated end-stage renal failure after PTA, while an estimated glomerular filtration rate ≥60 ml/ min/1.73 m 2 is sufficient to protect most recipients against this risk. The use of calcineurin inhibitors (CNIs) may contribute to a decline in renal function after PTA, while normalization of glucose levels could have beneficial effects on underlying diabetic nephropathy in the long term. 76, 77 These additional and important data underscore the key role of accurate recipient selection for safe PTA and appropriate management of immunosuppression. Probably, patients with hypoglycemia unawareness should be referred for PTA before development of diabetic nephropathy. The jury also deliberated that PTA improves quality of life, may stabilize/improve diabetic retinopathy (depending on severity of initial retinal damage), and may slow the progression of diabetic neuropathy. 32 Regarding hypoglycemia unawareness, islet cell transplantation could be an alternative option, but this issue was not addressed in the consensus. For many surgical procedures, there is a clear relationship between volume of activity and outcomes. 81 In transplantation, volumeoutcome relationship has been shown for the kidney, 82 liver, 83 heart, 84 and lung. 85 In the United States, approximately 70% of transplant centers are low volume. Low volume programs (one to six pancreas transplants per year) may be associated with worse outcomes. 86 Volume-outcome relationship was confirmed in Europe, 16 by the Scientific Registry of Transplant Recipients, 17 and in few studies. 18, 19 Based on these data, low volume seems to be associated with a higher risk for pancreas failure, 86 They also recommended that the center be responsible to ensure quality of the procedure and careful lifelong follow-up of the donor. in 2012. 96 Since then, only few additional cases (<20) were reported worldwide. 97, 98 All procedures were successful, but the generalizability of these results remains to be established due to both selection biases and small sample size. The larger experience with robotic renal transplantation, 99, 100 as well as with other complex intra-abdominal procedures requiring vascular anastomoses, 101, 102 shows that robotic assistance permits pancreas transplantation. Justification for the pursuit of further experience with robotic pancreas transplantation includes the possibility of minimizing the incidence and severity of local complications, such as perigraft fluid collections and surgical site infections, and potentially expediting postoperative recovery. Based on this background, experts could only conclude that robotic pancreas transplantation is feasible. In general, the use of donors not fulfilling ideal criteria was considered acceptable provided that the accumulation of additional risk factors and long ischemic times was avoided. In detail, in the setting of donation after brainstem death (DBD), experts did not recommend against the use of donors aged >40 years, 103 None. 2.11 -"Is machine perfusion of pancreas allografts feasible and associated with improved pancreas transplant outcomes?" Due to lack of data, this query cannot be answered at the present time. Conduct further studies in preclinical models. Abbreviations: DBD, donation after brainstem death; DCD, donation after circulatory death; HTK, Histidine-tryptophan-ketoglutarate; IGL-1, Institut Georges Lopez-1; NG, not graded. Imported grafts were not considered to be associated with inferior outcomes when compared to local grafts, provided that a proficient team performed the procurement and that cold preservation times were acceptably short. 138, 139 The use of imported grafts increases costs and, despite efforts, is associated with longer preservation times that entail higher peak levels of pancreatic enzymes. Finally, results of available studies could have been influenced by several biases such as selective reporting (i.e., lack of intention-to-treat design), and use of different procurement techniques and preservation solutions. Ideally, pancreatic grafts should be preserved for <12 h. 140, 141 Preservation times up to 24 h can still be accepted. Beyond this time limit, acceptance of a pancreatic graft for transplantation is based on individual circumstances, such as specific recipient needs. As for other recommendations, accumulation of risk factors should be avoided. No recommendation was drawn on the use of machine perfusion because of lack of clinical studies. 142 In general, a positive crossmatch contraindicates pancreas transplantation. Limited evidence shows that pretransplant B cell crossmatch positivity does not affect patient and pancreas graft survival, but is associated with higher rates of antibody-mediated rejection. 147, 148 Few solitary pancreas transplants were performed despite a positive crossmatch with good outcomes. 149 Initiation of a prospective and randomized study could also be considered. Percutaneous biopsy of pancreas grafts placed in the retroperitoneum appears feasible, but there is no proof that graft accessibility is improved when compared to grafts placed intraperitoneally due to a lack of comparative studies. Evaluate the rate of feasibility of percutaneous pancreas biopsy in pancreas allografts placed intra-and retroperitoneally. Abbreviations: NG, not graded; SPK, simultaneous pancreas kidney. AJT BOGGI et al. Quality score Agreement Proposed action 6.1 -"Is steroid usage versus steroid avoidance associated with improved immunologic outcomes?" Available evidence does not demonstrate that steroid avoidance is associated with inferior immunologic outcomes when compared to a policy of steroid maintenance. Retrospective and prospective studies to identify groups of patients who will better tolerate steroid avoidance. 6.2 -"Is steroid usage versus early steroid withdrawal associated with improved immunologic outcomes?" Available evidence does not demonstrate that early steroid withdrawal is associated with improved immunologic outcomes when compared to a policy of steroid maintenance. Retrospective and prospective studies to identify groups of patients who will better tolerate early steroid withdrawal. Prospective studies comparing early steroid withdrawal with steroid avoidance should be performed. 6.3 -"Is steroid withdrawal versus steroid maintenance associated with improved metabolic parameters?" Steroid withdrawal, when maintained long term, seems to be associated with improved metabolic parameters. Design and conduct prospective studies adequately powered to define the impact of steroid avoidance on metabolic parameters after pancreas transplantation in the setting of a homogenous recipient population and concurrent immunosuppression. 6.4 -"Is early steroid withdrawal versus steroid maintenance associated with improved metabolic parameters?" Early steroid withdrawal seems to be associated with improved metabolic parameters. Design and conduct prospective studies adequately powered to define the impact of early steroid withdrawal on metabolic parameters after pancreas transplantation in the setting of a homogenous recipient population and concurrent immunosuppression. 6.5 -"Is induction versus no induction therapy associated with improved immunologic outcomes?" The use of induction therapy is associated with improved immunologic outcomes when compared to a policy of no induction therapy. Additional studies are required to identify optimal induction therapy. 6.6 -"Is induction versus no induction therapy associated with more early complications?" Induction with depleting antibodies, when compared to no induction, is associated with increased rates and severity of early posttransplant infections that do not result in inferior clinical outcomes. Additional studies are required to identify optimal induction therapy. 6.7 -"Is induction versus no induction therapy associated with more oncologic complications?" There is no clear evidence that current induction agents increase oncologic complications. Retrospective studies, including registry analysis, should report on induction therapy and long-term oncologic complications in pancreas transplant recipients. 6.8 -"Is induction therapy with depleting antibodies versus induction therapy with nondepleting antibodies associated with improved immunologic outcomes?" In recipients at low immunologic risk (i.e., PRA <10%), there is no clear evidence that induction with depleting vs. nondepleting antibodies results in improved immunologic outcomes. Design and conduct prospective and randomized trials, comparing policies of induction with depleting antibodies vs. policies of induction with nondepleting antibodies in the setting of "standardized" maintenance immunosuppression, after stratification of recipients based on immunologic risk according to current standards. 6.9 -"Is induction therapy with depleting antibodies versus induction therapy with nondepleting antibodies associated with more early complications?" Depleting antibodies are associated with increased rates of early complications that do not result in inferior patient and graft survival. Further prospective randomized studies are required to identify optimal induction therapy and define the incidence and severity of early complications specifically caused by induction therapy. Future studies should be designed taking into consideration that m-TOR inhibitors probably should not be used in the first few months after transplantation, because of the high incidence of surgical complications. pancreas transplantation is associated with specific and less well-tolerated side effects. The role of m-TOR inhibitors in pancreas transplantation should be further explored. Future studies should be designed taking into consideration that m-TOR inhibitors probably should not be used in the first few months after transplantation, because of the high incidence of surgical complications. with an immunologic advantage when compared to CNI-based immunosuppression in pancreas transplantation. The role of m-TOR inhibitors in pancreas transplantation should be further explored. Future studies should be designed taking into consideration that m-TOR inhibitors probably should not be used in the first few months after transplantation, because of the high incidence of surgical complications. associated with more side effects in pancreas transplantation?" Due to lack of data, this query cannot be answered at the present time. The role of m-TOR inhibitors in pancreas transplantation should be further explored. Future studies should be designed taking into consideration that m-TOR inhibitors probably should not be used in the first few months after transplantation, because of the high incidence of surgical complications. increased formation of donor-specific antibodies in pancreas transplantation. The role of m-TOR inhibitors in pancreas transplantation should be further explored. Future studies should be designed taking into consideration that m-TOR inhibitors probably should not be used in the first few months after transplantation, because of the high incidence of surgical complications. The role of m-TOR inhibitors in pancreas transplantation should be further explored. Future studies should be designed taking into consideration that m-TOR inhibitors probably should not be used in the first few months after transplantation, because of the high incidence of surgical complications. Abbreviations: CNI, calcineurin inhibitor; m-TOR, mammalian target of rapamycin; NG, not graded; PRA, panel reactive antibody; SPK, simultaneous pancreas kidney. 100% Report observational studies focusing on incidence and severity of deep venous thrombosis and pulmonary embolism in SPK and in solitary pancreas transplantation recipients. There is no evidence on which strategy is preferred. Report observational studies as well as comparative studies to study the benefits and risks of different therapies or combinations thereof. recipients. Type of drug as well as dose and duration of prophylaxis can be tailored based on donor/recipient matching for CMV serological status. 98.8% None. ( transplantation and recipients of other simultaneous transplants (i.e., liver-kidney, heart-kidney, and lung-kidney). 65 Finally, there is also no evidence to prioritize graft allocation for SPK transplantation based on the type of diabetes (i.e., type 1 vs. type 2) or recipient age (< vs. >50 years). Baseline renal function is considered key to reduce the risk of have addressed this issue, this recipient population does not seem to be exposed to an undue risk of renal failure after PTA. [161] [162] [163] [164] The same recommendation was released for patients with the same level of renal function and nephrotic syndrome. However, this recommendation could not be graded as it was supported only by anecdotal cases. 165 In general, PTA improves the course of chronic complications of diabetes as compared to current medical therapies, 76, 77, 79, 80, 164, 166, 167 so that patients with evolving chronic complications could be considered for PTA before severe renal damage has occurred. In potential PAK recipients, a creatinine clearance ≤45 ml/min was not considered an absolute contraindication to sequential pancreas transplantation. Few and conflicting data exist on the prognostic implication of pre-PAK creatinine clearance using 45 ml/min as a cutoff. In a retrospective and multicenter study, a pre-PAK eGFR ≤ 45 ml/min was associated with an increased probability of kidney graft failure. 66 On the other hand, in another retrospective study, eGFR significantly increased 3 months after grafting in patients with pretransplant eGFR ≤45 ml/min. 168 In a retrospective and multicenter study reporting on PAK trans- Retrospective and randomized studies in seropositive patients receiving grafts from either seronegative or seropositive donors comparing CMV prophylaxis with preemptive therapy. 100% Observational studies as well as comparative studies. Abbreviations: CMV, cytomegalovirus; NG, not graded; SPK, simultaneous pancreas kidney. Obese patients may face a higher rate of early complications when compared to nonobese recipients 175-179 but obesity alone is not a contraindication to SPK transplant, considering that good results were reported. 116 Discussion highlighted also the importance of underweight (BMI < 18.5 kg/m 2 ), as a risk factor of long-term mortality. 116 History of amputation and coronary heart disease were both considered risk factors for inferior results, but neither was deemed an absolute contraindication to SPK transplantation. Advanced atherosclerotic peripheral arterial disease, including the need for limb amputation in diabetic patients, is associated with increased mortality. 180 The association of advanced atherosclerotic peripheral arterial disease with end-stage renal failure increases the risk of mortality. 181 In general, pre-SPK limb amputation predicts inferior transplant outcomes as it portends higher cardiovascular risk. 182 Similarly, pretransplant history of coronary artery disease increases the risk of major adverse cardiovascular events after transplantation. 183, 184 However, coronary artery disease is not a major risk factor for mortality if medically treated and revascularized according to standard guidelines. 185 Discussion highlighted the importance of assessment of coronary artery disease in all patients undergoing pancreas transplantation. Several studies, including three with a prospective design, have Systematically investigate autoimmune reactivity in pancreas transplant recipients and report on incidence, severity, and treatment of autoimmune recurrence. Abbreviations: DSA, donor-specific antibody; NG, not graded; SPK, simultaneous pancreas kidney. AJT BOGGI et al. None. 9.6 -"What are the effects of PTA on retinopathy?" Successful PTA contributes to stabilization/improvement in diabetic retinopathy. Prospective studies comparing PTA with standard medical diabetes therapies highly advisable. 9.7 -"What are the effects of PTA on nephropathy?" Functioning PTA improves the evolution of diabetic nephropathy. These beneficial effects may be offset by CNI-related nephropathy. More studies are needed to evaluate the role of associated albuminuria pre-PTA and to explore whether genetic factors play a role in affecting the course of native kidney function in PTA recipients. 9.8 -"What are the effects of PTA on neuropathy?" Evidence suggests that successful PTA improves the course of diabetic neuropathy. Studies are urgently needed on the impact of PTA on somatic and autonomic diabetic neuropathy. 9.9 -"What are the effects of PTA on the cardiovascular system?" There is insufficient evidence available on the effects of PTA on the cardiovascular system. pancreas transplantation. Bladder drainage, when compared to enteric drainage, does not increase immediate surgical complications but is associated with higher rates of late reintervention (mostly for enteric conversion). Only one study clearly showed a higher rate of surgical complications in bladder-drained transplants (41% vs. 26%; p = .04). 186 Need for enteric conversion was not considered a surgical complication in these studies, and was reported to occur in up to 20% of recipients. 190 Two recent long-term studies reported that >40% of patients with bladder drainage require enteric conversion at some point in time. 197, 207 Additionally, bladder drainage increased the rate of metabolic and urologic complications, 188, 198, [208] [209] [210] [211] [212] [213] [214] [215] [216] and did not improve immunologic outcome of either SPK 187, [190] [191] [192] [196] [197] [198] 205, 206, 208, 214, 217, 218 or solitary pancreas transplantations. 70, 171, 219 Duodeno-duodenostomy (vs. duodeno-jejunostomy) was not considered to clearly increase the overall rate of surgical complications after pancreas transplantation, despite higher rates of bleeding. [220] [221] [222] [223] [224] [225] Additionally, duodeno-duodenostomy was not associated with improved immunologic outcomes, because of easier graft surveillance (endoscopic biopsy) with earlier diagnosis of rejection, [222] [223] [224] as reported in a study. 221 Indeed, duodenal biopsy alone may not be sufficient to rule out rejection, as suggested by both ex- Regarding final graft position, intraperitoneal graft placement (vs. retroperitoneal graft placement) was not associated with higher incidence of surgical complications because of lack of comparative studies. 224, 225, 245, 246 The hypothesis that retroperitoneal graft placement facilitates percutaneous graft biopsy remains to be proven. The use of steroids remains prevalent in maintenance protocols after pancreas transplantation. 40 Despite heterogeneity in background immunosuppressive regimens complicating interpretation of data, steroid avoidance is feasible in a good proportion of pancreas transplant recipients and does not result in inferior results when compared to steroid maintenance. [247] [248] [249] [250] [251] [252] Early steroid withdrawal is also feasible. [253] [254] [255] [256] [257] [258] Steroids avoidance, if maintained long term, is associated with improved metabolic profile. 257,259-262 The use of induction therapy, typically in the form of depleting antibodies, is prevalent across all pancreas transplant categories. 40 Two randomized controlled trials showed that induction therapy is associated with improved immunologic outcomes when compared to a policy of no induction therapy. 263, 264 However, there is no clear evidence that induction with depleting vs. nondepleting antibodies results in improved immunologic outcomes in patients at low immunologic risk (i.e., PRA < 10%). Regarding safety, induction with depleting antibodies is associ- The main rationale for CNI-free immunosuppression is to avoid the side effects of CNI-based immunosuppression. However, long-term data on outcomes of patients maintained on CNI-free regimens after pancreas transplantation are lacking. Short-term data are sparse and suggest that this strategy is associated with inferior immunologic outcomes without a clear reduction in drug-related toxicity. 252, 262 Relatively more data are available for protocols of immuno- In comparison to CNI-based immunosuppression, experts agreed that CNI-free immunosuppression is associated with inferior immunologic outcomes without evidence of reduced drug-related toxicity. The use of tacrolimus is prevalent in all categories of pancreas transplantation. 40 One multicenter, prospective, and randomized study showed that tacrolimus achieved superior immunologic results when compared to cyclosporine in SPK transplant recipients, although the high incidence of pancreas allograft thrombosis recorded in the cyclosporine arm may constitute a major bias of this study. 267 A single center, prospective, and randomized study did not confirm the superiority of tacrolimus over cyclosporine in SPK transplant recipients. 268 Basically, the introduction of tacrolimus corresponded to clinical success in solitary pancreas transplantation and comparison with historical series using cyclosporine showed improved results. 72, 269 Reported experience with the use of once-a-day tacrolimus formulation in pancreas transplantation is limited. Data are available only for SPK transplantation and show that once-a-day tacrolimus formulation is associated with excellent patient and graft survival, and that patients can be safely converted from standard tacrolimus to long-acting tacrolimus. [270] [271] [272] [273] In comparison with cyclosporine, experts agreed that the use of tacrolimus is prevalent in all pancreas transplant categories and is associated with superior immunologic outcomes. No conclusion could be drawn on the comparative efficacy of once-a-day vs. twice-a-day tacrolimus formulations due to lack of supporting data. The use of mycophenolate formulations is clearly prevalent in pancreas transplantation. 40 A prospective, multicenter, randomized, open-label study comparing mycophenolate mofetil to azathioprine, in the setting of OKT3 induction and steroid/cyclosporine maintenance, did not demonstrate the superiority of mycophenolate mofetil in SPK transplantation. 279 An additional prospective and randomized study conducted at a single center showed that mycophenolate mofetil significantly decreased the incidence of biopsy-proven acute rejection in SPK transplantation. 280 A review showed that the use of mycophenolate mofetil in combination with a CNI and steroids, after induction treatment, was associated with a 40% reduction in the incidence of acute rejection at 1 year after pancreas transplantation. 281 Retrospective studies have shown that mycophenolate mofetil compared to azathioprine improves immunologic outcome of pancreas transplantation when used in combination with either tacrolimus or cyclosporine, but at the price of more gastrointestinal side effects that frequently require dose reduction. 269, 282, 283 In comparison to azathioprine, experts agreed that mycophenolate formulations improve immunologic outcomes but are associated with more gastrointestinal side effects. An analysis of all pancreas transplants included in the UNOS database from 1987 to 2016 showed that the use of m-TOR inhibitors when compared to immunosuppressive protocols without m-TOR inhibitors was associated with improved allograft survival and patient survival up to 10 years after transplantation. 284 However, there is no evidence that the use of m-TOR inhibitors improves immunologic outcomes of pancreas transplantation when compared to mycophenolate formulations. The results of a multicenter, prospective, and randomized study comparing sirolimus and mycophenolate mofetil in SPK recipients were never published. Preliminary data from this trial showed that sirolimus was potentially associated with improved immunologic outcomes 285 but at the price of a higher incidence of surgical complications (i.e., delayed wound healing, lymphocele, and incisional hernia) and hyperlipidemia. 286 Two retrospective studies showed that the results of sirolimus and mycophenolate mofetil were similar when used in combination with tacrolimus. 254, 287 A single center, randomized, and prospective study with 10-year follow-up showed significantly better rates of rejection with sirolimus, 288 although allograft and patient survival rates were similar. There are only few data on comparative efficacy of m-TORbased immunosuppression vs. CNI-based immunosuppression in pancreas transplantation when these drugs are used as primary immunosuppressants. In general, CNI-free immunosuppression in pancreas transplantation is associated with inferior immunologic outcomes. 251, 266 In selected patients at low immunologic risk, m-TOR inhibitors may allow CNI minimization, while maintaining satisfactory immunologic results. 252, 275, 276 Data from a recently published prospective and randomized study showed that immediate use of sirolimus after SPK transplantation, in the context of CNI-free immunosuppression, is associated with an increased rate of surgical complications. 277 Additionally, the use of m-TOR inhibitors in the setting of CNI-free immunosuppression could increase the formation of DSA. 289 This issue is not fully addressed in the literature. Reported outcomes range from no effect, 290 to increased development on nondonor-specific HLA antibodies, with immediate evidence of worse graft outcome, 291 and to an increased incidence of de novo DSA anti-class II HLA agents at 1 year after transplantation. 277 In comparison with mycophenolate formulations, and in the context of limited evidence, experts acknowledged that the use of m-TOR inhibitors is not clearly associated with an immunologic advantage. Additionally, when both drugs are used as primary immunosuppressants, experts agreed that the use of m-TOR inhibitors vs. mycophenolate formulations is associated with specific and less well-tolerated side effects. In comparison with CNI-based immunosuppression, experts agreed that the use of m-TOR inhibitors is not associated with an immunologic advantage. Lack of specific evidence did not allow experts to define if m-TOR-based immunosuppression is associated with more side effects. Vascular thrombosis is the leading cause of early graft loss in pancreas transplantation. 292 The high incidence of vascular thrombosis in pancreas grafts is explained by multiple factors such as the hyper- Regarding the use of prophylaxis or preemptive cytomegalovirus therapy, experts recommended prophylaxis in seronegative recipients receiving grafts from CMV-seropositive donors. 306, 313 In other donor/recipient pairs, either strategies were considered acceptable. This consensus was held before the SARS-CoV-2 pandemic. Therefore, any recommendations on vaccination against SARS- There is no specific evidence supporting protocol biopsies in SPK transplant recipients, but in solitary pancreas grafts protocol biopsy improved immunologic outcomes. 331, 332 Considering also that concordance between renal and pancreatic biopsy is not complete, 333 Few studies have addressed the effects of PTA on retinopathy (including one in comparison with insulin therapy and one in comparison with failed PTA). Generally, successful PTA is associated with improved stabilization of advanced retinopathy and increased lesion reversal in nonproliferative retinopathy. One study reports the deceleration of retinal damage early after PTA, with potential stabilization over time. 26, 78, 80 Experts acknowledged that successful PTA contributes to stabilization/improvement of diabetic retinopathy. Scant information is available on the effects of PTA on diabetic neuropathy. Published data suggest some improvements in nerve conduction velocity, autonomic function, and epinephrine response. 28, 166 Experts acknowledged that successful PTA may improve the course of diabetic neuropathy. A few studies evaluated the effects of SPK transplantation on the cardiovascular system, also in comparison with kidney transplant alone. SPK transplantation has been reported to be associated with lower rate of cardiovascular death and reduced progression of carotid and lower limb arterial damage. 52, 182, [373] [374] [375] [376] [377] Experts acknowledged that SPK transplantation has beneficial effects on the cardiovascular system, including lower rate of cardiovascular death compared with either dialysis or kidney alone transplantation. Limited data are available on the effects of PTA on the cardiovascular system, and mainly from a single group. PTA can lead to early and persistent reduction of a few cardiovascular risk factors (total and LDL cholesterol, blood pressure) and improved cardiac morphology and function (including diastolic parameters) as assessed by ultrasound evaluation. 29, 167, [375] [376] [377] Experts concluded that evidence available on the effects of PTA on the cardiovascular system is not sufficient to draw a final conclusion. Opportunities for research are presented as proposed actions for each recommendation in Tables 4-12. In general, the level of evidence was quite low demonstrating that well-designed studies as well as meta-analyses are greatly needed for many topics. Additional studies are more urgently needed for volume- Multicenter studies are particularly needed. As already reported while describing the methods of this consensus conference, 42 only data from full peer-reviewed manuscripts were considered. Consequently, we might have been missed additional information from these data sources. Some of the data examined and discussed to reach the consensus may have been influenced by local practice as well as geographical and institutional variations. As most studies were provided by the United States and Europe, the applicability of these guidelines in other countries may require adaptations to local practice, legislative framework, organizational needs, epidemiology of organ donation, and other geographical/cultural variations. Despite our effort to include all major transplant centers, and to specifically involve all physicians with known competence in pancreas transplantation, some prominent centers and influential colleagues may have not been invited or could not participate. However, having reached consensus among a large group of internationally recognized experts ensures balanced and competent assessment of available evidence. In conclusion, we have reported on 49 jury deliberations and 110 experts' recommendations, that we believe can be used to support and improve practice of pancreas transplantation worldwide. The main message from this consensus conference is that both SPK and PTA have the potential to improve patient survival in the long-term period, while all types of pancreas transplantation dramatically improve the quality of life of recipients. These advantages clearly appear to outweigh potential disadvantages, thus encouraging further implementation of pancreas transplantation. This Consensus Conference is dedicated in the loved memory of Mr. Fabrizio Iacopini, who made most of the local arrangements for the live sessions and unexpectedly died due to COVID-19 before these proceeding could be published. The first World Consensus Conference had no funding from commercial companies. The conference received a main unrestricted grant from Fondazione Pisa. The following Institutions also provided additional financial support: Regione Toscana, Università di Pisa, and Azienda Ospedaliero Universitaria Pisana. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. KDIGO clinical practice guideline on the evaluation and care of living kidney donors Nomenclature for kidney function and disease: report of a Kidney Disease: improving Global Outcomes (KDIGO) Consensus Conference KDIGO Clinical practice guideline on the evaluation and management of candidates for kidney transplantation Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients Posttransplant management of recipients undergoing liver transplantation for hepatocellular carcinoma Liver transplantation for cholangiocarcinoma and mixed hepatocellular cholangiocarcinoma: working group report from the ILTS transplant tncology consensus conference International Liver Transplantation Consensus Statement on end-stage liver disease due to nonalcoholic steatohepatitis and liver transplantation International liver transplantation society consensus statement on immunosuppression in liver transplant recipients European Association for the Study of the Liver. EASL clinical practice guidelines: liver transplantation Guidelines for heart transplantation UK guidelines for referral and assessment of adults for heart transplantation International guidelines for the selection of lung transplant candidates: 2006 update-a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation International guidelines for the selection of lung transplant candidates Transplant recipients are vulnerable to coverage denial under Medicare Part D Microalbuminuria and mortality in longduration type 1 diabetes Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis health-related quality of life, cognition, depression, vitamin D and health-care utilization in an ambulatory adult population with type 1 or type 2 diabetes mellitus and chronic kidney disease: a cross-sectional analysis Pancreas transplantation: a decade of decline A steady decline in pancreas transplantation rates Pancreas transplantation: an alarming crisis in confidence Prospective quality-of-life monitoring of simultaneous pancreas and kidney transplant recipients using the 36-item short form health survey Quality of life in simultaneous pancreas-kidney transplant recipients Quality of life after organ transplantation in type 1 diabetics with end-stage renal disease Health-related quality of life may improve after transplantation in pancreas-kidney recipients Health-related quality of life following kidney and simultaneous pancreas kidney transplantation Kidney function before pancreas transplant alone predicts subsequent risk of end-stage renal disease Pancreas transplant alone. A procedure coming of age Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy Pancreas transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients Present status of pancreas transplantation alone in non-uremic diabetic patients Solitary pancreas transplantation. Experience with 62 consecutive cases Successful pancreas transplantation alone is associated with excellent self-identified health score and glucose control: a retrospective study from a high-volume center in the United States Superior survival after simultaneous pancreas and kidney transplantation compared with transplantation of a kidney alone in diabetic recipients followed for 8 years Outcomes in diabetic patients after simultaneous pancreas-kidney versus kidney alone transplantation Simultaneous pancreas-kidney transplantation and living related donor renal transplantationin patients with diabetes: is there a difference in survival? Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure Improved patient survival in recipients of simultaneous pancreas-kidney transplant compared with kidney transplant alone in patients with type 1 diabetes mellitus and end-stage renal disease A reassessment of the survival advantage of simultaneous kidney-pancreas versus kidneyalone transplantation Mortality assessment for pancreas transplants Induction and immunosuppressive management of pancreas transplant recipients Decreased surgical risks of pancreas transplantation in the modern era pancreas transplantation: part I -Methods and results of literature search Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement An independent jury-based consensus conference model for the development of recommendations in medico-surgical practice AGREE Next Steps Consortium. The Global Rating Scale complements the AGREE II in advancing the quality of practice guidelines Antibody-mediated rejection of solidorgan allografts Understanding immunological response to desensitisation strategies in highly sensitised potential kidney transplant patients Physical status: the use and interpretation of anthropometry Long-term cardiovascular outcomes in type 1 diabetic patients after simultaneous pancreas and kidney transplantation compared with living donor kidney transplantation Renal transplantation in diabetic patients with or without simultaneous pancreatic transplantation 1986: data from the EDTA Registry Renal allograft and patient outcome after transplantation: pancreas-kidney versus kidney-alone transplants in type 1 diabetic patients versus kidney-alone transplants in nondiabetic patients Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival? Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure Simultaneous pancreaskidney transplant compared with kidney transplant in type I diabetic patients with end-stage renal disease Kidney allograft and patient survival in type I diabetic recipients of cadaveric kidney alone versus simultaneous pancreas/kidney transplants: a multivariate analysis of the UNOS database Dialysis, kidney transplantation, or pancreas transplantation for patients with diabetes mellitus and renal failure: a decision analysis of treatment options Health-related quality of life of patients awaiting kidney and simultaneous pancreas-kidney transplants The comparison of treatment results of type 1 diabetes mellitus complicated by endstage diabetic nephropathy in patients undergoing simultaneous pancreas and pre-emptive kidney transplantation (SPPkTx) and patients enrolled into the dialysis program-a c Outcomes of preemptive kidney with or without subsequent pancreas transplant compared with preemptive simultaneous pancreas/kidney transplantation The impact of pretransplant dialysis on simultaneous pancreas-kidney versus living donor kidney transplant outcomes The impact of multi-organ transplant allocation priority on wait-listed kidney transplant candidates New organ allocation system for combined liver-kidney transplants and the availability of kidneys for transplant to patients with stage 4-5 CKD Renal allograft failure predictors after PAK transplantation: results from the New England collaborative association of pancreas programs The impact of pancreas transplantation on kidney allograft survival Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant Survival after pancreas transplantation in patients with diabetes and preserved kidney function Over 500 solitary pancreas transplants in nonuremic patients with brittle diabetes mellitus Estimating the benefits of solitary pancreas transplantation in nonuremic patients with type 1 diabetes mellitus: a theoretical analysis Long-term (5 years) efficacy and safety of pancreas transplantation alone in type 1 diabetic patients Outcomes of recipients with pancreas transplant alone who develop end-stage renal disease Evolution of native kidney function after pancreas transplantation alone Decline in native renal function early after bladder-drained pancreas transplantation alone Reversal of lesions of diabetic nephropathy after pancreas transplantation Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys Long-term effects of pancreas transplantation on diabetic retinopathy and incidence and predictive risk factors for early worsening Long-term effects of pancreatic transplantation on diabetic neuropathy Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients Trends in hospital volume and operative mortality for high-risk surgery The volume-outcome relationship in deceased donor kidney transplantation and implications for regionalization Centre volume and resource consumption in liver transplantation The effect of transplant center volume on survival after heart transplantation: a multicenter study The impact of center volume on survival in lung transplantation: an analysis of more than 10,000 cases Transplant center volume and the risk of pancreas allograft failure The impact of surgeon volume on outcomes after pancreaticoduodenectomy: a metaanalysis High-volume hospitals with high-volume and low-volume surgeons: is there a "field effect" for pancreaticoduodenectomy? Effect of hospital volume, surgeon experience, and surgeon volume on patient outcomes after pancreaticoduodenectomy: a single-institution experience Pushing the envelope: living donor pancreas transplantation Segmental live donor pancreas transplantation: review and critique of rationale, outcomes, and current recommendations Conservation of the spleen with distal pancreatectomy Conservation of the spleen with distal pancreatectomy Twenty-three years of the Warshaw operation for distal pancreatectomy with preservation of the spleen Sinistral portal hypertension after live segmental pancreas donation: a long-term sequelae presenting with life-threatening upper gastrointestinal hemorrhage Laparoscopic robot-assisted pancreas transplantation: first world experience Robotic pancreas transplantation in a type 1 diabetic patient with morbid obesity: a case report The utility of robotic assisted pancreas transplants -a single center retrospective study Robotic kidney transplantation in the obese patient: 10-year experience from a single center Robotic kidney transplantation with regional hypothermia versus open kidney transplantation for patients with end-stage renal disease: an ideal stage 2B study Resection or repair of large peripancreatic arteries during robotic pancreatectomy Robotic pancreatoduodenectomy with vascular resection Pancreas transplants from donors aged 45 years or older Pancreas transplantation from marginal donors Long-term results after simultaneous pancreas-kidney transplantation using donors aged 45 years or older Contribution of donor and recipient characteristics to short-and long-term pancreas graft survival Influence of donor-and recipient-specific factors on the postoperative course after combined pancreas-kidney transplantation Influence of donor and recipient ages in survival of simultaneous pancreas-kidney transplantation Superior long-term results of simultaneous pancreas-kidney transplantation from pediatric donors Pancreas transplantation from pediatric donors: a united network for organ sharing registry analysis Pancreas transplantation from pediatric donors: a single-center experience Pancreas transplantation from very small pediatric donor using the "cephalic placement" technique: a case report Pancreata from pediatric donors restore insulin independence in adult insulin-dependent diabetes mellitus recipients Selected mildly obese donors can be used safely in simultaneous pancreas and kidney transplantation Report from the Japan Registry of Pancreas Transplantation (2000-2012): outcomes of pancreas transplantation from marginal donors Growth of a nation part I: impact of organ donor obesity on whole-organ pancreas transplantation Current state of pancreas preservation and implications for DCD pancreas transplantation Outcomes from pancreatic transplantation in donation after cardiac death: a systematic review and meta-analysis Donation after circulatory arrest in pancreas transplantation: a report of 10 cases First Canadian experience with donation after cardiac death simultaneous pancreas and kidney transplants Pancreas transplantation from donors after cardiac death: an update of the UNOS database Pancreas transplantation from donors after circulatory death: an irrational reluctance? Pancreas transplantation with grafts from donors deceased after circulatory death: 5 years single-center experience Simultaneous pancreaskidney transplant from donors after brain death vs donors after circulatory death: a single-center follow-up study over 3 decades Pancreas preservation with University of Wisconsin and Celsior solutions: a singlecenter, prospective, randomized pilot study Celsior versus Wisconsin solution in pancreas transplantation Increased pancreatitis in allografts flushed with histidine-tryptophan-ketoglutarate solution: a cautionary tale A prospective randomized multicenter trial comparing histidinetryptophane-ketoglutarate versus University of Wisconsin perfusion solution in clinical pancreas transplantation Histidine-tryptophanketoglutarate for pancreas allograft preservation: the Indiana University experience Early pancreas transplant outcomes with histidine-tryptophan-ketoglutarate preservation: a multicenter study Pancreas transplantation with histidine-tryptophan-ketoglutarate (HTK) solution and University of Wisconsin (UW) solution: is there a difference? Use of Georges Lopez Institute preservation solution IGL-1 in pancreas transplantation: a series of 47 cases Comparative impact on islet isolation and transplant outcome of the preservation solutions Institut Georges Lopez-1, University of Wisconsin, and Celsior Evaluation of Institut Georges Lopez-1 preservation solution in pig pancreas transplantation: a pilot study A quick technique for en bloc liver and pancreas procurement A simplified technique for the en bloc procurement of abdominal organs that is suitable for pancreas and small-bowel transplantation Successful procurement of 50 pancreatic grafts using a simple and fast technique No difference in transplant outcomes for local and import pancreas allografts Comparison of recipient outcomes following transplant from local versus imported pancreas donors Optimizing outcomes in pancreas transplantation: impact of organ preservation time Prolonged preservation increases surgical complications after pancreas transplants Hypothermic oxygenated machine perfusion of the human donor pancreas Use of ex vivo normothermic perfusion for quality assessment of discarded human donor pancreases A study of normothermic hemoperfusion of the porcine pancreas and kidney Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation Living donor pancreas transplantation in Japan Outcomes of simultaneous kidney-pancreas transplantation with positive cross-match Pancreas transplantation in crossmatch-positive recipients A positive T cell crossmatch and accelerated acute rejection of a pancreas-spleen allograft Outcomes of pancreas transplant recipients with de novo donor-specific antibodies Posttransplant donorspecific anti-HLA antibodies negatively impact pancreas transplantation outcome De novo donor-specific HLA antibodies: biomarkers of pancreas transplant failure Impact of de novo donorspecific anti-HLA antibodies on grafts outcomes in simultaneous pancreas-kidney transplantation Early findings of prospective anti-HLA donor specific antibodies monitoring study in pancreas transplantation: Indiana University Health Experience Impact of HLA matching on the outcome of simultaneous pancreas-kidney transplantation and -DQ matching in pancreas transplantation: effect on graft rejection and survival A multicenter analysis of the significance of HLA matching on outcomes after kidney-pancreas transplantation Matching in pancreas transplantation-a registry analysis HLA matching for simultaneous pancreas kidney transplantation in the United States: a multivariable analysis of the UNOS data Risk factors for type 1 diabetes recurrence in immunosuppressed recipients of simultaneous pancreas-kidney transplants Results of pancreas transplantation alone with special attention to native kidney function and proteinuria in type 1 diabetes patients Risk analysis for deterioration of renal function after pancreas alone transplant Long-term effects of pancreas transplant alone on nephropathy in type 1 diabetic patients with optimal renal function The beneficial effects of pancreas transplant alone on diabetic nephropathy Disappearance of nephrotic syndrome in type 1 diabetic patients following pancreas transplant alone Effects of pancreatic transplantation on diabetic neuropathy Amelioration of cardiac morphology and function in type 1 diabetic patients with sustained success of pancreas transplant alone Renal function in type 1 diabetics one year after successful pancreas transplantation Pancreas after kidney transplants in posturemic patients with type I diabetes mellitus The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation Pancreas transplantation of US and non-US cases from 2005 to 2014 as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) Preemptive transplantation for patients with diabetes-related kidney disease Preemptive versus nonpreemptive simultaneous pancreas-kidney transplantation: a single-center, long-term, follow-up study Comparison of 1-year patient and graft survival rates between preemptive and dialysed simultaneous pancreas and kidney transplant recipients Obesity as a risk factor after combined pancreas/kidney transplantation Influence of mild obesity on outcome of simultaneous pancreas and kidney transplantation Obesity was associated with inferior outcomes in simultaneous pancreas kidney transplant Impact of recipient body mass index on short-term and long-term survival of pancreatic grafts Obesity predicts increased overall complications following pancreas transplantation Arteriosclerosis obliterans and associated risk factors in insulin-dependent and non-insulin-dependent diabetes Clinical characteristics and survival in end-stage renal disease patients with arteriosclerosis obliterans Effects of simultaneous pancreas-kidney transplantation and kidney transplantation alone on the outcome of peripheral vascular diseases Major adverse cardiovascular events following simultaneous pancreas and kidney transplantation in the United Kingdom Pretransplant coronary artery disease associated with worse clinical outcomes in pancreas transplantation Risk factors for mortality in diabetic nephropathy patients accepted for transplantation Comparison of enteric versus bladder drainage in pancreas transplantation Portal venous and enteric exocrine drainage versus systemic venous and bladder exocrine drainage of pancreas grafts: clinical outcome of 40 consecutive transplant recipients A prospective comparison of systemic bladder versus portal-enteric drainage in vascularized pancreas transplantation A prospective comparison of bladder versus enteric drainage in vascularized pancreas transplantation Consolidation of enteric drainage for exocrine secretions in simultaneous pancreas-kidney transplant Comparison of pancreas transplantation with portal venous and enteric exocrine drainage to the standard technique utilizing bladder drainage of exocrine secretions Long-term pancreas allograft outcome in simultaneous pancreaskidney transplantation: a comparison of enteric and bladder drainage Primary enteric drainage of the pancreas revisited: a viable alternative to bladder drainage in simultaneous pancreas-kidney transplants Enteric versus bladder drainage in pancreas transplantation: initial experience at Niguarda Hospital, Milan Posttransplant infection in enteric versus bladder-drained simultaneous pancreaskidney transplant recipients Surgical complications in 123 consecutive pancreas transplant recipients: comparison of bladder and enteric drainage Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portalenteric versus systemic-bladder drainage Technical and immunologic progress in simultaneous pancreas-kidney transplantation Outcomes with the selective use of enteric exocrine drainage in pancreas transplantation Outcome of simultaneous kidney pancreas transplantation: a single center analysis Does surgical technique influence outcomes after simultaneous kidney-pancreas transplantation? Surgical complications are the main cause of pancreatic allograft loss in pancreas-kidney transplant recipients Bladder vs enteric drainage in simultaneous pancreas-kidney transplantation Initial Australasian experience with portal-enteric drainage in simultaneous pancreas-kidney transplantation Conversion from bladder to enteric drainage for complications after pancreas transplantation Enteric conversion after bladder-drained pancreas transplantation is not associated with worse allograft survival Enteric conversion of bladderdrained pancreas as a predictor of outcomes in almost 600 recipients at a single center Simultaneous pancreas/kidney transplantation-a comparison of enteric and bladder drainage of exocrine pancreatic secretions Drainage of the exocrine pancreas in clinical transplantation: comparison of bladder versus enteric drainage in a consecutive series Experience with 500 simultaneous pancreas-kidney transplants Effect of the surgical technique on long-term outcome of pancreas transplantation Urological complications after simultaneous renal and pancreatic transplantation Urological complications after simultaneous pancreas-kidney transplantation Long-term outcomes after simultaneous pancreas-kidney transplant Epidemiology, risk factors and impact on long-term pancreatic function of infection following pancreas-kidney transplantation Bladder-drained pancreas transplantation: urothelial innate defenses and urinary tract infection susceptibility Lessons learned from more than 1,000 pancreas transplants at a single institution Experience with simultaneous pancreas-kidney transplantation Solitary pancreas transplantation: a review of the UK experience over a period of 10 yr Exocrine drainage into the duodenum: a novel technique for pancreas transplantation Pancreas transplantation with enteroanastomosis to native duodenum poses technical challenges-but offers improved endoscopic access for scheduled biopsies and therapeutic interventions Simultaneous pancreaskidney transplantation with duodeno-duodenal anastomosis Outcomes in pancreas transplantation with exocrine drainage through a duodenoduodenostomy versus duodenojejunostomy 125 Cases of duodenoduodenostomy in pancreas transplantation: a single-centre experience of an alternative enteric drainage Duodenoduodenostomy in pancreas transplantation Correlation of rejection of the duodenum with rejection of the pancreas in a pig model of pancreaticoduodenal transplantation Cystoscopic biopsies in pancreaticoduodenal transplantation. Are duodenal biopsies indicative of pancreas dysfunction? Pancreas transplant rejection episodes are not revealed by biopsies of the donor duodenum in a prospective study with paired biopsies Evolution of pancreas transplantation: long-term results and perspectives from a highvolume center Portal drainage of pancreas allograft: surgical complications and graft survival Portal venous versus systemic venous drainage of pancreas grafts: impact on long-term results Portal and systemic venous drainage in pancreas and kidney-pancreas transplantation: early surgical complications and outcomes Impact of pancreatic venous drainage site on long-term patient and graft outcome in simultaneous pancreas-kidney transplantation Effects of portal versus systemic venous drainage in pancreas and kidney-pancreas transplantation A prospective comparison of simultaneous kidney-pancreas transplantation with systemic-enteric versus portal-enteric drainage Impact of portal venous pancreas graft drainage on kidney graft outcome in simultaneous pancreas-kidney recipients reported to UNOS Effect of pancreas transplantation on lipoprotein lipase, postprandial lipemia, and HDL cholesterol Effect of venous drainage site on insulin action after simultaneous pancreas-kidney transplantation Metabolic consequences of pancreatic systemic or portal venous drainage in simultaneous pancreas-kidney transplant recipients Proinsulinemia in simultaneous pancreas and kidney transplant recipients Portal versus systemic venous drainage of the pancreatic graft: the effect on glucose metabolism in pancreas and kidney transplant recipients Comparison of pancreas-transplanted type 1 diabetic patients with portalvenous versus systemic-venous graft drainage: impact on glucose regulatory hormones and the growth hormone/ insulin-like growth factor-I axis The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesteryl ester transfer in IDDM subjects A technique for retroperitoneal pancreas transplantation with portal-enteric drainage Pancreas transplantation: advantages of a retroperitoneal graft position Steroid-free three-drug maintenance regimen for pancreas transplant alone: comparison of induction with rabbit antithymocyte globulin +/− rituximab Alemtuzumab induction and steroid-free maintenance immunosuppression in pancreas transplantation Single dose of alemtuzumab induction with steroid-free maintenance immunosuppression in pancreas transplantation Steroid-free maintenance immunosuppression with rapamune and low-dose neoral in pancreas transplant recipients Reduction of CMV disease with steroid-free immunosuppresssion in simultaneous pancreas-kidney transplant recipients Calcineurin inhibitor-and steroid-free immunosuppression in pancreaskidney and solitary pancreas transplantation Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial A prospective study of rapid corticosteroid elimination in simultaneous pancreaskidney transplantation: comparison of two maintenance immunosuppression protocols: Tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus Alemtuzumab with rapid steroid taper in simultaneous kidney and pancreas transplantation: comparison to induction with antithymocyte globulin Comparing an early corticosteroid/late calcineurin-free immunosuppression protocol to a sirolimus-, cyclosporine A-, and prednisone-based regimen for pancreas-kidney transplantation Very early steroid withdrawal in simultaneous pancreas-kidney transplants Steroid avoidance or withdrawal for pancreas and pancreas with kidney transplant recipients Metabolic effects of a corticosteroid-free immunosuppressive regimen in recipients of pancreatic transplant Steroid avoidance versus steroid withdrawal after simultaneous pancreas-kidney transplantation Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression A prospective, randomized, open-label study of steroid withdrawal in pancreas transplantation-a preliminary report with 6-month follow-up Prospective, randomized, multi-center trial of antibody induction therapy in simultaneous pancreas-kidney transplantation Two-dose daclizumab regimen in simultaneous kidney-pancreas transplant recipients: primary endpoint analysis of a multicenter, randomized study Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: one-and two-year outcomes Thymoglobulin and its use in renal transplantation: a review Efficacy and safety of tacrolimus compared with cyclosporine microemulsion in primary simultaneous pancreas-kidney transplantation: 1-year results of a large multicenter trial Neoral versus prograf in simultaneous pancreas-kidney transplantation with portal venous drainage: three-year results of a single-center, openlabel, prospective, randomized pilot study Experimental and clinical experience with urine amylase monitoring for early diagnosis of rejection in pancreas transplantation Randomized open-label crossover assessment of Prograf vs Advagraf on immunosuppressant pharmacokinetics and pharmacodynamics in simultaneous pancreas-kidney patients Conversion from twice-daily to once-daily tacrolimus in simultaneous pancreas-kidney transplant patients Utilization of LCP-tacrolimus (Envarsus XR) in simultaneous pancreas and kidney transplant recipients A singlecenter experience with tacrolimus LCP (Envarsus XR) in pancreas transplant recipients De novo use of sirolimus in immunosuppression regimens in kidney and kidney-pancreas transplantation at the University of California Selective corticosteroid and calcineurin-inhibitor withdrawal after pancreas-kidney transplantation utilizing thymoglobulin induction and sirolimus maintenance therapy Thymoglobulin, sirolimus, and reduced-dose cyclosporine provides excellent rejection prophylaxis for pancreas transplantation Tacrolimus-versus sirolimus-based immunosuppression after simultaneous pancreas and kidney transplantation: 5-year results of a randomized trial Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: results of a prospective, randomized clinical trial Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine An evidence-based analysis of simultaneous pancreas-kidney and pancreas transplantation alone A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreaskidney transplantation Comparison of azathioprine and mycophenolate mofetil for the prevention of acute rejection in recipients of pancreas transplantation Use of mammalian target of rapamycin inhibitors for pancreas transplant immunosuppression is associated with improved allograft survival and improved early patient survival Sirolimus vs mycophenolate mofetil (MMF) in primary combined pancreas and kidney transplantation. Results of a long-term prospective randomized study Immunosuppression in pancreas transplantation: the Euro SPK trials and beyond Immunosuppression in pancreas transplantation: mycophenolate mofetil versus sirolimus Advantage of rapamycin over mycophenolate mofetil when used with tacrolimus for simultaneous pancreas kidney transplants: randomized, single center trial at 10 years Early immunosuppression treatment correlates with later de novo donor-specific antibody development after kidney and pancreas transplantation De novo donor-specific antibody formation in tacrolimus-based, mycophenolate versus mammalian target of rapamycin immunosuppressive regimens Pancreas transplantation utilizing thymoglobulin, sirolimus, and cyclosporine Hypercoagulable state associated with kidney-pancreas transplantation. Thromboelastogramdirected anti-coagulation and implications for future therapy Vascular graft thrombosis after pancreatic transplantation: univariate and multivariate operative and nonoperative risk factor analysis Pancreas transplantation: a managed cure approach to diabetes Technical failures after pancreas transplants: why grafts fail and the risk factors -a multivariate analysis Early allograft pancreatectomy-technical failure or acute pancreatic rejection? Single-shot antithrombin in human pancreas-kidney transplantation: reduction of reperfusion pancreatitis and prevention of graft thrombosis Heparin infusion in simultaneous pancreas and kidney transplantation reduces graft thrombosis and improves graft survival Simultaneous pancreas-kidney transplantation: to anticoagulate or not? Is that a question? Incidence of pancreas graft thrombosis using low-molecular-weight heparin Venous thromboembolic complications after kidney and kidney-pancreas transplantation: a multivariate analysis Post-transplant venous thromboembolic events and their effect on graft survival Venous thromboembolism and the risk of death and graft loss in kidney transplant recipients Pancreas graft thrombosis: causes, prevention, diagnosis, and intervention Six-month prophylaxis is cost effective in transplant patients at high risk for cytomegalovirus infection The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients Cytomegalovirus prophylaxis using oral ganciclovir or valganciclovir in kidney and pancreas-kidney transplantation under antibody preconditioning Long-term outcome of cytomegalovirus infection in simultaneous pancreas-kidney transplant recipients without ganciclovir prophylaxis Cytomegalovirus infection post-pancreas-kidney transplantation -results of antiviral prophylaxis in high-risk patients Incidence and outcomes of cytomegalovirus in pancreas transplantation with steroid-free immunosuppression Ganciclovir/acyclovir and fluconazole prophylaxis after simultaneous kidney-pancreas transplantation The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation Intra-abdominal fungal infections after pancreatic transplantation: incidence, treatment, and outcome Fungal infections in transplant recipients receiving alemtuzumab The incidence of fungal infections in pancreas transplant recipients in the absence of systemic antifungal prophylaxis Pneumocystis jiroveci pneumonia in kidney and simultaneous pancreas kidney transplant recipients in the present era of routine post-transplant prophylaxis: risk factors and outcomes Candidemia following solid organ transplantation in the era of antifungal prophylaxis: the Australian experience Antifungal prophylaxis for solid organ transplant recipients: seeking clarity amidst controversy Prevention of infection caused by Pneumocystis carinii in transplant recipients AST Infectious Diseases Community of Practice. Candida infections in solid organ transplantation A randomized trial of surgical antimicrobial prophylaxis with and without vancomycin in organ transplant patients Characterization and impact of wound infection after pancreas transplantation Prophylactic wound antibiotics for combined kidney and pancreas transplants Infectious disease complications of simultaneous pancreas kidney transplantation Experience with ATG short course high dose induction therapy in a series of 112 enteric drained pancreatic transplants Low postoperative wound infection rates are possible following simultaneous pancreaskidney transplantation Perioperative antibiotic prophylaxis to prevent surgical site infections in solid organ transplantation Vaccination of solid organ transplant candidates and recipients: guidelines from the American society of transplantation infectious diseases community of practice Immunogenicity of anti-HLA antibodies in pancreas and islet transplantation Experience with protocol biopsies after solitary pancreas transplantation Outcome of untreated grade II rejection on solitary pancreas allograft biopsy specimens Pancreas allograft rejection: analysis of concurrent renal allograft biopsies and posttherapy follow-up biopsies Concurrent biopsies of both grafts in recipients of simultaneous pancreas and kidney demonstrate high rates of discordance for rejection as well as discordance in type of rejection -a retrospective study Graft dysfunction in simultaneous pancreas kidney transplantation (SPK): results of concurrent kidney and pancreas allograft biopsies Histologic grading of acute allograft rejection in pancreas needle biopsy: correlation to serum enzymes, glycemia, and response to immunosuppressive treatment Thymoglobulin for induction or rejection therapy in pancreas allograft recipients: a single centre experience Acute pancreas allograft rejection is associated with increased risk of graft failure in pancreas transplantation Isolated pancreas rejections do not have an adverse impact on kidney graft survival whereas kidney rejections are associated with adverse pancreas graft survival in simultaneous pancreas kidney transplantation How should pancreas transplant rejection be treated? C4d-positive interacinar capillaries correlates with donor-specific antibodymediated rejection in pancreas allografts Pancreas allograft biopsies with positive c4d staining and anti-donor antibodies related to worse outcome for patients Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel The Banff 2015 kidney meeting report: current challenges in rejection classification and prospects for adopting molecular pathology Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema Antibodymediated rejection (AMR) after pancreas and pancreas-kidney transplantation Alemtuzumab induction and antibody-mediated kidney rejection after simultaneous pancreaskidney transplantation Acute cellular and antibody-mediated rejection of the pancreas allograft: incidence, risk factors and outcomes Diagnosis and treatment of pancreas rejection Recurrence of disease in pancreas transplants Islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation Zinc transporter 8 autoantibodies increase the predictive value of islet autoantibodies for function loss of technically successful solitary pancreas transplant Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation Immune monitoring of islet and pancreas transplant recipients Lessons from pancreas transplantation in type 1 diabetes: recurrence of islet autoimmunity Monitoring inflammation, humoral and cell-mediated immunity in pancreas and islet transplants Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy Effects of pancreaskidney transplantation on diabetic retinopathy Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus Impact of pancreas transplantation on diabetic secondary complications and quality of life Does pancreas transplantation influence the course of diabetic retinopathy? Effect of pancreas transplantation on diabetic retinopathy: a 20-case report Long-term outcomes after organ transplantation in diabetic end-stage renal disease Evolution of diabetic nephropathy in kidney grafts. Evidence that a simultaneously transplanted pancreas exerts a protective effect In patients with type 1 diabetes simultaneous pancreas and kidney transplantation preserves long-term kidney graft ultrastructure and function better than transplantation of kidney alone Follow-up study of sensory-motor polyneuropathy in Type 1 (insulin-dependent) diabetic subjects after simultaneous pancreas and kidney transplantation and after graft rejection Improvement of nerve conduction in diabetic neuropathy. A follow-up study 4 yr after combined pancreatic and renal transplantation Improvement in autonomic and gastric function following pancreas-kidney versus kidney-alone transplantation and the correlation with quality of life Diabetic neuropathy 3 years after successful pancreas and kidney transplantation Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas Autonomic neuropathy and survival in diabetes mellitus: effects of pancreas transplantation Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end-stage renal failure due to type 1 diabetes Pancreas transplantation improves vascular disease in patients with type 1 diabetes Evolution of carotid vascular lesions in kidney-pancreas and kidney-alone transplanted insulindependent diabetic patients Progression of macrovascular diseases is reduced in type 1 diabetic patients after more than 5 years successful combined pancreas-kidney transplantation in comparison to kidney transplantation alone First World Consensus Conference on pancreas transplantation: Part II -recommendations The data that support the findings of this study are available from the corresponding author upon reasonable request.