Pancreas transplantation (PT) is a definitive treatment for diabetes mellitus (DM), restoring endogenous insulin secretion and improving glycemic control. Despite its efficacy, PT is less common in South Korea compared to Western nations. This study aims to report the clinical outcomes of PT over 2 decades at a single center, focusing on surgical techniques, complications, and graft survival.

A retrospective analysis of 69 PT recipients at Seoul National University Hospital between January 2002 and December 2023 was conducted. Data on recipient and donor demographics, surgical details, immunosuppressive regimens, and graft outcomes were collected. Graft survival was evaluated using Kaplan-Meier analysis, with subgroup comparisons using the log-rank test. Graft failure was defined as graft removal, PT re-registration, insulin dependence exceeding 0.5 units/kg/day for more than 90 days, or patient death.

Among the 69 recipients, 50 (72.5%) had type 1 DM, and 18 (26.1%) had type 2 DM. Simultaneous pancreas-kidney (SPK) transplantations comprised 84.1% (n = 58), and pancreas-after-kidney (PAK) transplantations accounted for 10.1%. The 1-year and 5-year death-censored pancreas graft survival rates were 92.7% and 89.6%, respectively, with no significant difference between SPK and PAK (P = 0.330). Graft failure occurred in 10 patients, primarily due to pancreatitis and rejection. Donor-related factors, particularly anoxic brain injury, were significantly associated with lower graft survival (P = 0.045).

PT outcomes in this cohort align with international standards, emphasizing the importance of donor selection and tailored immunosuppression. Expanding PT indications to include selective type 2 DM patients could benefit South Korea's PT programs with adequate resource allocation.

Early failure of a pancreatic allograft due to complete thrombosis has an incidence of approximately 10% and is the main cause of comorbidity in pancreas transplantation. Although several risk factors have been identified, the exact mechanisms leading to this serious complication are still unclear. In this review, we define the roles of the individual components involved during sterile immunothrombosis-namely endothelial cells, platelets, and innate immune cells. Further, we review the published evidence linking the main risk factors for pancreatic thrombosis to cellular activation and vascular modifications. We also explore the unique features of the pancreas itself: the vessel endothelium, specific vascularization, and relationship to other organs-notably the spleen and adipose tissue. Finally, we summarize the therapeutic possibilities for the prevention of pancreatic thrombosis depending on the different mechanisms such as anticoagulation, anti-inflammatory molecules, endothelium protectors, antagonism of damage-associated molecular patterns, and use of machine perfusion.

The rate of early pancreas allograft failure remains high due to thrombosis but also to severity of rejection episodes. We investigated if adjunct anti-TNFα therapy was safe and could improve outcomes after pancreas transplantation. We investigated all pancreas transplants performed in our institution between 2010 and 2022. Etanercept, an anti TNFα therapy, was added to our standard immunosuppressive regimen since 2017 after approval from our institutional human ethics committee. Pancreas survival, rejection episodes, as well as infectious complications were analyzed. A total of 236 pancreas transplants were included, among whom 87 received Etanercept for induction. In multivariable analysis, after adjustment on confounding variables, pancreas survival did not differ between groups (HR = 0.92, CI 95% = 0.48; 1.73, p = 0.79). However, patients receiving Etanercept presented a significantly lower occurrence of pancreas rejection in multivariate analysis (HR = 0.36, CI 95% = 0.14; 0.95, p = 0.04). Patients receiving Etanercept did not experienced a higher risk of bacterial, fungal, CMV nor BK virus infections compared to the non-treated group. The use of anti-TNFα after pancreas transplantation was safe and did not increase infectious complications. Despite a similar rate of thrombosis, anti-TNFα significantly reduced pancreatic rejection, thus supporting its use among pancreas transplant recipients.

Simultaneous pancreas-kidney (SPK) transplantation is an established treatment for insulin-requiring diabetics with advanced chronic or end-stage kidney disease. Outcomes of SPK transplantation may vary according to socioeconomic factors such as funding sources. The aim of this study was to assess the association between insurance payer of transplant recipients and outcomes of SPK transplantation in the United States.

All adult primary SPK transplants performed in the United States between January 1, 1988, and December 31, 2017 were included, using data from the national Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients database. A total of 19,849 adult SPK transplant recipients were included in the study, after excluding patients who had insurance sources other than Medicaid, Medicare, or private; dual insurance; or were lost at 90-day follow-up. Post-transplant outcomes were analyzed in terms of allograft and recipient survival.

Recipients with private insurance had significantly lower risks of late kidney graft loss (hazard ratio [HR], 0.74), late pancreas graft loss (HR, 0.77), and late death (HR, 0.73) compared with those with Medicaid. Recipients with Medicare had a higher risk of late death (HR, 1.05). Private insurance recipients had better 10-year and 15-year kidney, pancreas, and patient graft survival rates across most racial/ethnic groups.

Recipient insurance status significantly influenced long-term outcomes after SPK transplantation. Transplant programs should consider publicly sponsored insurance status as a marker of poorer post-transplant survival to implement changes in both pre- and post-transplant strategies.

The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.

Type 1 diabetes mellitus is an autoimmune condition characterized by the destruction of pancreatic β-cells, necessitating insulin therapy to prevent life-threatening complications such as diabetic ketoacidosis. Despite advancements in glucose monitoring and pharmacological treatments, managing this disease remains challenging, often leading to long-term complications and psychological burdens, including diabetes distress. Advanced treatment options, such as whole-pancreas transplantation and islet transplantation, aim to restore insulin production and improve glucose control in selected patients with diabetes. The risk of transplant rejection necessitates immunosuppressive therapy, which increases susceptibility to infections and other adverse effects. Additionally, surgical complications, including infection and bleeding, are significant concerns, particularly for whole-pancreas transplantation. Recently, stem cell-derived therapies for type 1 diabetes have emerged as a promising alternative, offering potential solutions to overcome the limitations of formerly established transplantation methods. The purpose of this scoping review was to: (1) summarize the current evidence on achieved insulin independence following various transplantation methods of insulin-producing cells in patients with type 1 diabetes; (2) compare insulin independence rates among whole-pancreas transplantation, islet cell transplantation, and stem cell transplantation; and (3) identify limitations, challenges and potential future directions associated with these techniques. We systematically searched three databases (PubMed, Scopus, and Web of Science) from inception to November 2024, focusing on English-language, peer-reviewed clinical studies. The search terms used were 'transplantation' AND 'type 1 diabetes' AND 'insulin independence'. Studies were included if they reported on achieved insulin independence, involved more than 10 patients with type 1 diabetes, and had a mean follow-up period of at least one year. Reviewers screened citations and extracted data on transplant type, study population size, follow-up duration, and insulin independence rates. We identified 1380 papers, and after removing duplicates, 705 papers remained for title and abstract screening. A total of 139 English-language papers were retrieved for full-text review, of which 48 studies were included in this review. The findings of this scoping review indicate a growing body of literature on transplantation therapy for type 1 diabetes. However, significant limitations and challenges, like insufficient rates of achieved insulin independence, risks related to immunosuppression, malignant diseases, and ethical issues remain with each of the established techniques, highlighting the need for innovative approaches such as stem cell-derived islet transplantation to promote β-cell regeneration and protection.

Given the increasing frequency of simultaneous pancreas-kidney transplants performed in recipients with Type II diabetes and CKD, we sought to evaluate possible differences in the rates of allograft rejection, infection, and surgical complications in 298 Type I (T1D) versus 47 Type II (T2D) diabetic recipients of simultaneous pancreas-kidney transplants between 2006-2017. There were no significant differences in patient or graft survival. The risk of biopsy-proven rejection of both grafts was not significantly different between T2D and T1D recipients (HRpancreas = 1.04, p = 0.93; HRkidney = 0.96; p = 0.93). Rejection-free survival in both grafts were also not different between the two diabetes types (ppancreas = 0.57; pkidney = 0.41). T2D had a significantly lower incidence of de novo DSA at 1 year (21% vs. 39%, p = 0.02). There was no difference in T2D vs. T1D recipients regarding readmissions (HR = 0.77, p = 0.25), infections (HR = 0.77, p = 0.18), major surgical complications (HR = 0.89, p = 0.79) and thrombosis (HR = 0.92, p = 0.90). In conclusion, rejection, infections, and surgical complications after simultaneous pancreas-kidney transplant are not statistically significantly different in T2D compared to T1D recipients.

Background: Pancreas transplantation (PTX) remains the most effective treatment to prevent long-term complications and provide consistent euglycemia in patients with endocrine pancreatic insufficiency, mainly in type I diabetic patients. Considering early graft loss (EGL) and the perioperative complication rate, an optimal risk stratification based on donor risk factors is paramount. Methods: In our single-center study, we retrospectively assessed the risk factors for EGL and reduced graft survival in 97 PTXs (82 simultaneous pancreas and kidney [SPK], 11 pancreases transplanted after kidney [PAK] and 4 pancreases transplanted alone [PTA]) between 2010 and 2021. By statistically analyzing the incorporation of different donor risk factors using the Kaplan-Meier method and a log-rank test, we introduced a composite risk model for the evaluation of offered pancreas grafts. Results: The overall EGL rate was 6.5%. In the univariate analysis of donor characteristics, age > 45 years, BMI > 25 kg/m2, lipase > 60 U/L, cerebrovascular accident (CVA) as the cause of death, mechanical cardiopulmonary resuscitation (mCPR), cold ischemia time (CIT) > 600 min and retrieval by another center were identified as potential risk factors; however, they lacked statistical significance. In a multivariate model, age > 45 years (HR 2.05, p = 0.355), BMI > 25 kg/m2 (HR 3.18, p = 0.051), lipase > 60 U/L (HR 2.32, p = 0.148), mCPR (HR 8.62, p < 0.0001) and CIT > 600 min (HR 1.89, p = 0.142) had the greatest impact on pancreas graft survival. We subsumed these factors in a composite risk model. The combination of three risk factors increased the rate of EGL significantly (p = 0.003). Comparing the pancreas graft survival curves for ≥3 risk factors to <3 risk factors in a Kaplan-Meier model revealed significant inferiority in the pancreas graft survival rate (p = 0.029). Conclusions: When evaluating a potential donor organ, grafts with a combination of three or more risk factors should only be accepted after careful consideration to reduce the risk of EGL and to significantly improve outcomes after PTX.

In the United States, potential transplant candidates with insulin-dependent diabetes mellitus are inconsistently offered pancreas transplantation (PTx), contributing to a dramatic decline in pancreas allograft utilization over the past 2 decades. The American Society of Transplantation organized a workshop to identify barriers inhibiting PTx and to develop strategies for a national comeback. The 2-day workshop focused on 4 main topics: (1) referral/candidate selection, (2) organ recovery/utilization, (3) program performance/patient outcomes, and (4) enhanced education/research. Topics were explored through expert presentations, patient testimonials, breakout sessions, and strategic planning, including the identification of tasks for immediate focus. Additionally, a modified-Delphi survey was conducted among workshop members to develop and rate the importance of barriers, and the impact and feasibility of workgroup-identified improvement strategies. The panelists identified 16 barriers to progress and 44 strategies for consideration. The steps for a national comeback in PTx involve greater emphasis on efficient referral and candidate selection, better donor pancreas utilization practices, eliminating financial barriers to procurement and transplant, improving collaboration between transplant and diabetes societies and professionals, and increasing focus on PTx training, education, and research. Partnership between national societies, patient advocacy groups, and professionals will be essential to realizing this critical agenda.

About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis.

We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers.

Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers.

Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

Regenerative medicine solutions for type 1 diabetes are a rapidly developing field of medical technology. To date, these solutions have been principally cell-based treatments and at present, in Europe, these therapies are regulated under European Union regulations for advanced therapy medicinal products. But now, new emerging technology combining cellular therapy with medical devices is under development. The potential of this novel hybrid model to create a bioartificial pancreas to treat type 1 diabetes is tantalizing. However, incorporating medical devices creates a further layer of regulatory complexity. This article seeks to expose the complexity of this legal and regulatory landscape and demonstrate how evolving technology could challenge the entire existing legal paradigm. We start by summarizing the status of the only established cell-based therapy-transplantation. We set out the regulation of cellular therapies, their classification, and the role of statutory bodies. We examine the bottleneck of therapies moving from bench to bedside, and we consider the additional challenges of products, which use a combination of cells and medical devices. Finally, we argue that for the potential of this rapidly growing area of technology to be realized a seismic shift in how we regulate frontier cellular therapies will be required.

A 21-year-old woman diagnosed with cystic fibrosis developed cirrhosis, exocrine pancreatic insufficiency, and insulin-dependent diabetes mellitus. The patient qualified for double organ liver-pancreas transplantation beyond typical indications. The respiratory symptoms of cystic fibrosis were moderate and well-treated. The patient was endangered mainly by liver insufficiency and recurrent hypoglycemia, which was due to the treatment of diabetes with high doses of insulin. Computed tomography showed mild bronchiectasis, cirrhotic liver, splenomegaly, and atrophy of the pancreas. Pseudomonas aeruginosa colonized the upper respiratory tract. Gastrointestinal complications were sufficient for the patient to be qualified for combined liver-pancreas transplantation.

First, a standard hepatectomy was performed. The liver was transplanted orthotopically. Subsequently, the team performed pancreas transplantation through a separate incision. The donor's duodenum was anastomosed to the recipient's jejunum, close to the ligament of Treitz.

No serious complications were noted during the postoperative period. Transplanted organs started functioning without delay. The patient was discharged after 6 weeks in general good condition. Twenty months later, the patient felt well, and the grafts kept functioning properly.

Combined liver-pancreas transplantation in patients with CF restores exocrine and endocrine pancreatic function and minimizes the risk of life-threatening complications associated with liver insufficiency. Improvement of life quality coincides with the possibility of discontinuing insulin and pancreatic enzyme supplementation. The combination of liver and pancreas transplantation may prevent advanced pulmonary complications, extend the prognosis of survival, and improve the long-term life quality.

This single-center observational cohort study aimed to assess the potential benefits of simultaneous pancreas and kidney transplantation (SPK) in terms of mortality and kidney graft outcomes in Japanese individuals with type 1 diabetes (T1D) and end-stage kidney disease (ESKD). We first compared all-cause mortality rates between 78 SPK recipients and 108 non-transplanted individuals with T1D and ESKD. To mitigate the bias stemming from immortal time before receiving SPK, we utilized Cox regression models treating SPK as a time-dependent covariate. Next, we compared all-cause mortality rates and kidney graft loss rates between 65 SPK recipients and 58 kidney transplantation alone (KTA) recipients. Multivariate Cox hazard models and Fine and Gray competing-risk models were employed. SPK recipients experienced significantly lower all-cause mortality rates than non-transplanted individuals, even after accounting for immortal time bias (p = 0.015 by log-rank test, hazard ratio [HR] = 0.334, p = 0.025). When comparing SPK and KTA recipients, no statistically significant difference was observed in mortality rates (HR = 0.627, p = 0.588 by Cox model; HR = 0.385, p = 0.412 by Fine and Gray model) or kidney graft loss rates (HR = 0.612, p = 0.436 by Cox model; HR = 0.639, p = 0.376 by Fine and Gray model). Dysglycemia-associated mortality were observed in non-transplanted individuals and KTA recipients, but not in SPK recipients. These findings highlight the potential life-saving impact of SPK compared with intensive insulin therapy and dialysis. Additionally, this study suggests that both SPK and KTA may offer comparable outcomes. These findings have significant implications for clinical decision-making in the context of organ transplantation for individuals with T1D and ESKD.

Graft loss increases the risk of patient death after simultaneous pancreas-kidney (SPK) transplantation. The relative risk of each graft failure is complex due to the influence of several competing events.

This retrospective, single-center study compared 4-year patient survival according to the graft status using Kaplan-Meier (KM) and Competing Risk Analysis (CRA). Patient survival was also assessed according to five eras (Era 1: 2001-2003; Era 2: 2004-2006; Era 3: 2007-2009; Era 4: 2010-2012; Era 5: 2012-2015).

Between 2000 and 2015, 432 SPK transplants were performed. Using KM, patient survival was 86.5% for patients without graft loss (n = 333), 93.4% for patients with pancreas graft loss (n = 46), 43.7% for patients with kidney graft loss (n = 16), and 25.4% for patients with pancreas and kidney graft loss (n = 37). Patient survival was underestimated using KM versus CRA methods in patients with pancreas and kidney graft losses (25.4% vs. 36.2%), respectively. Induction with lymphocyte depleting antibodies was associated with 81% reduced risk (HR.19, 95% CI.38-.98, p = .0048), while delayed kidney function (HR 2.94, 95% CI 1.09-7.95, p = .033) and surgical complications (HR 2.94, 95% CI 1.22-7.08, p = .016) were associated with higher risk of death. Four-year patient survival increased from Era 1 to Era 5 (79% vs. 87.9%, p = .047).

In this cohort of patients, kidney graft loss, with or without pancreas graft loss, was associated with higher mortality after SPK transplantation. Compared to CRA, the KM model underestimated survival only among patients with pancreas and kidney graft losses. Patient survival increased over time.

Diabetes presents a pressing healthcare crisis, necessitating innovative solutions. Organoid technologies have rapidly advanced, leading to the emergence of bioengineering islet organoids as an unlimited source of insulin-producing cells for treating insulin-dependent diabetes. This advancement surpasses the need for cadaveric islet transplantation. However, clinical translation of this approach faces two major limitations: immature endocrine function and the absence of a perfusable vasculature compared to primary human islets. In this review, we summarize the latest developments in bioengineering functional islet organoids in vitro and promoting vascularization of organoid grafts before and after transplantation. We highlight the crucial roles of the vasculature in ensuring long-term survival, maturation, and functionality of islet organoids. Additionally, we discuss key considerations that must be addressed before clinical translation of islet organoid-based therapy, including functional immaturity, undesired heterogeneity, and potential tumorigenic risks.

BK polyomavirus (BKV) infection is a common complication of kidney transplantation. While BKV has been described in non-kidney transplant recipients, data are limited regarding its epidemiology and outcomes in pancreas transplant recipients.

We conducted a retrospective cohort study of adults who underwent pancreas transplantation from 2010-2020. The primary outcome was BKV DNAemia. Secondary outcomes were estimated glomerular filtration rate (eGFR) reduction by 30%, eGFR < 30 mL/min/1.73 m2 , endstage kidney disease, and pancreas allograft failure. Cox regression with time-dependent variables was utilized.

Four hundred and sixty-six patients were analyzed, including 74, 46, and 346 with pancreas transplant alone (PTA), pancreas-after-kidney, or simultaneous pancreas-kidney transplants, respectively. PTA recipients experienced a lower incidence of BKV DNAemia (8.8% vs. 32.9%; p < .001) and shorter duration of DNAemia (median 28.0 vs. 84.5 days). No PTA recipients with BKV DNAemia underwent kidney biopsy or developed endstage kidney disease. Lymphopenia, non-PTA transplantation, and older age were associated with BKV DNAemia, which itself was associated with pancreas allograft failure (adjusted hazard ratio 2.14, 95% confidence interval 1.27-3.60; p = .004). Among PTA recipients, BKV DNAemia was not associated with eGFR reduction or eGFR < 30 mL/min/1.73 m2 .

BKV DNAemia was common among PTA recipients, though lower than a comparable group of pancreas-kidney recipients. However, BKV DNAemia was not associated with adverse native kidney outcomes and no PTA recipients developed endstage kidney disease. Conversely, BKV DNAemia was associated with pancreas allograft failure. Further studies are needed to estimate the rate of BKV nephropathy in this population, and further evaluate long-term kidney outcomes.

Donor-recipient (D/R) size mismatch has been evaluated for a number of organs but not for pancreas transplantation.

We retrospectively evaluated 438 patients who had undergone pancreas transplantation. The D/R body surface area (BSA) ratio was calculated, and the relationship between the ratio and graft prognosis was evaluated. We divided the patients into two groups and evaluated graft survival. The incidence of pancreas graft thrombosis resulting in graft failure within 14 days and 1-year graft survival were compared using Kaplan-Meier curves, and the prognostic factors associated with graft thrombosis were identified by univariate and multivariate analyses.

The mean/median donor and recipient BSAs were 1.63 m2 /1.65 m2 , and 1.57 m2 /1.55 m2 , respectively; the mean and median D/R BSAs were both 1.05. The receiver operating characteristic curve cutoff for the D/R BSA ratio was 1.09, and significant differences were identified between patients with ratios of ≥1.09 (high group) versus <1.09 (low group). The incidence of graft thrombosis resulting in pancreas graft failure within 14 days was significantly higher in the high group than in the low group (p < .01). One-year overall and death-censored pancreas graft survival were significantly higher in the low group than in the high group (p < .01). Multivariate analysis identified recipient height, donor BSA, and donor hemoglobin A1c as significant independent factors for graft thrombosis. Cubic spline curve analysis indicated an increased risk of graft thrombosis with increasing D/R BSA ratio.

D/R size mismatch is associated with graft thrombosis after pancreas transplantation.

Type 1 diabetes mellitus (T1DM) is one of the important causes of chronic kidney disease (CKD) and end-stage renal failure (ESRF). Even with the best available treatment options, management of T1DM poses significant challenges for cli nicians across the world, especially when associated with CKD and ESRF. Substantial increases in morbidity and mortality along with marked rise in treatment costs and marked reduction of quality of life are the usual consequences of onset of CKD and progression to ESRF in patients with T1DM. Simultaneous pancreas-kidney transplant (SPK) is an attractive and promising treatment option for patients with advanced CKD/ESRF and T1DM for potential cure of these diseases and possibly several complications. However, limited availability of the organs for transplantation, the need for long-term immunosuppression to prevent rejection, peri- and post-operative complications of SPK, lack of resources and the expertise for the procedure in many centers, and the cost implications related to the surgery and postoperative care of these patients are major issues faced by clinicians across the globe. This clinical update review compiles the latest evidence and current recommendations of SPK for patients with T1DM and advanced CKD/ESRF to enable clinicians to care for these diseases.

Transplantation has transformed into a burgeoning field that is rapidly evolving to optimize organ distribution and survival outcomes. The years since 2012 (the last comprehensive study) have seen changes in transplantation, such as advances in immunotherapy and novel indices, that necessitate an updated analysis of survival benefit.

Our goal was to determine the survival benefit for solid-organ transplants in the United Network for Organ Sharing (UNOS) database for a three decade period and provide updates on advancements since 2012. Our retrospective analysis examined data containing U.S. patient records from September 1, 1987, to September 1, 2021.

We found that 3,430,272 life-years were saved over our transplant period (4.33 life-years saved per patient); kidney-1,998,492 life-years; liver -767,414; heart-435,312; lung-116,625; pancreas-kidney-123,463; pancreas-30,575; intestine-7901. After matching, 3,296,851 life-years were saved. Life-years saved and median survival increased for all organs between 2012 and 2021. Compared to 2012, median survival increased in kidney (from 12.4 to 14.76 years), liver (from 11.6 to 14.59), heart (9.5 to 11.73), lung (5.2 to 5.63), pancreas-kidney (from 14.5 to 16.88), pancreas (from 13.3 to 16.10). When compared to 2012, the percent transplanted increased in kidney, liver, heart, lung, and intestine, while pancreas-kidney and pancreas show decreased percent transplanted.

Our study underscores the tremendous survival benefits of solid organ transplantation (over 3.4 million life-years saved) and shows improvements since 2012. Our study also highlights areas of transplantation, notably pancreas transplants, that may necessitate reinvigorated attention.

Pancreas transplants from expanded criteria donors are performed widely in Japan because there is a shortage of brain-dead donors. However, the effectiveness of this strategy is unknown. We retrospectively studied 371 pancreas transplants to evaluate the possibility of pancreas transplantation from expanded criteria donors by the Pancreas Donor Risk Index (PDRI). Patients were divided into five groups according to quintiles of PDRI values (Q1-Q5). The 1-year pancreas graft survival rates were 94.5% for Q1, 91.9% for Q2, 90.5% for Q3, 89.3% for Q4, and 79.6% for Q5, and were significantly lower with a lower PDRI (p = 0.04). A multivariate analysis showed that the PDRI, donor hemoglobin A1c values, and pancreas transplantation alone significantly predicted 1-year pancreas graft survival (all p < 0.05). Spline curve analysis showed that the PDRI was incrementally associated with an increased risk of 1-year graft failure. In the group with a PDRI ≥ 2.87, 8/56 patients had graft failures within 1 month, and all were due to graft thrombosis. The PDRI is a prognostic factor related to the 1-year graft survival rate. However, pancreas transplantation from high-PDRI donors shows acceptable results and could be an alternative when the donor pool is insufficient.

Cytomegalovirus (CMV) is one of the most frequent infections after pancreas transplantation (PTx), and it is unclear whether CMV infection is associated with pancreas graft loss. A limited number of studies about the relationship between CMV infection and pancreas graft loss have been reported from Western countries, but there have been no reports from Japan. This study investigated the relationship between CMV infection and pancreas graft loss after PTx in a single Japanese institution.

This study included 58 patients who underwent PTx from deceased donors from April 2000 to March 2021 in our institution. We assessed pancreas graft loss based on CMV infection and disease and investigated the causes of graft loss, the time of onset of CMV disease, and the time of graft loss for each case.

The numbers of patients in the 4 categories of donor (D) and recipient (R) pretransplant anti-CMV antibody status were as follows: 4 (6.9%) in the D-/R- group, 6 (10.3%) in the D-/R+ group, 34 (58.6%) in the D+/R+ group, and 14 (24.1%) in the D+/R- group. Of the 58 patients, 74.1% and 44.1% received diagnoses of CMV infection and disease after PTx, respectively. There were no significant differences in the survival rates of pancreas graft loss stratified by CMV infection (P = .1809) or disease (P = .6241).

This study suggests that CMV infection and disease had no significant influence on pancreas graft loss in this Japanese institution.

Pancreas transplantation offers patients with diabetes an opportunity for glucose homeostasis. Current blood tests to surveil for rejection have poor sensitivity and specificity for identifying rejection, and pancreas biopsies are challenging and associated with morbidity and graft loss. Donor-derived cell-free DNA (dd-cfDNA) is shed from transplanted organs and detectable in peripheral blood. Thus, a potential dd-cfDNA blood test assessing rejection would be clinically advantageous.

One hundred eighty-one dd-cfDNA samples (n) were collected from 77 patients (N) up to 132 mo posttransplant.

The median dd-cfDNA level among all subjects was 0.28% (0.13%, 0.71%). In simultaneous pancreas-kidney (SPK) transplant recipients, the median dd-cfDNA level was 0.29% (0.13%, 0.71%), and it was 0.23% (0.08%, 0.71%) in pancreas transplant alone (PTA) recipients. When isolating for when without infection or rejection, the median dd-cfDNA level was 0.28% (0.13%, 0.64%) for SPK and 0.20% (0.00%, 0.32%) for PTA. Both transplant types approached 1.0% ≤1 mo posttransplant followed by a decrease in median dd-cfDNA. During episodes of rejection or infection, median dd-cfDNA levels were greater among all transplant types.

The mean dd-cfDNA level for all pancreas transplant recipients is <1.0%, consistent with the published kidney transplant rejection threshold (>1.0%), regardless of SPK or PTA. Early posttransplant dd-cfDNA levels are transiently higher than later measurements. Dd-cfDNA elevation also correlates with rejection and infection and thus is a promising biomarker for surveilling pancreas transplant dysfunction.

Pancreas transplant alone (PTA) recipients are more affected by pancreas graft thrombosis, and graft loss compared to simultaneous pancreas-kidney (SPK) recipients. The pathophysiology is unknown, but an increased immune response has been suggested in the PTA recipients. In this observational study, we compared perioperative thromboinflammation between PTA (n=32) and SPK (n=35) recipients, and between PTA recipients with (n=14) versus without (n=18) early graft thrombosis.

We measured C-reactive protein (CRP), plasma markers of activated coagulation and complement, and cytokines preoperatively and daily during the first postoperative week.

Preoperatively, coagulation and complement activation markers were comparable between PTA and SPK recipients, while cytokine concentrations were higher in SPK recipients (TNF, IL-8, IP-10, MCP-1, MIP-1α; all p<0.05). On the first postoperative day, PTA recipients had higher coagulation activation, measured as thrombin-antithrombin complex (TAT), than SPK recipients (p=0.008). In the first postoperative week, PTA recipients showed higher relative cytokine release (IL-6, IL-8, G-CSF, IP-10, MCP-1, and MIP-1α; all p<0.05) while SPK recipients showed higher absolute cytokine concentrations (TNF, IL-1ra, IL-8, MIP-1α, and IL-4; all p<0.05). PTA and SPK recipients showed similar terminal complement complex (TCC, sC5b-9) activation. On the first postoperative day, TCC (OR 1.2 [95% CI 1.0-1.5] for 0.1 CAU/ml increase, p=0.02) and CRP (OR 1.2 [95% CI 1.0-1.3] for 10 mg/L increase, p=0.04) were associated with an increased risk of early graft thrombosis. TCC was specific for graft thrombosis, while CRP increased with several complications. PTA recipients with compared to those without graft thrombosis had higher TCC pre- (p=0.04) and postoperatively (p=0.03).

The relative increase in postoperative thromboinflammatory response was more pronounced in PTA recipients. Complement activation was associated with an increased risk of graft thrombosis. This study indicates that innate immune activation rather than elevated levels may affect early postoperative pancreas graft thrombosis.

https://clinicaltrials.gov/ct2/show/NCT01957696, identifier NCT01957696.

The pancreas is very susceptible to ischemia-reperfusion injury. Early graft losses due to pancreatitis and thrombosis represent a major issue after pancreas transplantation. Sterile inflammation during organ procurement (during brain death and ischemia-reperfusion) and after transplantation affects organ outcomes. Sterile inflammation of the pancreas linked to ischemia-reperfusion injury involves the activation of innate immune cell subsets such as macrophages and neutrophils, following tissue damage and release of damage-associated molecular patterns and pro-inflammatory cytokines. Macrophages and neutrophils favor tissue invasion by other immune cells, have deleterious effects or functions, and promote tissue fibrosis. However, some innate cell subsets may promote tissue repair. This outburst of sterile inflammation promotes adaptive immunity activation via antigen exposure and activation of antigen-presenting cells. Better controlling sterile inflammation during pancreas preservation and after transplantation is of utmost interest in order to decrease early allograft loss (in particular thrombosis) and increase long-term allograft survival. In this regard, perfusion techniques that are currently being implemented represent a promising tool to decrease global inflammation and modulate the immune response.

Well-selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney-pancreas transplantation often experience dramatic improvements in quality of life and long-term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well-validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter.

Steroid avoidance in kidney transplantation has been proven noninferior. Long-term outcome data on steroid avoidance in simultaneous pancreas-kidney (SPK) remains scant.

Utilizing the Scientific Registry of Transplant Recipients between 2000 and 2020, we studied all primary crossmatch negative SPK recipients (N = 5683) who received antithymocyte globulin induction and were discharged alive with functioning grafts on tacrolimus and mycophenolate ± steroid maintenance. Recipients were grouped according to steroid use into 2 groups: steroid maintenance (n = 4191) and steroid avoidance (n = 1492). Kaplan-Meier curves censored at 10 y were generated for recipient and allograft survival by steroid maintenance. Predictors for recipient and graft survival were examined using Cox Proportional Hazards. Models were adjusted for age, body mass index, ethnicity, diabetes type, human leukocyte-antigen mismatches, cold ischemia time, transplant era, preemptive transplantation, and pancreas donor risk index with the transplant center included as a random effect.

Steroid avoidance gained popularity over time, accounting for over one-fourth of the studied cohort. One-year acute rejection rates by steroid avoidance were comparable for kidney (8.6% versus 9%, P  = 0.783); however, the pancreas rejection rate was lower in the steroid avoidance group (7.9% versus 10%; P  = 0.035). After adjustment, steroid avoidance did not influence recipient survival (lower level of confidence interval, adjusted hazard ratio, upper level of confidence interval: 0.94, 1.15, 1.39), pancreas (0.75, 0.93, 1.16), or kidney (0.95, 1.18, 1.45) death-censored survival, compared with steroid maintenance.

Accounting for the recipient and graft characteristics, steroid avoidance is associated with similar recipient, pancreas, and kidney graft outcomes compared with steroid maintenance in SPK recipients after antithymocyte globulin induction with tacrolimus and mycophenolate maintenance.

Graft outcomes in pancreas transplantation have improved in recent decades, but data are mainly derived from registries or prospective single-centre studies. This large epidemiological study was undertaken to investigate the impact of clinical and demographic factors on graft and patient survival in pancreas transplant recipients in Spain, and to provide robust, country-wide, practice-based data to complement registry findings.

We conducted a retrospective, longitudinal, epidemiological study to assess risk factors impacting patient and graft survival in pancreas transplant recipients in eight centres in Spain. All patients transplanted between 1 January 2008 and 31 December 2012 were included; data were collected until 31 December 2015. The Kaplan-Meier method was used for all time-to-event analyses, including patient survival, graft survival, acute rejection, and BPAR. For graft survival analysis, in cases of death with functioning graft, patients were censored without any event on the date of death. For acute rejection and BPAR, patients were censored without any event on the date of death or graft loss. Univariable and multivariable analyses (Cox proportional hazards model) were conducted to assess the association between baseline clinical and demographic characteristics and patient/graft survival.

Data were included for 241 (80.1%) simultaneous pancreas-kidney transplants, 56 (18.6%) pancreas-after-kidney transplants and 4 (1.3%) pancreas transplants alone. Mean±standard deviation time from diagnosis until transplantation was 26.1±7.5 years. Nineteen patients died, mainly due to infections (n=10); the remaining 282 patients (93.7%) survived from transplantation until the end of the study. Among 55 patients (18.3%) with pancreas graft loss, the main reasons were vascular thrombosis (n=19), chronic rejection (n=10), acute rejection (n=6) and death with a functioning graft (n=5). The overall rate of vascular-related death was 1.3% at 5 years post transplant. Univariable analysis showed that patient age and weight, donor age, previous kidney transplantation, previous cardiovascular events and need for insulin more than 48h post transplantation were significantly associated with pancreas graft survival. Of these, in multivariable analyses pancreas graft survival was inferior in patients who had received a previous kidney transplant prior to pancreas transplantation (log-rank test, p=0.0002). Glucose metabolism, renal function and cardiovascular risk factors were generally stable following transplantation.

The results of this multicentre study highlight the excellent patient and graft outcomes following pancreas transplantation, with a notably low incidence of cardiovascular events.

We aimed to assess the effect of donor pancreas extraction time (ET) on postoperative complications and graft function after pancreas transplantation (PT). We analyzed all consecutive donor pancreas procurements for the simultaneous pancreas and kidney transplantation (SPK) and the associated PT in a Swiss transplant center over a 20-year period. Pancreas ET was defined as the time from cold flush to static storage of the pancreas on ice. The primary endpoint was the effect of extraction time on surgical complications. Secondary endpoints comprised the effect of ET on graft function (insulin-free survival) and graft pancreatitis. Of 115 procured pancreas grafts the median donor pancreas ET was 65 min (IQR: 48-78 min). In multivariable analysis, ET did not negatively affect major complications (OR 1.41 [95% CI: .59-3.36]; p = .438) and insulin-free survival (HR 1.42 [95% CI: .55-3.63]; p = .459). The median CIT was 522 (441-608) min. CIT was associated with major complications (OR 2.51 [95% CI: 1.11-5.68]; p = .027), but without impact on insulin-free survival (HR 1.94 [95% CI: .84-4.48]; p = .119). Patients with and without graft pancreatitis had no statistically significant differences in ET and CIT (p = .164 and p = .47, respectively). In multivariable analysis, Amylase levels > 270 U/L on postoperative day 1 were significantly associated with major complications (OR 3.61 [95% CI: 1.06-12.32]; p = .040). Our results suggest that although no effect of ET on complications and graft function after PT was found, shorter CIT and less graft pancreatitis can have a positive impact on surgical complications. Results could possibly be influenced by the exceptional quality of the pancreas donors, with short travel distances and preservation times in Switzerland.

In cases after pancreas transplantation (PTx), the pancreas graft might be lost for various reasons, including a pancreatoduodenal graft-related complication or patient death with a functioning graft. Although the causes seem to have distinct characteristics, the causes of pancreas graft loss have not been characterized. This study aimed to characterize the causes of pancreas graft loss by analyzing data from a Japanese nationwide registry. This study included 391 patients who received simultaneous pancreas-kidney transplantation among 461 patients with PTx during the study period in approved institutions in Japan. We characterized each cause in terms of the timing of the cause-specific graft loss and preoperative factors associated with graft loss based on nationwide data from a Japanese nationwide registry. Among the 391 cases, 113 lost the pancreas graft due to patient death with a functioning graft (DWFG; n = 34, 44.2%), graft thrombus (n = 22, 28.6%), or chronic rejection (CR; n = 7, 9.1%). Average (± standard deviation) time from PTx to graft loss due to DWFG, graft thrombus, and CR was 3.70 ± 4.36, 0.02 ± 0.01, and 2.37 ± 2.08 years, respectively. Duration of type 1 diabetes mellitus and donor body mass index were significantly associated with pancreas graft loss due to DWFG and graft thrombus, respectively. This characterization showed that the timing and preoperative factors associated with pancreas graft loss were significantly different for different causes of graft loss. These results may inform PTx follow-up protocols to ensure that appropriate care is based on the cause of graft loss.

Enteric drainage in pancreas transplantation is complicated by an enteric leak in 5%-8%, frequently necessitating pancreatectomy. Pancreatic salvage outcomes are not well studied. Risk factors for enteric leak were examined and outcomes of attempted graft salvage were compared to immediate pancreatectomy. Pancreas transplants performed between 1995 and 2018 were reviewed. Donor, recipient, and organ variables including demographics, donor type, ischemic time, kidney donor profile index, and pancreas donor risk index were analyzed. Among 1153 patients, 33 experienced enteric leaks (2.9%). Donors of allografts that developed leak were older (37.9y vs. 29.0y, p = .001), had higher KDPI (37% vs. 24%, p < .001), higher pancreas donor risk index (1.83 vs. 1.32, p < .001), and longer cold ischemic time (16.5 vs. 14.8 h, p = .03). Intra-abdominal abscess and higher blood loss decreased the chance of successful salvage. Enteric leak increased 6-month graft loss risk (HR 13.9[CI 8.5-22.9], p < .001). However, 50% (n = 12) of allografts undergoing attempted salvage survived long-term. After 6 months of pancreas graft survival, salvage and non-leak groups had similar 5-year graft survival (82.5% vs. 81.5%) and mortality (90.9% vs. 93.5%). Enteric leaks remain a challenging complication. Pancreatic allograft salvage can be attempted in suitable patients and accomplished in 50% of cases without significantly increased graft failure or mortality risk.

Pancreas transplantation in patients with type 2 diabetes (T2D) remains relatively uncommon compared with pancreas transplantation in patients with type 1 diabetes (T1D); however, several studies have suggested similar outcomes between T2D and T1D, and the practice has become increasingly common. Despite this growing interest in pancreas transplantation in T2D, no study has systematically summarized the data to date. We systematically reviewed the literature on pancreas transplantation in T2D patients including patient and graft survival, glycemic control outcomes, and comparisons with outcomes in T2D kidney transplant alone and T1D pancreas transplant recipients. We searched biomedical databases from January 1, 2000, to January 14, 2021, and screened 3314 records, of which 22 full texts and 17 published abstracts met inclusion criteria. Full-text studies were predominantly single center (73%), whereas the remaining most often studied the Organ Procurement and Transplantation Network database. Methodological quality was mixed with frequent concern for selection bias and concern for inconsistent definitions of both T2D and pancreas graft survival across studies. Overall, studies generally reported favorable patient survival, graft survival, and glycemic control outcomes for pancreas transplantation in T2D and expressed a need to better characterize the T2D patients who would benefit most from pancreas transplantation. We suggest guidance for future studies, with the aim of supporting the safe and evidence-based treatment of end-stage T2D and judicious use of scarce resources.

Pancreas transplantation is considered a high-risk surgery with cardiovascular complications. Early detection of all potential cardiovascular risk factors can decrease the perioperative risk and improve the pancreas recipients' outcome. The present study aims to evaluate the association between serum uric acid (UA) levels and the prevalence of coronary artery disease (CAD) in patients eligible for pancreas transplantation. We prospectively enrolled 63 consecutive patients with type 1 diabetes (T1D) who underwent cardiological evaluation before pancreas transplantation in our center. Participants underwent clinical evaluation, laboratory assays, and coronary angiography. The median concentration of UA in patients with CAD was significantly higher than in participants without CAD (6.43 (4.93-7.26) vs. 4.41 (3.64-5.49) mg/dL, p = 0.0002). We showed the positive correlation between UA concentration and systolic blood pressure, pulse pressure (PP) and triglycerides (r = 0.271, p = 0.032; r = 0.327, p = 0.009; r = 0.354, p = 0.004, respectively). In a multivariate analysis, the concentration of UA (OR 2.044; 95% CI: 1.261-3.311, p = 0.004) was independently associated with the prevalence of CAD in pancreas transplant candidates with T1D. We demonstrated that elevated UA levels were strongly associated with the high prevalence of CAD in pancreas transplant candidates with T1D. To stratify cardiovascular risk, the measurement of the UA concentration should be considered in all T1D patients qualified for pancreas transplantation.

Due to the high vulnerability of the pancreas to ischemia-reperfusion injury, choices regarding preservation solution markedly affect pancreas transplant success. A retrospective single-center analysis of 380 pancreas transplants (2000-2019) was performed to correlate current preservation solutions with transplant outcomes. Early graft failure requiring transplantectomy within 30 days post-transplant occurred in 7.5% for University of Wisconsin (UW) group (n = 267), 10.8% of Celsior (CS) group (n = 83), 28.5% of Histidine-Tryptophan-Ketoglutarate (HTK) group (n = 7), and none for Institut Georges Lopez-1 (IGL-1) group (n = 23). The most common causes of technical failures in this cohort included abdominal hemorrhage (8.4%); graft pancreatitis (3.7%); fluid collections (2.6%); intestinal complications (6.6%); and vascular thrombosis (20.5%). Although IGL-1 solution provided lower surgical complication rates, no significant differences were found between studied groups. Nevertheless, HTK solution was associated with elevated pancreatitis rates. The best graft survival was achieved at 1 year using UW and IGL-1, and at 3 and 5 years using IGL-1 (p = 0.017). There were no significant differences in patient survival after a median follow-up of 118.4 months. In this setting therefore, IGL-1 solution appears promising for perfusion and organ preservation in clinical pancreas transplantation, compared to other commonly used solutions.

Type 1 diabetes is a chronic autoimmune disease affecting nearly 35 million people. This disease develops as T-cells continually attack the β-cells of the islets of Langerhans in the pancreas, which leads to β-cell death, and steadily decreasing secretion of insulin. Lowered levels of insulin minimize the uptake of glucose into cells, thus putting the body in a hyperglycemic state. Despite significant progress in the understanding of the pathophysiology of this disease, there is a need for novel developments in the diagnostics and management of type 1 diabetes. Extracellular vesicles (EVs) are lipid-bound nanoparticles that contain diverse content from their cell of origin and can be used as a biomarker for both the onset of diabetes and transplantation rejection. Furthermore, vesicles can be loaded with therapeutic cargo and delivered in conjunction with a transplant to increase cell survival and long-term outcomes. Crucially, several studies have linked EVs and their cargos to the progression of type 1 diabetes. As a result, gaining a better understanding of EVs would help researchers better comprehend the utility of EVs in regulating and understanding type 1 diabetes. EVs are a composition of biologically active components such as nucleic acids, proteins, metabolites, and lipids that can be transported to particular cells/tissues through the blood system. Through their varied content, EVs can serve as a flexible aid in the diagnosis and management of type 1 diabetes. In this review, we provide an overview of existing knowledge about EVs. We also cover the role of EVs in the pathogenesis, detection, and treatment of type 1 diabetes and the function of EVs in pancreas and islet β-cell transplantation.

Since the mid 20th century, transplantation has been a fast-developing field of contemporary medicine. The technical aspects of transplant operations were developed in the 1950s, with little significant change for >50 y. Those techniques allowed completion of various organ transplants and successful patient outcomes, but they also carried the inherent disadvantages of open surgery, such as postoperative pain, wound complications and infections, and prolonged length of hospital stay. The introduction and adoption of minimally invasive surgical techniques in the early 1990s to various surgical specialties including general, gynecologic, and urologic surgery led to significant improvements in postoperative patient care and outcomes. Organ transplantation, with its precision demanding vascular anastomoses, initially had been considered infeasible to accomplish with conventional laparoscopic devices. The institution of robotic surgical technology in the late 1990s and its subsequent wide utilization in fields of surgery changed its accessibility and acceptance. With the steady camera, 3D views, and multidirectional wrist motions, surgical robotics opened new horizons for technically demanding surgeries such as transplantation to be completed in a minimally invasive fashion. Furthermore, the hope was this technique could find a niche to treat patients who otherwise are not deemed surgical candidates in many fields including transplantation. Here in, robotics in kidney transplantation and its ability to help provide equity through access to transplantation will be discussed.