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To compare pancreaticoduodenectomy (PD) and Total Pancreatectomy with Islet AutoTransplantation (TP-IAT) in patients at high risk of Post-Operative Pancreatic Fistula (POPF).Criteria to predict the risk of POPF occurrence after PD are available. However, even when a high risk of POPF is predicted, TP is not currently accepted as an alternative to PD, because of its severe consequences on glycaemic control. Combining IAT with TP may mitigate such consequences.Randomized, open-label, controlled, bicentric trial (NCT01346098). Candidates for PD at high-risk pancreatic anastomosis (i.e., soft pancreas and duct diameter ≤3 mm) were randomly assigned (1:1) to undergo either PD or TP-IAT. The primary endpoint was the incidence of complications within 90 days after surgery.Between 2010 and 2019, 61 patients were assigned to PD (n=31) or TP-IAT (n=30). In the intention-to-treat analysis, morbidity rate was 90·3% after PD and 60% after TPIAT (P=0·008). According to complications' severity, PD was associated with an increased risk of grade ≥2 [OR 7·64 (95% CI 1·35-43·3), P=0·022], while the OR for grade ≥3 complications was 2·82 [(95% CI 0·86-9·24), P=0·086]. After TP-IAT, the postoperative stay was shorter [median 10·5 vs. 16·0 days; P0·001). No differences were observed in disease-free survival, site of recurrence, disease-specific survival and overall survival. TP-IAT was associated with a higher risk of diabetes [HR 9·1 (95% CI 3·76-21·9); P0·0001], but most patients maintained good metabolic control and showed sustained C-peptide production over time.TP-IAT may become the standard treatment in candidates for PD, when a high risk of POPF is predicted.

Periodic surges of COVID-19 patients seeking care in the hospital environment overwhelm systems reduce the availability of resources for treatment of non-COVID-19 cases (Zheng et al. in J Hosp Infect 106:325-329, 2020). Hospital flow and resource management could be greatly enhanced by differentiating patients who are likely at risk of adverse clinical outcomes from those who could safely be discharged after evaluation and managed outside of the hospital setting (Sun et al. in J Infect Dis 223:38-46, 2021). Herein, we propose a prognostic score named PEGALUS (Predictivity of Elderly age, arterial blood Gas Analysis and Lung UltraSound) that could potentially help clinicians properly and rapidly choose the appropriate allocation of COVID-19 patients admitted to the emergency department (ED).This observational prospective study enrolled COVID-19 patients who were admitted to the ED of IRCCS San Raffaele Hospital (HSR).230 COVID-19 patients were enrolled and 30-day follow-up data was collected. Composite outcome was death or need for oro-tracheal intubation (OTI). 50 patients (21.5%) reached the outcome during the observational period. In multivariate Cox analysis, age, POPEGALUS score performed at the admission can predict adverse outcomes in patients with COVID-19. The systematic application of this score might permit a more accurate and rapid treatment allocation in this setting.

Islet autotransplantation is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplantation for neoplasm located in the pancreatic neck or proximal body. Overall, disease-free and diabetes-free survivals were estimated and compared with those observed in 68 non diabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplantation. Median follow-up was 4 years. We observed no deaths and a low morbidity (non-serious procedure-related complications in 2 out of 25 patients). Patient and insulin independent survival at 4 years was 100% and 96%, respectively. Glucose homeostasis remained within non-diabetic range at all times for 19 out of 25 patients (73%). Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplantation had a longer diabetes-free survival than patients without islet autotransplantation (p=0.04). In conclusion, islet autotransplantation after extended pancreatic resection for neoplasm is a safe and successful procedure for preventing diabetes. This article is protected by copyright. All rights reserved. Islet autotransplant is particularly attractive to prevent diabetes after extended pancreatectomy for benign or borderline/malignant pancreas disease. Between 2008 and 2018, 25 patients underwent left extended pancreatectomy (>60%) and islet autotransplant for a neoplasm located in the pancreatic neck or proximal body. Overall, disease-free and diabetes-free survivals were estimated and compared with those observed in 68 nondiabetic patients who underwent distal pancreatectomy for pancreatic neoplasms without islet autotransplant. Median follow-up was 4years. We observed no deaths and a low morbidity (nonserious procedure-related complications in 2 of 25 patients). Patient and insulin-independent survival rates at 4years were 100% and 96%, respectively. Glucose homeostasis remained within a nondiabetic range at all times for 19 (73%) of 25 patients. Preoperative glycemic level and insulin resistance were major predictors of diabetes development in these patients. Patients undergoing islet autotransplant had a longer diabetes-free survival than did patients without islet autotransplant (P=.04). In conclusion, islet autotransplant after extended pancreatic resection for neoplasms is a safe and successful procedure for preventing diabetes.

Pancreatic surgery still remains burdened by high levels of morbidity and mortality with a relevant incidence of complications, even in high volume centers. This review highlights the interventional radiological management of complications after pancreatic surgery. The current literature regarding the percutaneous drainage of fluid collections due to pancreatic fistulas, percutaneous transhepatic biliary drainage due to biliary leaks and transcatheter embolization (or stent–graft) due to arterial bleeding is analyzed. Moreover, also, percutaneous intra-portal islet auto-transplantation for the prevention of pancreatogenic diabetes in case of extended pancreatic resection is also examined. Moreover, a topic not usually treated in other similar reviewsas percutaneous intra-portal islet auto-transplantation for the prevention of pancreatogenic diabetes in case of extended pancreatic resection is also one of our areas of focus. In islet auto-transplantation, the patient is simultaneously donor and recipient. Differently from islet allo-transplantation, it does not require immunosuppression, has no risk of rejection and is usually efficient with a small number of transplanted islets.

Funder: Fondazione Pisa, Pisa, Italy; Id: http://dx.doi.org/10.13039/100007368, Funder: Tuscany Region, Italy; Id: http://dx.doi.org/10.13039/501100009888, Funder: Pisa University Hospital, Pisa, Italy, Funder: University of Pisa, Pisa, Italy; Id: http://dx.doi.org/10.13039/501100007514, 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.

The immunosuppressive drug rapamycin may influence insulin sensitivity in insulin-responsive tissues. This study aimed at evaluating the effectiveness of rapamycin pre-treatment before pancreatic islet allotransplantation (ITx) in patients with type 1 diabetes mellitus (T1DM). Forty-one T1DM patients were studied. Thirteen patients with poor glycemic control underwent a short-term rapamycin treatment before ITx (Group 1), and they were compared to 28 patients undergoing ITx without rapamycin pre-treatment (Group 2). Outcomes were daily insulin requirement (DIR), fasting blood glucose, HbA1c, C-peptide and the SUITO index of beta-cell function. A subgroup of patients pre-treated with rapamycin before ITx underwent euglycemic hyperinsulinemic clamp with [6,6-2H2] glucose before and after ITx to evaluate insulin sensitivity. We found a significant reduction in DIR after rapamycin pre-treatment (− 8 ± 6 U/day, mean ± SD, p

Background: Pancreas transplants (PTx) from pediatric donors (PDs, age Methods: We retrospectively analyzed perioperative surgical complications and graft survival in T1D recipients of PTA or pancreas after kidney (PAK) transplant from PDs or adult donors (ADs) between Jan 2010 and May 2018. Data were collected through electronic medical record review. Results: A total of 43 PTx recipients (35 PTA) had data available for analyses. Age at PTx was 40.0±8.3 years, T1D duration 25±10 years, 46.5% female, BMI 23±3 k/m2. Nearly half (49%) pancreas grafts were from PDs. Median donor age was 18 [IQR: 16] years (min. 2, max 45 years). Donor characteristics (age, BMI, body surface area [BSA]) significantly differed between groups (all p Conclusions: PTx from PDs tended to be associated with less surgical complications vs. PTx from ADs. Graft survival was similar. Expanding selection criteria to include PDs would increase the availability of pancreas grafts and possibly improve clinical outcomes. Disclosure C. Conte: None. C. Socci: None. A. Secchi: None. P. Maffi: None.

Purpose of review: In patients with type 1 diabetes with extreme glycemic variability, the restoration of pancreas endocrine function is potentially and completely achieved with islets of Langerhans (tissue derived from whole organ) or pancreas (whole organ) transplantation. The aim of our review is to report on the latest studies and to highlight the benefits and risks of the two procedures, providing clearer, more selective, evidence-based clinical indications that also consider the impact on the degenerative complications of diabetes as a potential benefit. Recent findings: Clinical experience in this field has been dynamic over the last three decades, and has been characterized by the development of more standardized protocols and a clearer definition of clinical outcome. On the contrary, the recommendations thus far are not well delineated and tend to overlap, and the past ADA position statement for pancreas transplant alone has also been applied to islet transplant alone, without differentiation. Summary: Both outcome-driven and non-outcome-driven criteria are considered in the conclusions, in an attempt to streamline indications for islet-alone or pancreas-alone transplantation.

Curing type 1 diabetes means replacing the lost insulin secretion with a perpetual, autonomous, and self-regulating source of insulin delivery able to correct all the metabolic abnormalities and prevent the long-term chronic complications of the disease. In Milan, substantial experience in islet transplantation and beta-cell replacement has been gained and maintained during the last three decades, thereby achieving a leading position in the production of human islets for transplantation and its establishment as one of the most experienced centers in the world with more than 370 islet infusions performed and high-level scientific production. During this long period the field of islet transplantation has evolved significantly from the breakthrough of the first cases in early 1990s, since significant advances in islet isolation and engraftment, together with improved immunosuppressive strategies, have been reported. A major effort is now being focused on a special multidisciplinary and integrated project aiming at bringing islet transplantation and beta-cell replacement to the level of a successful clinical routine procedure.

Problematic hypoglycemia, defined as two or more episodes per year of severe hypoglycemia or as one episode associated with impaired awareness of hypoglycemia, extreme glycemic lability, or major fear and maladaptive behavior, is a challenge, especially for patients with long-standing type 1 diabetes. Individualized therapy for such patients should include a composite target: optimal glucose control without problematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithm based on evidence of efficacy given the limitations of educational, technological, and transplant interventions. All patients with problematic hypoglycemia should undergo structured or hypoglycemia-specific education programs (stage 1). Glycemic and hypoglycemia treatment targets should be individualized and reassessed every 3–6 months. If targets are not met, one diabetes technology—continuous subcutaneous insulin infusion or continuous glucose monitoring—should be added (stage 2). For patients with continued problematic hypoglycemia despite education (stage 1) and one diabetes technology (stage 2), sensor-augmented insulin pumps preferably with an automated low-glucose suspend feature and/or very frequent contact with a specialized hypoglycemia service can reduce hypoglycemia (stage 3). For patients whose problematic hypoglycemia persists, islet or pancreas transplant should be considered (stage 4). This algorithm provides an evidence-informed approach to resolving problematic hypoglycemia; it should be used as a guide, with individual patient circumstances directing suitability and acceptability to ensure the prudent use of technology and scarce transplant resources. Standardized reporting of hypoglycemia outcomes and inclusion of patients with problematic hypoglycemia in studies of new interventions may help to guide future therapeutic strategies.

Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation.We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n = 4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n = 6) or BM (n = 3) to evaluate islet transplant function and survival.We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity.Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.

In recent times, the global prevalence of diabetes has increased substantially, reaching 8.3% in 2014, which corresponds to 387 million patients. Studies in Europe and USA have shown increased incidence of type 1 Diabetes (T1D) over time at a rate of 3-5% per year. Another most worrying feature of the rapid increase of diabetes is the emergence of type 2 Diabetes (T2D) in children, adolescents, and young adults. The well-known behavioral risks factors and epigenetic mechanisms recently observed require an integrated approach to prevent T2D. Diabetes significantly influences the patient' survival, quality of life, and development of organ system degeneration. Epidemiological studies have shown increased mortality in diabetic patients, especially women, which increased approximately fivefold, whereas cardiovascular mortality increased 20- to 30-fold when compared to the normal population. Diabetes is the leading cause of end-stage renal disease and vision loss in developed countries. Around 40% of T1D and T2D start on renal replacement therapy. While after 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1 and 50.2%, respectively. However, the most prevalent chronic complication of diabetes is neuropathy. Distal Symmetric Polyneuropathy occurs in at least 20% of people with T1D after 20 years and in 10-15% of newly diagnosed T2D, increasing to 50% after 10 years. Cardiovascular Autonomic Neuropathy may be present in up to 60% of patients after 15 years and is an independent risk factor for cardiovascular mortality.

BACKGROUND: To assess feasibility, safety, and metabolic outcome of islet auto transplantation (IAT) in patients undergoing completion pancreatectomy because of sepsis or bleeding after pancreatic surgery. METHODS: From November 2008 to October 2016, approximately 22 patients were candidates to salvage IAT during emergency relaparotomy because of postpancreatectomy sepsis (n = 11) or bleeding (n = 11). Feasibility, efficacy, and safety of salvage IAT were compared with those documented in a cohort of 36 patients who were candidate to simultaneous IAT during nonemergency preemptive completion pancreatectomy through the pancreaticoduodenectomy. RESULTS: The percentage of candidates that received the infusion of islets was significantly lower in salvage IAT than simultaneous IAT (59.1% vs 88.9%, P = 0.008), mainly because of a higher rate of inadequate islet preparations. Even if microbial contamination of islet preparation was significantly higher in candidates to salvage IAT than in those to simultaneous IAT(78.9% vs 20%, P < 0.001), there was no evidence of a higher rate of complications related to the procedure. Median follow-up was 5.45 ± 0.52 years. Four (36%) of 11 patients reached insulin independence, 6 patients (56%) had partial graft function, and 1 patient (9%) had primary graft nonfunction. At the last follow-up visit, median fasting C-peptide was 0.43 (0.19-0.93) ng/mL; median insulin requirement was 0.38 (0.04-0.5) U/kg per day, and median HbA1c was 6.6% (5.9%-8.1%). Overall mortality, in-hospital mortality, metabolic outcome, graft survival, and insulin-free survival after salvage IAT were not different from those documented after simultaneous IAT. CONCLUSIONS: Our data demonstrate the feasibility, efficacy, and safety of salvage IAT after relaparotomy.

Type 1 diabetes mellitus (T1D) is an autoimmune disease that compromises b cell function [1]. Whenever possible, islet transplantation (IT) becomes necessary in order to restore the endocrine function and to achieve exogenous insulin independence [2, 3]. In people with T1D, after islet transplantation, the quality of life has been shown to be improved along with a better glycemic control [1–3]. However, several conditions may lead to graft dysfunction and the need for re-introduction of exogenous insulin arises. Physical activity can be a therapeutic tool for increasing insulin sensitivity and improving glycemic control [4, 5]. Studies regarding the immunomodulatory effect of exercise are needed but it seems that exercise helps to alleviate the side effects of immunosuppression like the progression of insulin resistance, without worsening the autoimmune reaction [6, 7]. This report is a longitudinal study covering 7 years (2005–2011) after islet transplantation in a patient that became, alternating rest and training periods, a halfmarathon runner. We document how exercise training may be relevant not only for the physical performance per se but also for preventing symptoms of graft dysfunction.

High levels of donor-derived high-mobility group box 1 (HMGB1) protein have been associated with poor islet graft outcome in mouse models. The aim of our work was to determine whether HMGB1 released by human islets had independent proinflammatory effects that influence engraftment in humans. Human islet preparations contained and released HMGB1 in different amounts, as determined by Western blot and ELISA (median 17 pg/ml/IEQ/24 h; min–max 0–211, n = 74). HMGB1 release directly correlated with brain death, donor hyperamilasemia, and factors related to the pancreas digestion procedure (collagenase and digestion time). HMGB1 release was significantly positively associated with the release of other cytokines/chemokines, particularly with the highly released “proinflammatory” CXCL8/IL-8, CXCL1/GRO-α, and the IFN-γ-inducible chemokines CXCL10/IP-10 and CXCL9/MIG. HMGB1 release was not modulated by Toll-like receptor 2, 3, 4, 5, and 9 agonists or by exposure to IL-1β. When evaluated after islet transplantation, pretransplant HMGB1 release was weakly associated with the activation of the coagulation cascade (evaluated as serum cross-linked fibrin products), but not with the immediate posttransplant inflammatory response. Concordantly, HMGB1 did not affect short-term human islet function. Our data show that human islet HMGB1 release is a sign of “damaged” islets, although without any independent direct role in graft failure.

Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific alloantibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.

The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function.

In recent times, the global prevalence of diabetes has increased substantially, reaching 8.3% in 2014, which corresponds to 387 million patients. Studies in Europe and USA have shown increased incidence of type 1 Diabetes (T1D) over time at a rate of 3-5% per year. Another most worrying feature of the rapid increase of diabetes is the emergence of type 2 Diabetes (T2D) in children, adolescents, and young adults. The well-known behavioral risks factors and epigenetic mechanisms recently observed require an integrated approach to prevent T2D. Diabetes significantly influences the patient' survival, quality of life, and development of organ system degeneration. Epidemiological studies have shown increased mortality in diabetic patients, especially women, which increased approximately fivefold, whereas cardiovascular mortality increased 20- to 30-fold when compared to the normal population. Diabetes is the leading cause of end-stage renal disease and vision loss in developed countries. Around 40% of T1D and T2D start on renal replacement therapy. While after 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1 and 50.2%, respectively. However, the most prevalent chronic complication of diabetes is neuropathy. Distal Symmetric Polyneuropathy occurs in at least 20% of people with T1D after 20 years and in 10-15% of newly diagnosed T2D, increasing to 50% after 10 years. Cardiovascular Autonomic Neuropathy may be present in up to 60% of patients after 15 years and is an independent risk factor for cardiovascular mortality.

Objectives- Circulating angiogenic cells (CACs) are vascular-committed bone-marrow derived cells expressing endothelial and stem cell markers that are dysfunctional in type 1 diabetes (T1D). We studied if restoration of endogenous beta cells function with islet transplantation is associated with better CACs function. Research design and methods- 18 T1D patients, 14 insulin independent islet-transplanted patients (ITA) and 14 healthy controls (C) were studied cross-sectionally. In vivo (CACs percentage/apoptosis and migratory/differentiation assay) and in vitro studies [colony forming unit endothelial cells (CFU-ECs) counting, CACs percentage/apoptosis, cytokine production and migratory/differentiation assay] were performed, together with endothelial dependent dilatation (EDD) test in vivo. The addition of serial concentrations IL-8 and anti-IL8 in vitro cultures was performed to assess IL-8 mediated cell survival/apoptosis. Results- The percentage of alive and apoptotic CACs did not differ among the 3 groups. CFU-ECs absolute number obtained from T1D, but not from ITA, was reduced compared to C (C=7.3±1.9, T1D=0.9±0.4 and ITA=4.7±1.9; p

Aims/hypothesis: Type 1 diabetes is considered non-reversible at end-stage disease when there is no measurable insulin production. However, there are indications that insulin-producing beta cells could be present or return if autoimmunity could be controlled. We therefore sought to determine whether immunosuppression therapy can reinstate beta cell function in patients with long-term type 1 diabetes. Methods: We examined pancreatic beta cell function in 22 patients with long-term type 1 diabetes (median disease duration 27 years), who had been receiving rapamycin monotherapy (0.1 mg/kg; target trough levels 8-10 ng/ml; 26-314 days) as pre-conditioning for islet transplantation. As control, beta cell function was measured in 14 patients (median disease duration 17 years) who were waiting for an islet transplant without rapamycin pre-conditioning. Results: Fasting C-peptide increased from 0.076 nmol/l (C-peptide responders). Exogenous insulin requirement decreased from 0.64 U/kg daily (IQR 0.56-0.72) to 0.57 U/kg (IQR 0.45-0.70; p = 0.01), but this reduction was significant only in the 12C-peptide-responsive patients. Rapamycin monotherapy was also associated with a decrease in insulin antibody titre (median decrease 110 to 35.9 U/ml; p < 0.001) and fasting serum proinsulin (median decrease 0.51 to 0.28 pmol/l; p = 0.001). All variables remained unchanged in the 14 control patients. Conclusions/interpretation: Therapies to reinstate beta cell function may be applicable to patients with long-term C-peptide-negative type 1 diabetes. Trial registration: ClinicalTrial.gov NCT01060605 Funding: This study was funded by Telethon Italy and the Juvenile Diabetes Research Foundation (JT01Y01 and grant no. 6-2006-1098) and the European Union (DIAPREPP Project, FP7-HEALTH-202013). E. Bonifacio is funded by the Deutsche Forschungsgemeinschaft (FZ111). © 2010 Springer-Verlag

Diabet. Med. 27, 960–964 (2010) Abstract Aims Few longitudinal imaging studies of liver-engrafted islets after islet transplantation are available for islet-transplant-alone (ITA) and islet-after-kidney (IAK) transplanted patients. Particularly controversial is the link between islet function and the appearance of islet-induced liver focal fatty changes. Aims of this study were to assess liver focal fatty changes at ultrasound after islet transplantation and their relationship with islet function. Methods The timing of first ultrasound detection of liver focal fatty changes and the prevalence and duration of these changes were assessed in 30 IAK transplanted patients, in five ITA patients and, retrospectively, in full-, partial- and no-function groups, according to islet function evaluated 1 year after transplantation. Patients with persistent ultrasound detected liver focal fatty changes underwent liver biopsy. Ultrasound positive and negative patients with functioning islets were compared for islet-function and C-peptide-levels during the follow-up. Variations of cholesterol/triglycerides and other metabolic parameters were also recorded at 1 year. Results Liver focal fatty changes at ultrasound were found in 12 patients (10/30 IAK, 2/5 ITA). First detection was at 6 months in eight cases and at 12 months in four cases. Liver ultrasound changes were of more than 1 year duration in eight cases. Steatosis was found histologically in 8/8 patients. At 12 months, liver ultrasound changes were detected to a greater extent in patients with partial islet function (10/12, eight IAK, two ITA) compared with patients with full islet function. C-peptide-levels were significantly lower in ultrasound-positive than in ultrasound-negative patients. At 18 months, ultrasound- positive patients were more prone to worsening of their function (9/12) compared with ultrasound-negative patients (3/18). No statistically significant differences of cholesterol/triglycerides levels were found in either the total number of patients or the IAK and ITA patients. Conclusions Liver focal fatty changes at ultrasound (steatosis) after islet transplantation in IAK and ITA patients may represent an early sign of altered graft function.

OBJECTIVE-Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4(+)CD25(+)FOXP3(+) T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs. RESEARCH DESIGN AND METHODS-nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation. RESULTS-We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4(+) CD25(-) effector T-cells compared with that before treatment. CONCLUSIONS-These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function. OBJECTIVE—Rapamycin is an immunosuppressive drug currently used to prevent graft rejection in humans, which is considered permissive for tolerance induction. Rapamycin allows expansion of both murine and human naturally occurring CD4CD25FOXP3 T regulatory cells (nTregs), which are pivotal for the induction and maintenance of peripheral tolerance. Preclinical murine models have shown that rapamycin enhances nTreg proliferation and regulatory function also in vivo. Objective of this study was to assess whether rapamycin has in vivo effects on human nTregs. RESEARCH DESIGN AND METHODS—nTreg numbers and function were examined in a unique set of patients with type 1 diabetes who underwent rapamycin monotherapy before islet transplantation. RESULTS—We found that rapamycin monotherapy did not alter the frequency and functional features, namely proliferation and cytokine production, of circulating nTregs. However, nTregs isolated from type 1 diabetic patients under rapamycin treatment had an increased capability to suppress proliferation of CD4 CD25 effector T-cells compared with that before treatment. CONCLUSIONS—These findings demonstrate that rapamycin directly affects human nTreg function in vivo, which consists of refitting their suppressive activity, whereas it does not directly change effector T-cell function. Diabetes 57:2341–2347, 2008

OBJECTIVE—The β-score is a highly regarded approach to the assessment of transplant functionality. Our aim was to develop an index of β-cell function that hinges on the pillars of the β-score (daily insulin requirement and A1C), has a straightforward physiological interpretation, and does not require the execution of an insulin stimulation test. RESEARCH DESIGN AND METHODS—The new index is denoted transplant estimated function (TEF) and is obtained from the daily insulin requirement and A1C. TEF estimates the amount of insulin secreted daily and can be normalized to the number of transplanted islets, thus permitting evaluation of the cost-effectiveness of the transplant. TEF was compared with the area under the curve of C-peptide [AUC(C-pep)] concentration over 24 h, as well as the acute insulin response to intravenous glucose (AIRglu) and to arginine (AIRarg). The association between TEF and β-score was also investigated. RESULTS—The correlation of TEF with 24-h AUC(C-pep) was r = 0.73 (P < 0.005), whereas that for β-score versus 24-h AUC(C-pep) was r = 0.33 (NS). The correlation of TEF with AIRglu was r = 0.59 (P < 0.001) and close to that for β-score versus AIRglu (r = 0.65, P < 0.001). The correlation of TEF with AIRarg was r = 0.33 (P < 0.005) and was similar to that for β-score versus AIRarg (r = 0.34, P < 0.005). TEF and β-score were correlated well (r = 0.69, P < 0.0001) and showed similar time profiles. CONCLUSIONS—TEF estimates daily insulin secretion, it is simpler than the β-score, and its performance against reference indexes of β-cell secretion is in line with that exhibited by β-score. TEF can be normalized to the number of transplanted islets and thereby provides a benchmarking tool to evaluate the cost-effectiveness of the transplant.

OBJECTIVE: Islet allotransplantation is a less invasive alternative to surgical pancreas transplantation for Type 1 diabetes, while percutaneous intraportal islet autotransplantation (PIPIAT) is usually performed after pancreatic surgery to prevent diabetes. Our aim was to assess the feasibility, radiological aspects, complications and clinical outcome of PIPIAT following pancreatic surgery for not only chronic pancreatitis but also benign and malignant nodules. METHODS: From 2008 to 2012, 41 patients were enrolled for PIPIAT 12-48 h after pancreatic surgery (extended pancreatic surgery for chronic pancreatitis and benign/malignant neoplasms). PIPIAT was performed using a combined ultrasonography and fluoroscopy-guided technique (4-F catheter). PIPIAT feasibility, median follow-up and metabolic (insulin independence rate, graft function based on C-peptide levels) and oncologic outcomes were recorded. RESULTS: PIPIAT was not performed in 7/41 patients (4 cases for an inadequate islet mass, 2 cases for haemodynamic instability and 1 case for islet culture contamination), while it was successfully performed in 34/34 patients. Procedure-related major complications occurred in four patients: two bleedings requiring transfusions, one patient with left portal vein thrombosis and one patient with sepsis. Median follow-up duration was 546 days. Insulin independence was achieved in 15/34 (44%) patients, partial graft function in 16/34 (47%) patients and no function in 3/34 (9%) patients. None of the 17 patients with malignant nodules developed liver metastases during follow-up. CONCLUSION: PIPIAT, performed under ultrasound and fluoroscopy combined guidance and not requiring immunosuppression, is feasible, with a relatively low complication rate and a better metabolic outcome than allotransplantation. ADVANCES IN KNOWLEDGE: PIPIAT can prevent pancreatogenic diabetes. Ultrasound is a useful tool for the guidance and monitoring of PIPIAT.

OBJECTIVE—The purpose of this study was to evaluate whether islet transplantation may stabilize polyneuropathy in uremic type 1 diabetic patients (end-stage renal disease [ESRD] and type 1 diabetes), who received a successful islet-after-kidney transplantation (KI-s). RESEARCH DESIGN AND METHODS—Eighteen KI-s patients underwent electroneurographic tests of sural, peroneal, ulnar, and median nerves: the nerve conduction velocity (NCV) index and amplitudes of both sensory action potentials (SAPs) and compound motor action potentials (CMAPs) were analyzed longitudinally at 2, 4, and 6 years after islet transplantation. Skin content of advanced glycation end products (AGEs) and expression of their specific receptors (RAGE) were also studied at the 4-year follow-up. Nine patients with ESRD and type 1 diabetes who received kidney transplantation alone (KD) served as control subjects. RESULTS—The NCV score improved in the KI-s group up to the 4-year time point (P = 0.01 versus baseline) and stabilized 2 years later, whereas the same parameter did not change significantly in the KD group throughout the follow-up period or when a cross-sectional analysis between groups was performed. Either SAP or CMAP amplitudes recovered in the KI-s group, whereas they continued worsening in KD control subjects. AGE and RAGE levels in perineurium and vasa nervorum of skin biopsies were lower in the KI-s than in the KD group (P < 0.01 for RAGE). CONCLUSIONS—Islet transplantation seems to prevent long-term worsening of polyneuropathy in patients with ESRD and type 1 diabetes who receive islets after kidney transplantation. No statistical differences between the two groups were evident on cross-sectional analysis. A reduction in AGE/RAGE expression in the peripheral nervous system was shown in patients receiving islet transplantation.

OBJECTIVE—Islet transplantation alone is an alternative for the replacement of pancreatic endocrine function in patients with type 1 diabetes. The aim of our study was to assess the impact of the Edmonton immunosuppressive protocol (tacrolimus-sirolimus association) on kidney function. RESEARCH DESIGN AND METHODS—Nineteen patients with type 1 diabetes and metabolic instability received islet transplantation alone and immunosuppressive therapy according to the Edmonton protocol. Serum creatinine (sCr), creatinine clearance (CrCl), and 24-h urinary protein excretion (UPE) were assessed at baseline and during a follow-up of 339 patient-months. RESULTS— After islet transplantation we observed 1) sCr within the normal range in all but two patients in whom sCr increased immediately after islet transplantation, and despite withdrawal of immunosuppression, patients progressed to end-stage renal disease (ESRD); 2) CrCl remained within the normal range for those patients who had normal baseline values and decreased, progressing to ESRD in two patients with a decreased baseline CrCl; and 3) 24-h UPE worsened (>300 mg/24 h) in four patients. In the two patients who progressed to ESRD, the worsening of 24-h UPE occurred immediately after islet transplantation. In one patient 24-h UPE worsening occurred at 18 months, and, after withdrawal of immunosuppression, it returned to the normal range. In another patient 24-h UPE increased at 24 months and remained stable while immunosuppression was continued. CONCLUSIONS—In type 1 diabetic patients receiving islet transplantation alone, the association of tacrolimus and sirolimus should be used only in patients with normal kidney function. Alternative options for immunosuppressive treatment should be considered for patients with even a mild decrease of kidney function.

OBJECTIVE—Diabetes, hypertension, dyslipidemia, obesity, nephrotoxicity of certain immunosuppressive drugs, and the persistence of a chronic alloimmune response may significantly affect graft survival in end-stage renal disease (ESRD) type 1 diabetic patients who have undergone kidney transplant. The aim of this study was to ascertain the impact of kidney alone (KD) or combined kidney-pancreas (KP) transplantation on renal energy metabolism. RESEARCH DESIGN AND METHODS—We assessed high-energy phosphates (HEPs) metabolism by using, in a cross-sectional fashion, 31P-magnetic resonance spectroscopy in the graft of ESRD type 1 diabetic transplanted patients who received KD (n = 20) or KP (n = 20) transplant long before the appearance of overt chronic allograft nephropathy (CAN). Ten nondiabetic microalbuminuric kidney transplanted patients and 10 nondiabetic kidney transplanted patients with overt CAN were chosen as controls subjects. RESULTS—Simultaneous KP transplantation patients showed a higher β-ATP/inorganic phosphorus (Pi) ratio (marker of the graft energy status) versus the other groups, and a positive correlation between β-ATP/Pi phosphorus ratio and A1C was found. In the analysis limited to the subgroup of normoalbuminuric patients, the difference in β-ATP/Pi was still detectable in KP patients compared with KD transplantation. CONCLUSIONS—KP transplantation was associated with better HEPs than in KD transplantation, suggesting that restoration of β-cell function positively affects kidney graft metabolism.

Introduction The gap between the number of diabetic patients on the waiting list for transplantation and the number of pancreas donors is growing and it is mandatory to extend criteria for donor eligibility. Several reports showed the feasibility of pancreas transplantation from pediatric donors with comparable outcomes to adult donors in terms of long-term β-cell function. However, there is no consensus about donor age and weight limits. Case Report We present two cases of pancreas transplantation alone (PTA) from very small pediatric donors: a 2-year-old female (weight 13 kg, height 88 cm) and a 6-year-old male (weight 29 kg, height 122 cm). We used a novel “cephalic placement” technique. The pancreas was placed upon the aortic carrefour with cephalic pole upward with 3 anchorage points: the left common iliac vein (or the inferior cava vein), the right common iliac artery, and an ileal loop. Results No postoperative thrombosis occurred and the patients gained insulin independence instantaneously. CT scan performed on postoperative day 3 showed regular organ perfusion in both cases. Graft volume and surface calculated by CT reconstruction were, respectively, 25 cc and 89 cm 2 in the first case, and 46.5 cc and 123 cm 2 in the second case. Postoperative mixed meal tolerance tests showed normal glycemic profile. Patients are actually insulin independent at 4 years and 8 months. Conclusions Pancreases from very young pediatric donors are adequate to restore insulin independence after PTA in adult patients. The “cephalic placement” technique is feasible and effective using very small pancreases.

A portion of transplanted islets is lost during engraftment as a result of stressful events, involving hypoxia and production of proinflammatory molecules by islets. Two of these molecules (monocyte chemoattractant protein-1, CCL2/MCP-1 and tissue factor, TF) are directly correlated with reduced graft function. We evaluated which factors reduce islet proinflammatory conditions. In particular the effects of different culture media supplemented with proteins or antioxidant agents on CCL2/MCP-1 and TF human islet release were evaluated. We observed that human islets after culture in final wash culture medium (FW) significantly decreased CCL2/MCP-1 release and TF production compared with CMRL and M199. These effects were independent from the type of protein added to the media (human serum, human albumin, fetal calf serum). Glutathione in FW further decreased CCL2/MCP-1 in a dose-dependent manner. Culture conditions can modulate the proinflammatory state of islets, and could be used in clinical islet transplantation to reduce inflammation during engraftment. A portion of transplanted islets is lost during engraftment as a result of stressful events, involving hypoxia and production of proinflammatory molecules by islets. Two of these molecules (monocyte chemoattractant protein-1, CCL2/MCP-1 and tissue factor, TF) are directly correlated with reduced graft function. We evaluated which factors reduce islet proinflammatory conditions. In particular the effects of different culture media supplemented with proteins or antioxidant agents on CCL2/MCP-1 and TF human islet release were evaluated. We observed that human islets after culture in final wash culture medium (FW) significantly decreased CCL2/MCP-1 release and TF production compared with CMRL and M199. These effects were independent from the type of protein added to the media (human serum, human albumin, fetal calf serum). Glutathione in FW further decreased CCL2/MCP-1 in a dose-dependent manner. Culture conditions can modulate the proinflammatory state of islets, and could be used in clinical islet transplantation to reduce inflammation during engraftment.

The immunosuppressive activity of rapamycin (RAPA) and its efficacy as an anti-rejection agent in organ transplantation have been ascribed principally to its anti-proliferative effects on T cells, while the activity on monocytes is partially unknown. In vitro, RAPA reduced monocyte survival by inducing a caspase-independent cell death. RAPA-induced monocyte cell death (RAPA-CD) was impeded by activation of granulocyte macrophage-colony stimulating factor family receptors or toll-like receptor 4, and by exposure to inflammatory cytokines. In vivo, in patients who received RAPA monotherapy as part of pre-conditioning for islet transplantation, RAPA affected survival of myeloid lineage cells. In the peripheral blood, CD33(+) and CD14(+) cells decreased, whereas lymphocytes appeared unaffected. In the bone marrow, myeloid precursors such as CD15(+) and CD15(+)/CD16(+) were selectively and significantly decreased, but no major cytotoxic effects were observed. The RAPA-CD suggests a dependence of monocytes on mammalian target of RAPA pathways for nutrient usage, and this feature implies that RAPA could be selectively useful as a treatment to reduce monocytes or myeloid cells in conditions where these cells negatively affect patient, suggesting a potential anti-inflammatory action of this drug.

OBJECTIVE—Cardiovascular mortality and morbidity are major problems in type 1 diabetic patients with end-stage renal disease (ESRD). The aim of this study was to determine whether islet transplantation can improve cardiovascular function in these patients. RESEARCH DESIGN AND METHODS—We assessed various markers of cardiac function at baseline and 3 years later in a population of 42 type 1 diabetic patients with ESRD who received a kidney transplant. Seventeen patients then received an islet transplant that had persistent function as defined by long-term C-peptide secretion (kidney-islet group). Twenty-five patients did not receive a functioning islet transplant (kidney-only group). RESULTS—GHb levels were similar in the two groups, whereas the exogenous insulin requirement was lower in the kidney-islet group with persistent C-peptide secretion. Overall, cardiovascular parameters improved in the kidney-islet group, but not in the kidney-only group, with an improvement of ejection fraction (from 68.2 ± 3.5% at baseline to 74.9 ± 2.1% at 3 years posttransplantation, P < 0.05) and peak filling rate in end-diastolic volume (EDV) per second (from 3.87 ± 0.25 to 4.20 ± 0.37 EDV/s, P < 0.05). Time to peak filling rate remained stable in the kidney-islet group but worsened in the kidney-only group (P < 0.05). The kidney-islet group also showed a reduction of both QT dispersion (53.5 ± 4.9 to 44.6 ± 2.9 ms, P < 0.05) and corrected QT (QTc) dispersion (67.3 ± 8.3 to 57.2 ± 4.6 ms, P < 0.05) with higher erythrocytes Na+-K+-ATPase activity. In the kidney-islet group only, both atrial natriuretic peptide and brain natriuretic peptide levels decreased during the follow-up, with a stabilization of intima-media thickness. CONCLUSIONS—Our study showed that type 1 diabetic ESRD patients receiving a kidney transplant and a functioning islet transplant showed an improvement of cardiovascular function for up to 3 years of follow-up compared with the kidney-only group, who experienced an early failure of the islet graft or did not receive an islet graft.

OBJECTIVE—Diabetes, hypertension, infections, and nephrotoxicity of certain immunosuppressive drugs (i.e., calcineurin inhibitors) can reduce functional survival of the kidney graft. Our aim was to evaluate survival, hypertrophy, and vascular function of the kidney graft in end-stage renal disease (ESRD) type 1 diabetic patients after transplant. RESEARCH DESIGN AND METHODS—The study population consisted of 234 ESRD type 1 diabetic patients who underwent kidney-pancreas (KP; 166 patients), successful kidney-islet (KI-s; 24 patients), and kidney (KD; 44 patients) transplant. Kidney size, graft survival, vascular function, and microalbuminuria were evaluated prospectively yearly for 6 years. Sixty-eight protocol kidney biopsies were performed routinely between 1993 and 1998 cross-sectionally (3.2 ± 0.3 years from kidney transplant). RESULTS—The KP and KI-s groups had better cumulative kidney graft survival at 6 years than did the KD group (KP: 73%; KI-s: 86%; KD: 42%, P < 0.01). The KP group but not the KI-s/KD groups showed a persistent kidney graft hypertrophy up to 6 years of follow-up. A significant increase in creatinine levels from baseline to year 6 was evident in the KD group (1.58 ± 0.08 to 2.78 ± 0.44 mg/dl, P < 0.05) but not in the KP/KI-s groups. The KP/KI-s groups only showed a reduction of renal resistance index from baseline to year 6 (KP at baseline: 0.74 ± 0.01 to 0.68 ± 0.01%, P < 0.01; KI-s at baseline: 0.72 ± 0.02 to 0.69 ± 0.02%, P < 0.05). At year 6, an increase from baseline in urinary albumin excretion was observed only in the KD group (31.4 ± 9.0 to 82.9 ± 33.6 mg/l, P < 0.05). Preliminary data suggested that graft nitric oxide (NO) expression was higher in the KP/KI-s groups than in the KD group (data not shown). CONCLUSIONS—In ESRD type 1 diabetic patients, KP and KI-s compared with KD resulted in enhanced kidney graft survival, hypertrophy, and vascular function.

Islet survival in the early posttransplantation period is likely to be influenced by inflammatory events in and around islets. Twenty-seven human islet preparations were transplanted by 24 infusions into 14 patients with brittle type 1 diabetes under the Edmonton protocol. Patients were monitored for their coagulation [cross-linked fibrin degradation products (XDPs)] and liver function test [ aspartate and alanine aminotransferase (AST and ALT)] as markers of early posttransplant complications, and these were correlated with in vitro islet number, purification, volume, monocyte-chemoattractant protein-1 (CCL2/MCP-1) and tissue factor (TF) islet release. Consistent with activation of coagulation pathways and hepatic damage, serum XDP values increased early after 11 infusions and transaminase after 13 of 24 infusions. TF and CCL2/MCP-1 were detected in supernatants of 21 and 22 islet preparations, respectively. Serum XDP peak values were correlated with TF/equivalent islets (EI) (r(2) = 0.26, P = 0.001) and CCL2/MCP-1/EI (r(2) = 0.42; P < 0.001); serum transaminase areas under the curve in the first week posttransplantation were correlated with CCL2/MCP-1/EI (r(2) = 0.55; P < 0.001 for ALT and r(2) = 0.51; P = 0.001 for AST) and TF/EI (r(2) = 0.31; P = 0.002 for ALT, and r(2) = 0.36; P = 0.002 for AST). These data suggest that reducing the islet proinflammatory state may be a means to reduce the early posttransplant complications and perhaps improve islet engraftment. Islet survival in the early posttransplantation period is likely to be influenced by inflammatory events in and around islets. Twenty-seven human islet preparations were transplanted by 24 infusions into 14 patients with brittle type 1 diabetes under the Edmonton protocol. Patients were monitored for their coagulation [cross-linked fibrin degradation products (XDPs)] and liver function test [ aspartate and alanine aminotransferase (AST and ALT)] as markers of early posttransplant complications, and these were correlated with in vitro islet number, purification, volume, monocyte-chemoattractant protein-1 (CCL2/MCP-1) and tissue factor (TF) islet release. Consistent with activation of coagulation pathways and hepatic damage, serum XDP values increased early after 11 infusions and transaminase after 13 of 24 infusions. TF and CCL2/MCP-1 were detected in supernatants of 21 and 22 islet preparations, respectively. Serum XDP peak values were correlated with TF/equivalent islets (EI) (r(2) = 0.26, P = 0.001) and CCL2/MCP-1/EI (r(2) = 0.42; P < 0.001); serum transaminase areas under the curve in the first week posttransplantation were correlated with CCL2/MCP-1/EI (r(2) = 0.55; P < 0.001 for ALT and r(2) = 0.51; P = 0.001 for AST) and TF/EI (r(2) = 0.31; P = 0.002 for ALT, and r(2) = 0.36; P = 0.002 for AST). These data suggest that reducing the islet proinflammatory state may be a means to reduce the early posttransplant complications and perhaps improve islet engraftment.

Purpose To investigate the influence of diabetes mellitus on patient and graft survival among renal versus renal–pancreatic recipients. Methods Among 270 renal transplants performed from 1985 to 2002, a total of 204 (75%) were in diabetic patients and 66 (25%) in nondiabetic patients. Among the 204 diabetic patients 161 (60%) kidneys were transplanted simultaneously with a pancreatic graft (SKPT group). The overall group of patient included 164 (61%) men and 106 (39%) women with mean time on dialysis of 31 ± 21 months (range 0 to 126 months). The mean duration of diabetes was 24 ± 7 years (range 5 to 51 years). Ninety-nine percent of the patients were on renal replacement therapy (79% hemodialysis and 20% peritoneal dialysis). Results The overall rejection rate was similar (NS). Both patient and kidney graft survival rates were worse in diabetics. Patient survival was 82% at 5 years among patients undergoing SKPT, 60% in diabetics receiving only a kidney, and 88% in nondiabetic transplanted patients. Kidney graft survival at 5 years was 77% in diabetics receiving SKPT, 68% in diabetics receiving a kidney alone, and 82% in nondiabetic patients. Overall patient survival was significantly greater among nondiabetics (P = .002) or in diabetics who received SKPT compared with diabetics who only had a kidney transplant (P = .001). Conclusions This retrospective clinical evaluation confirms that combined pancreas and kidney transplantation should be the first choice to insulin-dependent diabetes mellitus (IDDM) patients with end-stage diabetic nephropathy.

OBJECTIVE Autoimmune diseases, including type 1 diabetes, are thought to have a Th17-cell bias and/or a T-regulatory cell (Treg) defect. Understanding whether this is a hallmark of patients with type 1 diabetes is a crucial question that is still unsolved, largely due to the difficulties of accessing tissues targeted by the disease. RESEARCH DESIGN AND METHODS We phenotypically and functionally characterized Th17 cells and Tregs residing in the pancreatic-draining lymph nodes (PLNs) of 19 patients with type 1 diabetes and 63 nondiabetic donors and those circulating in the peripheral blood of 14 type 1 diabetic patients and 11 healthy subjects. RESULTS We found upregulation of Th17 immunity and functional defects in CD4+CD25bright Tregs in the PLNs of type 1 diabetic subjects but not in their peripheral blood. In addition, the proinsulin-specific Treg-mediated control was altered in the PLNs of diabetic patients. The dysfunctional Tregs isolated from diabetic subjects did not contain contaminant effector T cells and were all epigenetically imprinted to be suppressive, as defined by analysis of the Treg-specific demethylated region within the forkhead box P3 (FOXP3) locus. CONCLUSIONS These data provide evidence for an unbalanced immune status in the PLNs of type 1 diabetic subjects, and treatments restoring the immune homeostasis in the target organ of these patients represent a potential therapeutic strategy.

Background. The aim of this study was to evaluate the effects of islet transplantation on patient survival and diabetic vascular complications. Methods. Thirty-seven type 1 uremic diabetic kidney transplant patients underwent islet transplantation (KI group). Uremic type 1 diabetic kidney-pancreas (KP group, n=162), kidney-alone (KD group, n=42) transplant patients, and uremic type 1 diabetic patients still on hemodialysis (HD+DM group, n=196) constituted the control groups for survival and endothelial morphology. Results. Patient survival was similar in the KI and KP groups and higher than in the HD+DM group (P