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Background Graft quality from extended criteria donors (ECDs) is extremely wide, and a reliable evaluation parameter is required. So far, biopsy is widely used to evaluate ECD organs and to decide whether double (DKT) or single (SKT) kidney transplantation should be performed. The aim of this study is to compare renal resistance (RR) trend during hypothermic machine perfusion (HMP) with a preimplantation biopsy score. Methods From December 2014 to April 2020, HMP has been systematically applied to all organs from ECDs for at least 3 hours. All grafts underwent a preimplantation biopsy histologic assessment with Karpinski's score. SKTs or DKTs were performed accordingly. RR trend during the first 180 minutes of HMP was compared with the biopsy score. Results Eighty-three kidneys were used to perform 57 transplantations (31 SKTs and 26 DKTs). A biopsy confirmed suitability for transplantation in all cases, and the median score was 4 (range, 2-7). Kidneys with a score of 5 to 7 had significantly higher RR value than kidneys with a score of 0 to 4 at basal time (3.35 vs 2.71; P = .074), at 60 minutes (1.24 vs 0.94; P = .031), at 120 minutes (1.10 vs 0.81; P = .010), and at 180 minutes (1.00 vs 0.77; P = .022). A cutoff value of RR ≥0.88 at 120 minutes of perfusion had the best sensibility and specificity (0.71 and 0.75, respectively) to discriminate kidneys with a score of 5 to 7 from kidneys with a score of 0 to 4. No differences were found in postoperative outcomes between SKT and DKT recipients. Conclusions RR trend during HMP correlates with the histologic score in ECD kidneys and can be used as a reliable parameter to evaluate graft quality.

Background and aims Obesity-related cardiometabolic risk factors associate with COVID-19 severity and outcomes. Epicardial adipose tissue (EAT) is associated with cardiometabolic disturbances, is a source of proinflammatory cytokines and a marker of visceral adiposity. We investigated the relation between EAT characteristics and outcomes in COVID-19 patients. Methods and results This post-hoc analysis of a large prospective investigation included all adult patients (≥18 years) admitted to San Raffaele University Hospital in Milan, Italy, from February 25th to April 19th, 2020 with confirmed SARS-CoV-2 infection who underwent a chest computed tomography (CT) scan for COVID-19 pneumonia and had anthropometric data available for analyses. EAT volume and attenuation (EAT-At, a marker of EAT inflammation) were measured on CT scan. Primary outcome was critical illness, defined as admission to intensive care unit (ICU), invasive ventilation or death. Cox regression and regression tree analyses were used to assess the relationship between clinical variables, EAT characteristics and critical illness. One-hundred and ninety-two patients were included (median [25th-75th percentile] age 60 years [53-70], 76% men). Co-morbidities included overweight/obesity (70%), arterial hypertension (40%), and diabetes (16%). At multivariable Cox regression analysis, EAT-At (HR 1.12 [1.04-1.21]) independently predicted critical illness, while increasing PaO2/FiO2 was protective (HR 0.996 [95% CI 0.993; 1.00]). CRP, plasma glucose on admission, EAT-At and PaO2/FiO2 identified five risk groups that significantly differed with respect to time to death or admission to ICU (log-rank p, Graphical abstract Image 1

Clinical deterioration of COVID-19 patients is still a challenging event to predict in the emergency department (ED). The present study developed an artificial neural network using textual and tabular data from ED electronic medical reports. Predicted outcomes were 30-day mortality and ICU admission. Consecutive patients between February 20 and May 5, 2020, from Humanitas Research Hospital and San Raffaele Hospital, in the Milan area, were included. COVID-19 patients were 1296. Textual predictors were patient history, physical exam, and radiological reports. Tabular predictors were age, creatinine, C-reactive protein, hemoglobin, and platelet count. Tabular-textual model performance indices were compared to a model implementing only tabular data. For 30-day mortality, the combined model yielded slightly better performances than the tabular model, with AUC 0.84 ± 0.02, F-1 score 0.56 ± 0.04 and an MCC 0.44 ± 0.04. Tabular model performance was: AUC 0.84 ± 0.02, F-1 score 0.55 ± 0.03 and MCC 0.43 ± 0.04. As for ICU admission, the combined model was not superior to the tabular one. The present data points to the effectiveness of a textual and tabular model for COVID-19 prognosis prediction. Also, it may support the ED physician in their decision-making process.

Chronic metabolic alterations such as post-transplant diabetes mellitus (PTDM), dyslipidaemias and overweight/obesity significantly impact on kidney transplant (KT) outcomes. This joint position statement is based on the evidence on the management of metabolic alterations in KT recipients (KTRs) published after the release of the 2009 KDIGO clinical practice guideline for the care of KTRs. Members of the Italian Society of Nephrology (SIN), the Italian Society for Organ Transplantation (SITO) and the Italian Diabetes Society (SID) selected to represent professionals involved in the management of KTRs undertook a systematic review of the published evidence for the management of PTDM, dyslipidaemias and obesity in this setting. The aim of this work is to provide an updated review of the evidence on the prevention, diagnosis and treatment of metabolic alterations in KTRs, in order to support physicians, patients and the Healthcare System in the decision-making process when choosing among the various available options.

Aims Abnormalities in the oculomotor system may represent an early sign of diabetic neuropathy and are currently poorly studied. We designed an eye-tracking-based test to evaluate oculomotor function in patients with type 1 diabetes. Methods We used the SRLab—Tobii TX300 Eye tracker®, an eye-tracking device, coupled with software that we developed to test abnormalities in the oculomotor system. The software consists of a series of eye-tracking tasks divided into 4 classes of parameters (Resistance, Wideness, Pursuit and Velocity) to evaluate both smooth and saccadic movement in different directions. We analyzed the oculomotor system in 34 healthy volunteers and in 34 patients with long-standing type 1 diabetes. Results Among the 474 parameters analyzed with the eye-tracking-based system, 11% were significantly altered in patients with type 1 diabetes (p p = 0.02). The classes of Velocity and Pursuit were less frequently altered in patients with type 1 diabetes as compared to healthy subjects, with anomalous measurements mainly observed in patients with diabetic neuropathy. Conclusions Abnormalities in oculomotor system function can be detected in patients with type 1 diabetes using a novel eye-tracking-based test. A larger cohort study may further determine thresholds of normality and validate whether eye-tracking can be used to non-invasively characterize early signs of diabetic neuropathy. Trial: NCT04608890.

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.

Background: Obesity may negatively impact clinical outcomes in kidney transplant (KT) recipients. Limited information is available on the prevalence of obesity in this population, and on the lifestyle habits associated with obesity. Methods: we conducted an online, anonymous survey to assess of the proportion of KT recipients with obesity, adherence to the Mediterranean diet (i.e., a dietary regimen with proven renal and cardiovascular outcomes) using the MEDI-Lite questionnaire, and level of physical activity using the International Physical Activity Questionnaire (IPAQ) short form among KT recipients. Results: 255 KT recipients participated. Median (25th–75th quartile) age was 56.0 (48.0; 62.0) years, 43.9% female, median BMI 23.9 (21.6; 26.5) kg/m2. The proportion of KT recipients with obesity was 9.8% (95% confidence interval, 6.4 to 14.1%). Adequate adherence to the Mediterranean diet (Medi-Lite score >9) was overall low (44.7%; 40.0 vs. 45.2% in those with or without obesity, respectively; p = 0.618). In participants with obesity the Medi-Lite score inversely correlated with BMI (R = −0.45; p < 0.025). Overall, 30.6% of participants had a low level of physical activity (44.0 vs. 29.1% of those with or without obesity, respectively; p = 0.125). The amount of energy expended walking was significantly lower among participants with obesity (462 (0.0; 1436) vs. 1056 (433; 2005) METs/week, p = 0.017). Conclusions: the burden of obesity among KT recipients is similar to that of the general population. Adherence to the Mediterranean diet was generally low, and nearly one-third of participants had a low level of physical activity. Building specialized multidisciplinary teams to manage obesity in KT recipients is urgently needed.

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.

Background:Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. Methods:The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered withClinicalTrials.gov,NCT01656135,NCT02252055,NCT02085629,NCT02244801,NCT02371434,NCT02129881, andNCT02091232. Findings:The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2–18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. Interpretation:Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.

A combined kidney and pancreas transplant is a therapeutic option for patients with type 1 diabetes and end-stage renal disease. After successful transplantation, fertility is rapidly restored, allowing women of childbearing age to have spontaneous pregnancies and men to father pregnancies. These pregnancies are at increased risk for maternal and neonatal adverse outcomes due to immunosuppressive therapy, comorbidities, previous type 1 diabetes and previous transplant surgery, although the majority ends with the birth of a live and healthy offspring. Hypertension, miscarriages, diabetes, infections, graft rejections, preterm delivery and low birth weight may complicate pregnancies after pancreas-kidney transplantation. Since not all immunosuppressive drugs can be safely used in pregnancy, it is important to review immunosuppressive treatment before conception. Adequate pre-conception counseling is important to inform women and their partners about potential risks for the pregnancy and the grafts and the advantages of pregnancy planning. These pregnancies should be managed within a multidisciplinary team, comprising a transplant physician, an endocrinologist, a nephrologist, an obstetrician and a neonatologist. Last but not least, it is very important to continue collecting data on the pregnancies in pancreas-kidney transplantation with the aim to improve knowledge and to generate evidence-based guidelines for the care of women after pancreas-kidney transplants who are considering a pregnancy.

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

Kidney transplantation (KT) may restore fertility in chronic kidney disease (CKD). The reasons why maternofetal outcomes are still inferior to the overall population are only partially known. Comparison with the CKD population may offer some useful insights for management and counselling.Aim of this study was to analyse the outcomes of pregnancy after KT, compared with a large population of nontransplanted CKD patients and with low-risk control pregnancies, observed in Italy the new millennium.We selected 121 live-born singletons after KT (Italian study group of kidney in pregnancy, national coverage about 75%), 610 live-born singletons in CKD, and 1418 low-risk controls recruited in 2 large Italian Units in the same period (2000-2014). The following outcomes were considered: maternal and fetal death; malformations; preterm delivery; small for gestational age (SGA) baby; need for the neonatal intensive care unit; doubling of serum creatinine or increase in CKD stage. Data were analyzed according to kidney diseases, renal function (staging according to CKD-epidemiology collaboration), hypertension, maternal age, parity, ethnicity.Maternofetal outcomes are less favourable in CKD and KT as compared with the low-risk population. CKD stage and hypertension are important determinants of results. Kidney transplantation patients with estimated glomerular filtration rate greater than 90 have worse outcomes compared with CKD stage 1 patients; the differences level off when only CKD patients affected by glomerulonephritis or systemic diseases ("progressive CKD") are compared with KT. In the multivariate analysis, risk for preterm and early-preterm delivery was linked to CKD stage (2-5 vs 1: relative risk 3.42 and 3.78) and hypertension (RR 3.68 and 3.16) while no difference was associated with being a KT or a CKD patient.The maternofetal outcomes in patients with kidney transplantation are comparable with those of nontransplanted CKD patients with similar levels of kidney function impairment and progressive and/or immunologic kidney disease.

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.

Background Transplantation of kidneys from donation after cardiocirculatory death (DCD) donors is becoming an ever-increasing reality. So far, biopsy histologic assessment is the main parameter for evaluation of graft suitability, but it has several drawbacks and has poor reliability. The aim of this study is to verify if real-time renal resistance (RR) measurement during hypothermic machine perfusion (HMP) can be used as a reliable parameter to evaluate the quality of grafts from DCD and extracorporeal membrane oxygenation (ECMO) donors. Methods From January 2015 to September 2018, HMP has been systematically applied to all organs from DCD and ECMO donors. All grafts underwent preimplantation biopsy histologic assessment with Karpinski’s score. Single kidney transplants (SKTs) or double kidney transplants (DKTs) were performed according to biopsy score results. Kidneys were considered suitable for transplant if RR reached ≤ 1.0 within 3 hours of perfusion. RR trend and postoperative outcome were analyzed considering biopsy score and donor type. Results A total of 30 kidneys (15 from DCD and 15 from ECMO donors) were used to perform 26 transplants (22 SKTs and 4 DKTs). Considering RR trend, all grafts were considered suitable for transplant within 1 hour of perfusion. Biopsy confirmed this result in all cases, and median score was 3 (range, 0-7). SKT score kidneys had lower starting RR than DKT ones (1.88 vs 2.88; P = .04) but identical final RR (0.58 vs 0.57; P = .76). DKT recipients had faster postoperative creatinine reduction than SKT recipients but similar postoperative day 30 value (1.42 vs 1.15 mg/dL; P = .20). No differences were found between DCD and ECMO grafts in terms of RR trend and postoperative outcome. Conclusions HMP can be an alternative to histologic biopsy assessment for evaluation of transplant suitability of DCD and ECMO kidneys. If acceptability threshold is reached, SKT can be performed in all cases. ECMO donors should be considered like DCD donors.

Background Acute respiratory failure (ARF) is a common cause of presentation to the Emergency Department (ED). High flow nasal cannula (HFNC) has been introduced as an alternative way to administer oxygen. Objectives We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing HFNC with conventional oxygen therapy (COT) and noninvasive ventilation (NIV) exclusively in the ED setting. Methods Inclusion criteria were: RCTs on adults with ARF admitted to the ED, investigating HFNC vs. COT or other modes of ventilation. Trials that compared HFNC support outside the ED, were published as an abstract, or nonrandomized were excluded. Results Four RCTs comparing HFNC with COT and one HFNC to NIV met the criteria. Overall, 775 patients were included. The meta-analysis of the studies comparing HFNC and COT showed no differences in intubation requirement, treatment failure, hospitalization, or mortality. Intolerance was significantly higher with HFNC (risk ratio 6.81 95% confidence interval 1.18–39.19; p = 0.03). In the only available RCT comparing HFNC with NIV, no difference was found for intubation rate, treatment failure, tolerance, and dyspnea. Conclusions We did not find any benefit of HFNC compared with COT and NIV in terms of intubation requirement, treatment failure, hospitalization, and mortality; COT was better tolerated.

Background The risk of wound healing complications (WHCs) and the early use of mammalian target of rapamycin inhibitors after kidney transplantation (KT) have not been fully addressed. Methods The NEVERWOUND study is a 3-month, multicenter, randomized, open-label study designed to evaluate whether a delayed (ie, 28 ± 4 d posttransplant) immunosuppression regimen based on everolimus (EVR) reduces the risk of WHC versus EVR started immediately after KT. Secondary endpoints were treatment failure (biopsy-proven acute rejection, graft loss, or death), delayed graft function, patient and graft survival rates, and renal function. Results Overall, 394 KT recipients were randomized to receive immediate (N = 197) or delayed (N = 197) EVR after KT. At 3 months, WHC-free rates in the immediate EVR versus delayed EVR arm, considering the worst- and best-case scenario approach, were 0.68 (95% confidence interval [CI], 0.62-0.75) versus 0.62 (95% CI, 0.55-0.68) (log-rank P = 0.56) and 0.70 (95% CI, 0.64-0.77) versus 0.72 (95% CI, 0.65-0.78) (log-rank P = 0.77), respectively. The 3- and 12-month treatment failure rates, delayed graft function and renal function, and patient and graft survival were not different between the arms. Conclusions The early introduction of EVR after KT did not increase the risk of WHC, showing good efficacy and safety profile.

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.

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.

Post-transplantation diabetes mellitus (PTDM) may severely impact both short- and long-term outcomes of kidney transplant recipients (KTRs) in terms of graft and patient survival. However, PTDM often goes undiagnosed, is underestimated or poorly managed. A diagnosis of PTDM should be delayed until the patient is on stable maintenance doses of immunosuppressive drugs, with stable kidney graft function and in the absence of acute infections. Risk factors for PTDM should be assessed during the pre-transplant evaluation period, in order to reduce the likelihood of developing diabetes. The oral glucose tolerance test (OGTT) is considered as the gold standard for diagnosing PTDM, whereas HbA1c is not reliable during the first months after transplantation. Glycaemic targets should be individualised, and comorbidities such as dyslipidaemia and hypertension should be treated with drugs that have the least possible impact on glucose metabolism, at doses that do not interact with immunosuppressants. While insulin is the preferred agent for treating inpatient hyperglycaemia in the immediate post-transplantation period, little evidence is available to guide therapeutic choices in the management of PTDM. Metformin and incretins may offer some advantage over other glucose lowering agents, particularly with respect to risk of hypoglycaemia and weight gain. Tailoring immunosuppressive regimens may be of help, although maintenance of good kidney function should be prioritized over prevention/treatment of PTDM. The aim of this narrative review is to provide an overview of the available evidence on management and prevention of PTDM, with a focus on the available therapeutic options.

Hypothermic machine perfusion (HPM) grants a better postoperative outcome in transplantation of organs procured from extended criteria donors (ECDs) and donors after cardiac death (DCD). So far, the only available parameter for outcome prediction concerning those organs is pretransplant biopsy score. The aim of this study is to evaluate whether renal resistance (RR) trend during HPM may be used as a predictive marker for post-transplantation outcome. From December 2015 to present, HMP has been systematically applied to all organs from ECDs and DCD. All grafts underwent pretransplantation biopsy evaluation using Karpinski's histological score. Only organs that reached RR value ≤1.0 within 3 hours of perfusion were transplanted. Single kidney transplantation (SKT) or double kidney transplantation (DKT) were performed according to biopsy score results. Sixty-five HMPs were performed (58 from ECDs and 7 from DCD/ECMO donors). Fifteen kidneys were insufficiently reconditioned (RR 1) and were therefore discarded. Forty-nine kidneys were transplanted, divided between 21 SKT and 14 DKT. Overall primary nonfunction (PNF) and delayed graft function (DGF) rate were 2.9 and 17.1%, respectively. DGF were more common in kidneys from DCD (67 vs. 7%; P = 0.004). Biopsy score did not correlate with PNF/DGF rate (P = 0.870) and postoperative creatinine trend (P = 0.796). Recipients of kidneys that reached RR ≤ 1.0 within 1 hour of HMP had a lower PNF/DGF rate (11 vs. 44%; P = 0.033) and faster serum creatinine decrease (POD10 creatinine: 1.79 mg/dL vs. 4.33 mg/dL; P = 0.019). RR trend is more predictive of post-transplantation outcome than biopsy score. Hence, RR trend should be taken into account in the pretransplantation evaluation of the organs.

BK virus (BKV) associated nephropathy (BKVAN) is still an important cause of allograft dysfunction after kidney transplantation (KT). Recent data have shown that the new interferon (IFN)-λ family has been ascribed antiviral properties similar to IFNα, and that the response to IFNλ in kidney is restricted to epithelial cells, suggesting that the IFNλ system evolves as specific protection of the epithelia. We aimed to test the hypothesis of correlation between a single nucleotide polymorphism (C/T dimorphism rs12979860) in the genomic region of IL28B and BKVAN, in patients after KT. Fifty kidney-transplanted patients were included as follow: Group 1 (BKV+/BKVAN+): 11 patients with active BKV− replication and biopsy-proven BKVAN; Group 2 (BKV+/BKVAN−): 22 patients with active BKV− replication but without evidence of BKVAN; Group 3 (BKV−/BKVAN−): 17 patients without evidence of BKV− replication (control group). Here we show that the C/C genotype was statistically higher in group 2 than in group 1 and BKVAN was detected significantly more frequently in patients with C/T and T/T genotypes than in patients with C/C genotype. We therefore propose IL28B polymorphism (rs12979860), as a predictor-marker to differentiate between patients with self-limited, even if persistent, BKV− reactivation and patients with a high risk of progression towards BKVAN, and to modulate the clinical management of these patients accordingly.

During the last century, obesity has become a global epidemic. The effect of obesity on renal transplantation may occur in perioperative complications and impairment of organ function. Obese patients have metabolic derangements that can be exacerbated after transplantation and obesity directly impacts most transplantation outcomes. These recipients are more likely to develop adverse graft events, such as delayed graft function and early graft loss. Furthermore, obesity is synergic to some immunosuppressive agents in triggering diabetes and hypertension. As behavioral weight loss programs show disappointing results in these patients, bariatric surgery has been considered as a means to achieve rapid and long-term weight loss. Up-to-date literature shows laparoscopic bariatric surgery is feasible and safe in transplantation candidates and increases the rate of transplantation eligibility in obese patients with end-stage organ disease. There is no evidence that restrictive procedures modify the absorption of immunosuppressive medications. From 2013 to 2016 we performed six bariatric procedures (sleeve gastrectomy) on obese patients with renal transplantation; mean preoperative body mass index (BMI) was 39.8 kg/m2. No postoperative complication was observed and no change in the immunosuppressive medications regimen was needed. Mean observed estimated weight loss was 27.6%, 44.1%, 74.2%, and 75.9% at 1, 3, 6, and 12 months follow-up, respectively. Our recommendation is to consider patients with BMI >30 kg/m2 as temporarily ineligible for transplantation and as candidates to bariatric surgery if BMI >35 kg/m2. We consider laparoscopic sleeve gastrectomy as a feasible, first-choice procedure in this specific population.

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.

Although microvascular complications of diabetes (retinopathy, neuropathy, and nephropathy) affect different organs, they are strongly correlated to each other. Based on recent data, their onset and progression could be directly monitored, focusing our attention only on the eye. When confirmed and standardized, this approach could allow one to simplify the way in which we follow the progression of different diabetic complications, and thus establish new strategies aimed at preventing, treating and, hopefully, inducing the remission of microvascular complications of diabetes.

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.

Diabetic nephropathy is the leading and possibly the most devastating complication of diabetes, with a prevalence ranging from 25 to 40 % in diabetic individuals, and as such represents an important challenge for public health worldwide. As a major cause of end-stage renal disease, diabetic nephropathy also accounts for a large proportion of deaths in diabetic individuals. To date, therapeutic options for overt diabetic nephropathy include medical interventions to reduce blood glucose levels and to control blood pressure and proteinuria. Recent evidence suggests a strong role for inflammation in the development and progression of diabetic nephropathy. Various immune cells, cytokines and chemokines have been implicated in the onset of diabetic nephropathy, while immune-related transcription factors and adhesion molecules have been correlated with the establishment of a renal proinflammatory microenvironment. Both inflammation and immune activation may promote severe distress in the kidney, with subsequent increased local fibrosis, ultimately leading to the development of end-stage renal disease. Stem cells are undifferentiated cells capable of regenerating virtually any organ or tissue and bearing important immunoregulatory and anti-inflammatory properties. Due to the aforementioned considerations, significant interest has been ignited with regard to the use of stem cells as novel therapeutics for diabetic nephropathy. Here, we will be examining in detail how anti-inflammatory properties of different populations of stem cells may offer novel therapy for the treatment of diabetic nephropathy.

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.

Although microvascular complications of diabetes (retinopathy, neuropathy, and nephropathy) affect different organs, they are strongly correlated to each other. Based on recent data, their onset and progression could be directly monitored, focusing our attention only on the eye. When confirmed and standardized, this approach could allow one to simplify the way in which we follow the progression of different diabetic complications, and thus establish new strategies aimed at preventing, treating and, hopefully, inducing the remission of microvascular complications of diabetes.