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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

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.

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.

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.

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 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.

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.

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.

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.

Pancreas transplantation is the more effective cure for type 1 diabetes. Although intensive insulin scheme has been demonstrated to reduce the incidence of diabetes related complication, only pancreas transplantation normalizes glycometabolic control, avoids the risk of severe hypoglycemic events and prevents or in some case ameliorates diabetes related complications. In this review it will be analyzed the impact of pancreas transplantation on diabetes related complication and patient survival. Islet cell transplantation has recently emerged as one the most promising therapeutic approaches to improving glycometabolic control in type 1 diabetic patients and, in many cases, to obtaining insulin independence. Islet cell transplantation requires a relatively short hospital stay and has the advantage of being a relatively noninvasive procedure. The rate of insulin independence 1 year after islet cell transplantation has significantly improved in recent years Data from a recent international Trial confirmed that islet cell transplantation can be potentially a cure for type 1 diabetes. Recent data indicate that insulin independence after islet cell transplantation is associated with an improvement in glucose metabolism and quality of life and with a reduction in hypoglycemic episodes. Islet cell transplantation is still in its initial stages, and many obstacles still need to be overcome. Once clinical islet transplantation has been successfully established, this treatment could even be offered to diabetic patients long before the onset of diabetic complications or to patients with life-threatening hypoglycemic unawareness and brittle diabetes.

Endothelial progenitor cells (EPCs) enter the systemic circulation in response to cues related to vascular damage and need for neovascularization. Thus, EPCs could become readily accessible informers of vascular status and enable the survey of vascular pathologies during preclinical stages. To identify EPC changes with biomarker potential, we investigated whether discrete EPC abnormalities were associated with early nonproliferative diabetic retinopathy (NPDR). Two EPC subtypes with different functions have been characterized to date—one solely committed to the endothelial lineage and the other carrying both endothelial and monocytic markers. We found that only the latter, colony-forming units (CFU)-Hill cells, manifested abnormalities in type 1 diabetic patients with NPDR compared with control subjects. The abnormalities consisted in an increased number of colonies formed in vitro and downregulation of the molecules that facilitate homing at sites of vascular injury. The abnormalities were absent in type 1 diabetic patients free of retinopathy and other complications, despite long diabetes duration, but were detected in some of the patients without clinical retinopathy after short diabetes duration. CFU-Hill cells are potential informers of diabetic microangiopathy but may be preempted from carrying out reparative functions if the molecular abnormalities compromise interactions with the damaged vascular wall.

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.

Type 1 diabetes is a chronic disease that can impact patient survival and quality of life because of acute and chronic complications. Although intensive insulin scheme treatment has been shown to reduce the incidence of diabetes-related complications, only pancreas transplantation has been shown to be able to alter them and in some cases to revert them. In this review, an extensive view of the effect of pancreas transplantation on diabetes-related complication will be described.This review will focus on patients survival, diabetic nephropathy, neuropathy, cardiovascular event, comparing their incidence in type 1 diabetic patients treated with insulin and in type 1 diabetic patients receiving kidney, kidney-pancreas or pancreas alone graft. The review will focus mostly on the papers published in the last decade, with a particular attention to those on new aspects of graft function analysis like spectroscopy. Moreover, a comparison with islet transplantation procedure will be performed.This review will give an update on the potential of pancreas transplantation, give a guide for clinical practice and help to consider pancreas transplantation as an alternative to insulin treatment for selected patients.

In this study we analyzed the role of CCL2, a member of the chemokine family, in early graft damage. Using simultaneous kidney-pancreas transplantation (SPK) as a model, we showed that brain death significantly increases circulating CCL2 levels in humans. We found that in such situations, high donor CCL2 levels (measured before organ recovery and at the onset of cold preservation) correlate with increased postreperfusion release of CCL2 by both the graft and recipient throughout the week following transplantation (n = 28). In a retrospective study of 77 SPK recipients, we found a significant negative association between high donor levels of CCL2 and graft survival. Decreased survival in these patients is related to early posttransplant complications, including a higher incidence of pancreas thrombosis and delayed kidney function. Taken together our data indicate that high CCL2 levels in the donor serum predict both an increase in graft/recipient CCL2 production and poor graft survival. This suggests that the severity of the inflammatory response induced by brain death influences the posttransplant inflammatory response, independent of subsequent ischemia and reperfusion.

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.

Islet cell transplantation recently has emerged as one the most promising therapeutic approaches to improving glycometabolic control in type 1 diabetic patients, and, in many cases, to obtaining insulin independence. Islet cell transplantation requires a relatively short hospital stay and has the advantage of being a relatively noninvasive procedure. The rate of insulin independence 1 year after islet cell transplantation has improved significantly in recent years (60% at 1 year after transplantation compared to the 15% in the past years). Data from a recent international trial confirmed that islet cell transplantation potentially can be a cure for type 1 diabetes. Recent data indicate that insulin independence after islet cell transplantation is associated with an improvement in glucose metabolism and quality of life and with a reduction in hypoglycemic episodes. Islet cell transplantation is still in its initial stages, and many obstacles still need to be overcome. Once clinical islet transplantation has been established, this treatment could be offered to diabetic patients long before the onset of diabetic complications or to patients with life-threatening hypoglycemic unawareness and brittle diabetes.

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.

Islet cell transplantation is an attractive alternative therapy to conventional insulin treatment or vascularized whole pancreas transplantation for type 1 diabetic patients. It represents a successful example of somatic cell therapy in humans based on complex procedures for islet isolation from whole pancreas. The islets, that are only 1% of the total pancreas tissue, are isolated by two steps method starting with collagenase digestion that operates a rapid dissociation of the stromal component of the gland, while preserving islet anatomical integrity. After digestion, islets are then separated from exocrine tissue by centrifugation in density gradients. Transplantation consists of a simple injection of few milliliter-purified tissue in the portal vein through a percutaneous trans- hepatic approach performed in local anesthesia. Several studies have now demonstrated that islet transplant can replace pancreatic endocrine function without major side effects and with liver viability preservation in selected patients affected by longterm type 1 diabetes. It can restore endogenous insulin secretion, achieve insulin independence in more than 80% of patients, and recover the metabolism of glucose, protein and lipids. Improved control of glycated HbA1c, reduced risk of recurrent hypoglycemia and of diabetic complications are also seen as important benefits of islet cell transplantation, irrespective of the status of insulin independence. Many protocols are now on going for reduction of immunosuppression therapy in recipients, induction of tolerance, and prolongation of graft function.

OBJECTIVES To test whether left ventricular (LV) dysfunction affecting type 1 diabetic-uremic patients was associated with abnormal heart high-energy phosphates (HEPs) and to ascertain whether these alterations were also present in recipients of kidney or kidney-pancreas transplantation. BACKGROUND Heart failure is the major determinant of mortality in patients with diabetic uremia. Both uremia and diabetes induce alterations of cardiac HEPs metabolism. METHODS Magnetic resonance imaging and phosphorous magnetic resonance spectroscopy of the LV were performed in the resting state by means of a 1.5-T clinical scanner. Eleven diabetic-uremic patients, 5 nondiabetic patients with uremia, 11 diabetic recipients of kidney transplantation, and 16 diabetic recipients of combined kidney-pancreas transplantation were studied in a cross-sectional fashion. Eleven nondiabetic recipients of kidney-only transplant and 13 healthy subjects served as control groups. RESULTS Uremic patients had higher LV mass, diastolic dysfunction, and lower phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio in comparison with recipients of kidney-pancreas or nondiabetic recipients of kidney transplant. In diabetic recipients of kidney transplant the PCr/ATP ratio was higher than in uremic patients but was lower than in the controls. Recipients of combined kidney-pancreas transplant had a higher ratio than uremic patients but no difference was found in comparison with controls. CONCLUSIONS Altered resting myocardial HEPs metabolism may contribute to LV dysfunction in diabetic-uremic patients. In diabetic recipients of kidney transplantation, a certain degree of LV metabolic and functional impairment was found. In combined kidney-pancreas recipients the resting LV metabolism and function were not different than in controls.

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.

Background. Simultaneous pancreas-kidney (SPK) transplantation has become accepted therapy for patients with type 1 diabetes and end-stage renal disease. This 3-year study compared the metabolic effects of tacrolimus- and cyclosporin microemulsion (ME)-based immunosuppressive therapy in this clinical setting. Methods. The study population comprised the 205 patients enrolled in the Euro-SPK 001 study. Glucose metabolism parameters [fasting blood glucose, fasting C-peptide and glycated haemoglobin (HbA(1c))], blood lipids (total cholesterol and triglycerides) and pancreatic enzymes (lipase and amylase) were monitored at regular intervals during the study. Blood pressure was also carefully monitored and compared with target levels for diabetic patients. Results. Fasting C-peptide and HbA(1c) levels were within the normal ranges in the two treatment groups throughout the 3 years. Fasting blood glucose was higher during the first 2 months post-transplant in the tacrolimus group than in the cyclosporin-ME group, but no differences were seen thereafter. From month 2 post-transplant, mean levels of total cholesterol were significantly lower among patients receiving tacrolimus than among those in the cyclosporin-ME group. In addition, patients receiving cyclosporin-ME showed serological features of mild pancreatitis, with elevated blood amylase and lipase levels during the first 6 months post-transplant. The two regimens were comparable with respect to hypertension. Conclusions. Except for lipid profiles, no major differences in metabolic effects or blood pressure control were observed over the 3 years in SPK transplant patients receiving immunosuppression based on tacrolimus or cyclosporin-ME. In view of the potential risk of hypertension, antihypertensive strategies should be implemented for all patients.

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.

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

Peripheral neuropathy is one of the most common secondary complications of diabetes mellitus, causing severe and prolonged morbidity. However, clinical and experimental studies have reported that careful glucose control may prevent, stabilize, and/or reverse neuropathy and other chronic diabetic complications. Unfortunately, insulin therapy does not prevent the development or progression of chronic lesions in the vessels, kidneys, eyes, or nerves of the diabetic patient. There is great interest in investigating other forms of endocrine replacement therapy, such as transplantation of the pancreas or of the islets of Langerhans (IT). Diabetic polyneuropathy (DP) evolution is characterized by progressive demyelination and axonal loss and is manifested by signs and symptoms on physical examination and abnormalities in nerve conduction studies (NCS). NCS provide reliable, noninvasive, objective measures of peripheral nerve function and constitute the most important technique for the evaluation of the severity of DP in clinical trials. Several research groups have demonstrated that skin biopsy with measurement of intraepidermal nerve fiber density is another method minimally invasive and repeatable that provides direct pathologic evidence of axonal damage in diabetic neuropathy. Fifty-one consecutive IDDM patients with or without end stage renal disease were enrolled at the moment of islet (Is), kidney (KD), kidney-pancreas (KP) or kidney-islet (KI) transplantation. Patients underwent skin biopsy punch, neurologic examination and neurophysiological investigation. Particularly, 20 pts underwent KP tx, 16 KD tx, 10 islet tx and 5 KI. The patients were comparable for duration of diabetes, dialysis (when present), age, lipid profile. In half of the patients a follow-up of 2 years has been reached. After KP tx, and partially with KI, a complete normalization of glycometabolic control has been achieved, with statistically lower HbA1c in comparison with KD group (KP = 6.2; 0.1% vs. KD = 8.4; 0.5%; p

Percutaneous intra-portal islet transplantation (PIPIT) is a less invasive, safer, and repeatable therapeutic option for brittle type 1 diabetes, compared to surgical pancreas transplantation. Hepatic steatosis is a consequence of the islet engraftment but it is curiously present in a limited number of patients and its meaning is controversial. The aims of this study were to assess hepatic steatosis at ultrasound (US) after PIPIT investigating its relationship with graft function and its role in predicting the clinical outcome. From 1996 to 2012, 108 patients underwent PIPIT: 83 type-1 diabetic patients underwent allotransplantation, 25 auto-transplantation. US was performed at baseline, 6, 12, and 24 months, recording steatosis prevalence, first detection, duration, and distribution. Contemporaneously, steatotic and non-steatotic patients were compared for the following parameters: infused islet mass, insulin independence rate, beta-score, C-peptide, glycated hemoglobin, exogenous insulin requirement, and fasting plasma glucose. Steatosis at US was detected in 21/108 patients, 20/83 allo-transplanted and 1/25 auto-transplanted, mostly at 6 and 12 months. Infused islet mass was significantly higher in steatotic than non-steatotic patients (IE/kg: S = 10.822; NS = 6138; p = 0.001). Metabolically, steatotic patients had worse basal conditions, but better islet function when steatosis was first detected, after which progressive islet exhaustion, along with steatosis disappearance, was observed. Conversely, in non-steatotic patients these parameters remained stable in time. Number of re-transplantations was significantly higher in steatotic than in non-steatotic patients (1.8 vs 1.1; p = 0.001). Steatosis at US seems to be related to the islet mass and local overworking activity. It precedes metabolic alterations and can predict graft dysfunction addressing to therapeutic decisions before islet exhaustion. If steatosis does not appear, no conclusion can be drawn. (C) 2015 Elsevier Ltd. All rights reserved.

Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100-65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient.

T regulatory type 1 (Tr1) cell-mediated induction of tolerance in preclinical models of transplantation is remarkably effective. The clinical application of such a therapy in patients on dialysis undergoing kidney transplantation should take into account the possible alterations of the immune system observed in these patients. Herein, we aimed at testing the ability to generate donor-specific Tr1 cell-enriched lymphocytes from patients on dialysis on the waiting list for kidney transplantation.The Tr1 cell-enriched lymphocytes were generated by coculturing interleukin-10-producing dendritic cells obtained from healthy donors with peripheral blood mononuclear cells (PBMCs) of patients on dialysis, following the same protocol used in a previous cell therapy clinical trial to prevent graft-versus-host disease. Alternatively, purified CD4(+) T cells were used instead of total PBMCs. The ability to generate clinical-grade Tr1 cell-enriched products was defined by testing the reduced response to restimulation with mature dendritic cells generated from the original donor (i.e., anergy assay).The Tr1 cell-enriched medicinal products generated from PBMCs of patients on dialysis showed a low anergic phenotype, incompatible with their eventual clinical application. This was irrespective of HLA matching with the donor or the intrinsically reduced ability to proliferate in response to alloantigens. On the contrary, the use of purified CD4(+) T cells isolated from patients on dialysis led to the generation of a highly anergic donor-specific medicinal product containing an average of 10% Tr1 cells.The Tr1 cell-enriched medicinal products can be efficiently generated from patients on dialysis by carefully tailoring the protocol on the patients' immunological characteristics.

To report the urological complications after simultaneous renal and pancreatic transplantation.Retrospective study.Teaching hospital, Italy.143 consecutive patients having simultaneous renal and pancreatic transplantation by one of three techniques. 33 segmental pancreas with duct occlusion, 77 whole pancreas with bladder diversion, and 33 enteric diversion with systemic (n = 26) or portal venous drainage (n = 7). Urological complications were related to the pancreatic transplant, to the renal transplant, or unrelated to the transplant.Morbidity.After occlusion of the duct and enteric diversion, there were no urological complications related to the pancreatic transplant. On the other hand, among the 77 patients with pancreatic drainage into the bladder, urological complications were common (56/77; 73%). Complications related to the renal transplant were recorded in 6/33 (18%), 26/77 (34%) and 12/33 (36%), respectively. Complications unrelated to the transplant occurred in 6/77 patients (8%) in the bladder drainage group. Five patients after bladder drainage required cystoenteric conversion.Enteric diversion is a safe alternative to bladder diversion and results in significantly fewer urological complications.

SummaryThe role of circulating factors in regulating colonic stem cells (CoSCs) and colonic epithelial homeostasis is unclear. Individuals with long-standing type 1 diabetes (T1D) frequently have intestinal symptoms, termed diabetic enteropathy (DE), though its etiology is unknown. Here, we report that T1D patients with DE exhibit abnormalities in their intestinal mucosa and CoSCs, which fail to generate in vitro mini-guts. Proteomic profiling of T1D+DE patient serum revealed altered levels of insulin-like growth factor 1 (IGF-I) and its binding protein 3 (IGFBP3). IGFBP3 prevented in vitro growth of patient-derived organoids via binding its receptor TMEM219, in an IGF-I-independent manner, and disrupted in vivo CoSC function in a preclinical DE model. Restoration of normoglycemia in patients with long-standing T1D via kidney-pancreas transplantation or in diabetic mice by treatment with an ecto-TMEM219 recombinant protein normalized circulating IGF-I/IGFBP3 levels and reestablished CoSC homeostasis. These findings demonstrate that peripheral IGF-I/IGFBP3 controls CoSCs and their dysfunction in DE.Video Abstract

Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications.

Insulin was shown to induce protein anabolism in vivo mainly by inhibiting proteolysis. Heterotopic pancreas transplantation in type 1 diabetes mellitus is characterized by peripheral hyperinsulinemia due to systemic rather than portal insulin delivery. Therefore, we studied the postabsorptive muscle protein metabolism in type 1 diabetic patients with or without pancreas transplantation. The forearm balance technique was performed in 9 type 1 diabetic patients on exogenous insulin treatment, in 4 type 1 diabetic patients following successful pancreas transplantation and in 6 healthy volunteers. Labelled leucine and phenylalanine were infused to quantify whole-body and muscle protein synthesis, respectively. In the postabsorptive state, whole-body protein synthesis (leucine kinetics) was similar in pancreas-transplanted patients and controls. In contrast, muscle protein synthesis tended to be less negative in pancreas-transplanted patients with respect to type 1 diabetic patients and healthy volunteers. The present data suggest that recipients with peripheral insulin delivery and chronic hyperinsulinemia are characterized by a preferential stimulation of protein synthesis in muscle rather than in the splanchnic district. When insulin was infused acutely, while maintaining euglycemia, the whole-body and muscle protein synthesis rates were approximately halved in type 1 diabetic patients with and without pancreas transplantation. We conclude that pancreas transplantation is able to normalize basal and insulin-stimulated protein metabolism. Chronic hyperinsulinemia counteract steroid-induced protein degradation by means of a mild, but persistent stimulation of muscle protein synthesis.