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Many kidney transplant (KT) centers decline patients with a body mass index (BMI) ≥40 kg/mWe performed a single-center, retrospective review of adult KTs comparing BMI ≥40 patients (n = 84, BMI = 42±2 kg/mBMI ≥40 patients were on dialysis longer (5.2±3.2 years vs. 4.1±3.5 years, p = 0.03) and received lower kidney donor profile index (KDPI) kidneys (40±25% vs. 53±26%, p = 0.003). There were no significant differences in prevalence of delayed graft function, reoperations, readmissions, wound complications, patient survival, or renal function at 1 year. Long-term graft survival was higher for BMI ≥40 patients, including after adjusting for KDPI (BMI ≥40: aHR = 1.79, 95% CI = 1.09-2.9). BMI ≥40 patients had similar BMI change in the first year post-transplant (delta BMI: BMI ≥40 +0.9±3.3 vs. BMI40 +1.1±3.2, p = 0.59).Overall outcomes after KT were comparable in BMI ≥40 patients compared to a matched cohort with lower BMI with improved long-term graft survival in obese patients. BMI-based exclusion criteria for KT should be reexamined in favor of a more individualized approach. This article is protected by copyright. All rights reserved.

The influence of sex on outcomes following simultaneous pancreas-kidney transplantation (SPKT) in the modern era is uncertain.We retrospectively studied 255 patients undergoing SPKT from 11/2001 to 8/2020. Cases were stratified according to donor (D) sex, recipient (R) sex, 4 D/R sex categories, and D/R sex-matched versus mismatched.D-male was associated with slightly higher patient (p = .08) and kidney (p = .002) but not pancreas (p = .23) graft survival rates (GSR) compared to D-female. There were no differences in recipient outcomes other than slightly higher pancreas thrombosis (8% R-female vs. 4.2% R-male, p = .28) and early relaparotomy rates in female recipients (38% R-female vs. 29% R-male, p = .14). When analyzing the 4 D/R sex categories, the two D-male groups had higher kidney GSRs compared to the two D-female groups (p = .01) whereas early relaparotomy and pancreas thrombosis rates were numerically higher in the D-female/R-female group compared to the other three groups. Finally, there were no significant differences in outcomes between sex-matched and sex-mismatched groups although overall survival outcomes were lower with female donors irrespective of recipient sex.The influence of D/R sex following SPKT is subject to multiple confounding issues but survival rates appear to be higher in D-male/R-male and lower in D-female/R-male categories.

Long-term outcomes of kidney transplantation from deceased donors (DDKTs) with terminal acute kidney injury (AKI) are not well defined.Single center retrospective review of DDKTs from 1/31/07-12/31/19. AKI kidneys were defined by a doubling of the donor's admission serum creatinine (SCr) level AND a terminal SCr ≥2.0 mg/dl.188 AKI DDKTs were performed, including 154 from brain-dead standard criteria donors (SCD). Mean donor age was 36 years and mean Kidney Donor Profile Index was 50%; mean admission and terminal SCr levels were 1.3 mg/dl and 3.1 mg/dl, respectively. With a mean follow-up of 94 months (median 89 months), overall patient (both 71.3%) and graft survival (54% AKI vs. 57% non-AKI) rates were comparable to concurrent DDKTs from brain-dead non-AKI SCDs (n = 769). Delayed graft function (DGF) was higher in AKI kidney recipients (47% vs. 20% non-AKI DDKTs, p0.0001). DGF was associated with lower graft survival in recipients of both AKI and non-AKI SCD kidneys but the impact was earlier and more pronounced in non-AKI recipients.Despite having more than twice the incidence of DGF, kidneys from deceased donors with terminal AKI have long-term outcomes comparable to non-AKI SCD kidneys and represent a safe and effective method to expand the donor pool. This article is protected by copyright. All rights reserved.

Background A long-standing effort is dedicated towards the identification of biomarkers allowing the prediction of graft outcome after kidney transplant. Extracellular vesicles (EVs) circulating in body fluids represent an attractive candidate, as their cargo mirrors the originating cell and its pathophysiological status. The aim of the study was to investigate EV surface antigens as potential predictors of renal outcome after kidney transplant. Methods We characterized 37 surface antigens by flow cytometry, in serum and urine EVs from 58 patients who were evaluated before, and at 10–14 days, 3 months and 1 year after transplant, for a total of 426 analyzed samples. The outcome was defined according to estimated glomerular filtration rate (eGFR) at 1 year. Results Endothelial cells and platelets markers (CD31, CD41b, CD42a and CD62P) in serum EVs were higher at baseline in patients with persistent kidney dysfunction at 1 year, and progressively decreased after kidney transplant. Conversely, mesenchymal progenitor cell marker (CD1c, CD105, CD133, SSEEA-4) in urine EVs progressively increased after transplant in patients displaying renal recovery at follow-up. These markers correlated with eGFR, creatinine and proteinuria, associated with patient outcome at univariate analysis and were able to predict patient outcome at receiver operating characteristics curves analysis. A specific EV molecular signature obtained by supervised learning correctly classified patients according to 1-year renal outcome. Conclusions An EV-based signature, reflecting the cardiovascular profile of the recipient, and the repairing/regenerative features of the graft, could be introduced as a non-invasive tool for a tailored management of follow-up of patients undergoing kidney transplant.

Complications leading to early technical failure have been the Achilles' heel of simultaneous pancreas-kidney transplantation (SPKT). The study purpose was to analyze longitudinally our experience with early surgical complications following SPKT with an emphasis on changes in practice that improved outcomes in the most recent era.Single center retrospective review of all SPKTs from 11/1/01 to 8/12/20 with enteric drainage. Early relaparotomy was defined as occurring within 3 months of SPKT. Patients were stratified into two sequential eras: Era 1 (E1): 11/1/01-5/30/13; Era 2 (E2) 6/1/13-8/12/20 based on changes in practice that occurred pursuant to donor age and pancreas cold ischemia time (CIT).255 consecutive SPKTs were analyzed (E1, n = 165; E2, n = 90). E1 patients received organs from older donors (mean E1 27.3 vs. E2 23.1 years) with longer pancreas cold CITs) (mean E1 16.1 vs. E2 13.3 h, both p .05). E1 patients had a higher early relaparotomy rate (E1 43.0% vs. E2 14.4%) and were more likely to require allograft pancreatectomy (E1 9.1% vs. E2 2.2%, both p .05). E2 patients underwent systemic venous drainage more frequently (E1 8% vs. E2 29%) but pancreas venous drainage did not influence either relaparotomy or allograft pancreatectomy rates. The most common indications for early relaparotomy in E1 were allograft thrombosis (11.5%) and peri-pancreatic phlegmon/abscess (8.5%) whereas in E2 were thrombosis, pancreatitis/infection, and bowel obstruction (each 3%).Maximizing donor quality (younger donors) and minimizing pancreas CIT are paramount for reducing early surgical complications following SPKT.

Background Organ transplantation is predicted to increase as life expectancy and the incidence of chronic diseases rises. Regenerative medicine-inspired technologies challenge the efficacy of the current allograft transplantation model. Methods A literature review was conducted using the PubMed interface of MEDLINE from the National Library of Medicine. Results were examined for relevance to innovations of organ bioengineering to inform analysis of advances in regenerative medicine affecting organ transplantation. Data reports from the Scientific Registry of Transplant Recipient and Organ Procurement Transplantation Network from 2008 to 2019 of kidney, pancreas, liver, heart, lung and intestine transplants performed, and patients currently on waiting lists for respective organs, were reviewed to demonstrate the shortage and need for transplantable organs. Results Regenerative medicine technologies aim to repair and regenerate poorly functioning organs. One goal is to achieve an immunosuppression-free state to improve quality of life, reduce complications and toxicities, and eliminate the cost of lifelong antirejection therapy. Innovative strategies include decellularization to fabricate acellular scaffolds that will be used as a template for organ manufacturing, three-dimensional printing and interspecies blastocyst complementation. Induced pluripotent stem cells are an innovation in stem cell technology which mitigate both the ethical concerns associated with embryonic stem cells and the limitation of other progenitor cells, which lack pluripotency. Regenerative medicine technologies hold promise in a wide array of fields and applications, such as promoting regeneration of native cell lines, growth of new tissue or organs, modelling of disease states, and augmenting the viability of existing ex vivo transplanted organs. Conclusion The future of organ bioengineering relies on furthering understanding of organogenesis, in vivo regeneration, regenerative immunology and long-term monitoring of implanted bioengineered organs.

The purpose of this study was to analyze the combined effect of cold ischemia time (CIT) and donation after cardiac death (DCD, with requisite warm ischemia time, WIT) on kidney transplant (KT) outcomes.Single center retrospective review of DCD KT recipients stratified by CIT.From 6/08 to 10/20, we performed 446 DCD KTs (115 CIT ≤20, 205 CIT 20-30, 88 CIT 30-40, 38 CIT ≥40 h). Mean WITs (26/25/27/23 min) and KDPI values (59%/55%/55%/59%) were similar while mean CITs (16.4/23.6/33.4/42.5 h) and pump times (10.3/13.6/16.1/20.4 h) differed across groups (P .05). With a mean 6-year follow-up, patient survival (84%/84%/74%/84%) was similar. Kidney graft survival (GS) (72%/72%/56%/58%) and death censored GS (DCGS) (82%/80%/63%/67%) rates decreased whereas rates of primary nonfunction (PNF, .9%/2.4%/9.1%/7.9%) and delayed graft function (DGF) (36%/48%/50%/69%) increased with longer CIT (≥30 h, P .05). Meaningful years free of dialysis, which we refer to as Allograft Life Years, were achieved in all cohorts (4.5/4.3/3.9/4.3 years per patient transplanted).DCD donor kidneys with prolonged CIT (≥30 h) are associated with increased rates of DGF and PNF, along with decreased GS and DCGS. Despite this, Allograft Life Years were gained even with longer CITs, demonstrating the utility of using these allografts.

The influence of African American (AA) recipient race on outcomes following simultaneous pancreas-kidney transplantation (SPKT) is uncertain.From 11/01 to 2/19, we retrospectively studied 158 Caucasian (C) and 57 AA patients (pts) undergoing SPKT.The AA group had fewer patients on peritoneal dialysis (30% C vs. 14% AA), more patients with longer dialysis duration (28% C vs. 51% AA), more sensitized (PRA ≥20%) patients (6% C vs. 21% AA), and more patients with pretransplant C-peptide levels ≥2.0 ng/ml (11% C vs. 35% AA, all P .05). With a mean 9.2 year follow-up, patient survival (65% C vs. 77% AA, P = .098) slightly favored the AA group, whereas kidney (55% C vs. 60% AA) and pancreas (48% C vs. 54% AA) graft survival rates (GSRs) were comparable. Death-censored kidney (71% C vs. 68% AA) and pancreas (both 62%) GSRs demonstrated that death with a functioning graft (DWFG) was more common in C vs. AA patients (23% C vs. 12% AA, P = .10). The incidence of death-censored dual graft loss (usually rejection) was 7% C versus 21% AA (P = .005).Following SPKT, AA patients are at a greater risk for dual immunological graft loss whereas C patients are at greater risk for DWFG.

Following simultaneous pancreas-kidney transplantation (SPKT), survival outcomes are reported as equivalent in patients with detectable pretransplant C-peptide levels (Cp+) and a "type 2″ diabetes mellitus (DM) phenotype compared to type 1 (Cp negative [Cp-]) DM. We retrospectively compared 46 Cp+ patients pretransplant (≥2.0 ng/mL, mean 5.4 ng/mL) to 46 Cp- (level 0.5 ng/mL) case controls matched for recipient age, gender, race, and transplant date. Early outcomes were comparable. Actual 5-year patient survival (91% versus 94%), kidney graft survival (69% versus 86%, p = .15), and pancreas graft survival (60% versus 86%, p = .03) rates were lower in Cp+ versus Cp- patients, respectively. The Cp+ group had more pancreas graft failures due to insulin resistance (13% Cp+ versus 0% Cp-, p = .026) or rejection (17% Cp+ versus 6.5% Cp-, p = .2). Post-transplant weight gain 5 kg occurred in 72% of Cp+ versus 26% of Cp- patients (p = .0001). In patients with functioning grafts, mean one-year post-transplant HbA1c levels (5.0 Cp+ versus 5.2% Cp-) were comparable, whereas Cp levels were higher in Cp+ patients (5.0 Cp+ versus 2.6 ng/mL Cp-). In this matched case-control study, outcomes were inferior in Cp+ compared to Cp- patients following SPKT, with post-transplant weight gain, insulin resistance, and rejection as potential mitigating factors.

The current review summarizes contemporary decellularization and hydrogel manufacturing strategies in the field of tissue engineering and regenerative medicine.Decellularized extracellular matrix (ECM) bioscaffolds are a valuable biomaterial that can be purposed into various forms of synthetic tissues such as hydrogels. ECM-based hydrogels can be of animal or human origin. The use of human tissues as a source for ECM hydrogels in the clinical setting is still in its infancy and current literature is scant and anecdotal, resulting in inconclusive results.Thus far the methods used to obtain hydrogels from human tissues remains a work in progress. Gelation, the most complex technique in obtaining hydrogels, is challenging due to remarkable heterogeneity of the tissues secondary to interindividual variability. Age, sex, ethnicity, and preexisting conditions are factors that dramatically undermine the technical feasibility of the gelation process. This is contrasted with animals whose well defined anatomical and histological characteristics have been selectively bred for the goal of manufacturing hydrogels.

The influence of recipient age on outcomes following simultaneous pancreas-kidney transplantation (SPKT) in the modern era is uncertain. METHODS We retrospectively studied 255 patients undergoing SPKT from 11/01 to 8/20. Recipients were stratified according to age group: age

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.

Organ transplantation faces two major challenges. First, we need to urgently identify a potentially inexhaustible source of organs. Second, we need to make immunosuppression-free transplantation possible. Many strategies have been implemented to increase the donor pool, yet the gap between the demand and the offer remains too wide and, as a consequence, the number of patients dying on the waiting list keeps rising. Tolerance has been pursued for decades, yet it remains an elusive goal outside liver transplantation, where the weaning off immunosuppression appears a safe option in selected cases. As the field of regenerative medicine has shown immense potential to address these challenges, transplant medicine should embrace the opportunity to join forces and partner with it. Regenerative medicine will enable organ-on-demand whereby patients will receive organs that will not be rejected and in a timely fashion. This will make registration in the waiting list and antirejection medications unnecessary and, as the new organs will be implanted immediately after fabrication, ischemia-reperfusion injury secondary to organ preservation will not be a problem anymore. The journey has just begun. As organ transplantation has become the standard of care for many end-stage diseases, its success has become its pitfall. The demand for organs has been steadily increasing in the last years and will continue to do so as chronic noncommunicable diseases such as hypertension, diabetes, and obesity progress to a pandemic level (Perico and Remuzzi, 2012). The average waiting time for patients to receive an organ has increased, with an overwhelming majority waiting 5 years or more. Correspondingly, the mortality rate of those on the lengthening waiting list is rising while the overall probability of receiving an organ in the appropriate time is dropping (Delmonico and McBride, 2008). As a consequence of the steep demand and plummeting supply of organs, initiatives to increase the donor pool have been implemented but have failed to match the demand. Such initiatives include transplanting organs across immunological barriers, paired donations, and expanding the criteria of transplantable organs from deceased and living donors (Vincenti et al., 2016; Massie et al., 2014; Bozek et al., 2018; Orandi et al., 2019). Nonetheless, as it stands, organ transplantation still faces two major challenges that have hindered its progression: the lack of an inexhaustible supply of organs to keep up with the demand and the ultimate goal of an immunosuppression-free state Regenerative medicine is dedicated to replacing, repairing, and regenerating impaired organs and tissues to restore normal function, posing a solution to the major challenges faced by transplant medicine

Islet transplantation is emerging as a therapeutic option for type 1 diabetes, albeit, only a small number of patients meeting very stringent criteria are eligible for the treatment because of the side effects of the necessary immunosuppressive therapy and the relatively short time frame of normoglycemia that most patients achieve. The challenge of the immune-suppressive regimen can be overcome through microencapsulation of the islets in a perm-selective coating of alginate microbeads with poly-l-lysine or poly- l-ornithine. In addition to other issues including the nutrient supply challenge of encapsulated islets a critical requirement for these cells has emerged as the need to engineer the microenvironment of the encapsulation matrix to mimic that of the native pancreatic scaffold that houses islet cells. That microenvironment includes biological and mechanical cues that support the viability and function of the cells. In this study, the alginate hydrogel was modified to mimic the pancreatic microenvironment by incorporation of extracellular matrix (ECM). Mechanical and biological changes in the encapsulating alginate matrix were made through stiffness modulation and incorporation of decellularized ECM, respectively. Islets were then encapsulated in this new biomimetic hydrogel and their insulin production was measured after 7 days in vitro. We found that manipulation of the alginate hydrogel matrix to simulate both physical and biological cues for the encapsulated islets enhances the mechanical strength of the encapsulated islet constructs as well as their function. Our data suggest that these modifications have the potential to improve the success rate of encapsulated islet transplantation.

Islet transplantation (ITx) has the potential to become the standard of care in beta cell replacement medicine but its results remain inferior to those obtained with whole pancreas transplantation. The protocols currently used for human islet isolation are under scrutiny because they are based on the enzymatic digestion of the organ, whereby the pancreas is demolished, its connections to the body are lost and islets are irreversibly damaged. Islet damage is characterized by critical factors such as the destruction of the extracellular matrix (ECM), which represents the 3D framework of the islet niche and whose loss is incompatible with islet euphysiology. Researchers are proposing the use of ECM-based scaffolds derived from the mammalian pancreas to address this problem and ultimately improve islet viability, function, and lifespan. Currently available methods to obtain such scaffolds are harsh because they are largely detergent based. Thus, we propose a new, detergent-free method that creates less ECM damage and can preserve critical components of pancreatic ECM. The results show that the newly developed decellularization protocol allowed the achievement of complete DNA clearance while the ECM components were retained. The ECM obtained was tested for cytotoxicity and encapsulated with human pancreatic islets which showed a positive cellular behavior with insulin secretion when stimulated with glucose challenge. Collectively, we propose a new method for the decellularization of the human pancreas without the use of conventional ionic and non-ionic chemical detergents. This protocol and the ECM obtained with it could be of use for both in vitro and in vivo applications.

The clinical benefit of islet allo- and autotransplantation is limited by a massive loss of implanted cells immediately postimplantation. Episodes of more subtle beta cell loss occur during the natural history of type 1 diabetes and at later time points posttransplantation. Our understanding of the disease and the development of innovative therapies to preserve or restore a sufficient beta-cell mass would benefit from noninvasive measures to detect and quantify episodes of beta-cell destruction. This can be assessed indirectly by monitoring changes in functional beta-cell mass, most precisely and accurately by hyperglycemic clamp test. Non-secreted beta cell-selective proteins, unmethylated gene regions, and microRNAs (miRs) have been validated as circulating markers of ongoing beta-cell damage. In the context of islet transplantation, 65 kDa-glutamate decarboxylase and miR-375 have been most closely associated with beta-cell loss and subsequent graft function.

Diabetes is a debilitating disease affecting millions of people and leading to billions of dollars in healthcare expenditures. While exogenous insulin therapy can be highly effective, it does not completely replace the function of pancreatic islets and is fraught with complications when used long term for diabetes management. Islet transplantation has a high potential to treat these patients, especially type 1 diabetics who have lost a pancreatic function due to autoimmunity against these cells, but fundamental challenges specific to an effective encapsulation system need to be overcome. Macroencapsulation devices offer an effective delivery platform, as they protect the islets from the immune environment of the recipient, allow for less-invasive treatment (compared to organ transplant), reduce cost, can accommodate many sources of cells (e.g., allogenic, xenogenic, iPS) and have been shown to produce exogenous insulin independence. Although encapsulation devices have met several challenges, the synergistic convergence of knowledge from stem cell biology, immunology material science, and nanotechnology will allow us to get closer to the objective of achieving long-term survival and function of encapsulated cells, ease of application, and ultimately, a cost-effective treatment for patients.

Pancreas benching preparation is of crucial importance for the success of transplantation. It is a complex and time-consuming procedure requiring stapling, many suture ligations, and vessel reconstruction. Organ damage occurs in more than 50% of pancreas procurement. Therefore, a profound knowledge of the pancreas anatomy and variations is necessary to avoid and to recognize lesions during both pancreas procurement and bench work. The back-table preparation of the pancreas involves the following stages: (1) inspection of the graft, (2) duodenal dissection/shortening with stapler, (3) suture/ligation of the vessels at the root of the mesentery and inferior mesenteric vein, (4) removal of the excess fat surrounding the pancreas and ligation of small vessels and lymphatics, (5) limited dissection and mobilization of the splenic and superior mesenteric arteries and portal vein and removal of excess ganglion tissue, (6) vascular reconstruction with the Y graft, and (7) spleen can be removed before or after graft implantation.

A summary of the First Signature Series Event, “Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases,” held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies.

Intestinal failure is a serious clinical condition characterized by loss of motility, absorptive function, and malnutrition. Current treatments do not provide the optimal solution for patients due to the numerous resulting complications. A bioengineered bowel that contains the necessary cellular components provides a viable option for patients. In this study, human tissue-engineered bowel (hTEB) was developed using a technique, whereby human-sourced smooth muscle cells were aligned and neoinnervated using human-sourced neural progenitor cells, resulting in the formation of intrinsically innervated smooth muscle sheets. The sheets were then rolled around hollow tubular chitosan scaffolds and implanted in the omentum of athymic rats for neovascularization. Four weeks later, biopsies of hTEB showed vascularization, normal cell alignment, phenotype, and function. During the biopsy procedure, hTEB was transplanted into the same rat's native intestine. The rats gained weight and 6 weeks later, hTEB was harvested for studies. hTEB was healthy in color with normal diameter and with digested food in the lumen, indicating propulsion of luminal content through the hTEB. Histological studies indicated neomucosa with evidence of crypts and villi structures. This study provides proof of concept that hTEB could provide a viable treatment to lengthen the gut for patients with gastrointestinal disorders.

BACKGROUND The potential of a mesenchymal stem cell (MSC) therapy to accelerate the repair of ischemically damaged human kidneys during 24 hours of warm perfusion was evaluated. The hypothesis was that by administering MSC directly to the renal tissue, there would be an improved opportunity for cellular repair mediated by intrarenal paracrine effects. METHODS Studies were performed using the exsanguinous metabolic support (EMS) tissue-engineering platform. Five pairs of human kidney allografts from donation after circulatory death donors were studied. One human kidney was EMS perfused for 24 hours (control), whereas its paired kidney was EMS perfused with MSC (1 × 10). The kidneys were evaluated for DNA synthesis, cytokine/chemokine synthesis, cytoskeletal regeneration, and mitosis. RESULTS Treatment with MSC resulted in reduced inflammatory cytokines synthesized by the kidneys. Mesenchymal stem cell treatment led to a significant increase in the synthesis of adenosine triphosphate and growth factors resulting in normalization of metabolism and the cytoskeleton. Toluidine Blue staining of MSC-treated kidneys demonstrated a significant increase in the number of renal cells undergoing mitosis (26%) compared with EMS perfusion alone. CONCLUSIONS To our knowledge, our work is the first to have demonstrated actual renal regeneration while ischemically damaged human kidneys are perfused ex vivo for 24 hours. The observed regeneration entails: increased synthesis of adenosine triphosphate, a reduced inflammatory response, increased synthesis of growth factors, normalization of the cytoskeleton and mitosis. The ability to regenerate renal tissue ex vivo sufficiently to result in immediate function could revolutionize transplantation by solving the chronic organ shortage.

Inflammatory bowel disease (IBD), namely, Crohn's disease and ulcerative colitis, remains a grievous and recalcitrant problem incurring significant human and health care costs, even in consideration of the growing incidence. Initial goals of care aimed to achieve the induction and maintenance of clinical remission. The advent of novel treat-to-target approaches using patient stratification, early introduction of immunosuppressants and rapid escalation to biologics or early use of combination therapy has refocused the goals of care toward the achievement of mucosal healing. This is in an attempt to preserve intestinal function, decrease hospitalization and surgery rates and improve the quality of life of affected patients. Cellular therapeutics for the treatment of IBD offers an unprecedented opportunity to change the current paradigm from single-targeted to systems-targeted therapy, trying to dampen the whole inflammatory cascade instead of a only molecule. Therefore, as we move forward, the importance of designing informative and possibly adaptive trial designs, standardizing methodologies, harmonizing goals of therapy and evaluating methods cannot be underemphasized. In this article, we review the current literature on the application of mesenchymal stromal cells for the treatment of IBD in an effort to establish a consensus on designing efficient and consistent clinical trials for the intravenous use of this cellular therapy in IBD.

Emerging technologies in regenerative medicine are crucial to overcome the organ donor shortage and the limitations in conventional diabetes treatments. A bioengineered pancreas, obtained through the development of a three-dimensional scaffold from both animal and human extracellular matrix, represents the endeavor to provide alternative therapies to pancreatic transplantation. This alternative hopes to provide the needed components, supply a temporary substrate that enhances cellular function, and aid organized development before implantation. This chapter will present an overview of the different techniques used to engineer scaffolds from natural and synthetic materials. We will discuss their main properties and applications in the regenerative medicine pancreatic research field.

Background The need to expand the organ donor pool remains a formidable challenge in kidney transplantation (KT). The use of expanded criteria donors (ECDs) represents one approach, but kidney discard rates are high because of concerns regarding overall quality. Dual KT (DKT) may reduce organ discard and optimize the use of kidneys from marginal donors. Study design We conducted a single-center retrospective review of outcomes in adult recipients of DKTs from adult marginal deceased donors (DD) defined by limited renal functional capacity. If the calculated creatinine clearance in an adult DD was

Extracellular matrix (ECM) materials have had remarkable success as scaffolds in tissue engineering (TE) and as therapies for tissue injury whereby the ECM microenvironment promotes constructive remodeling and tissue regeneration. ECM powder and solubilized derivatives thereof have novel applications in TE and RM afforded by the capacity of these constructs to be dynamically modulated. The powder form allows for effective incorporation and penetration of reagents; hence, ECM powder is an efficacious platform for 3D cell culture and vehicle for small molecule delivery. ECM powder offers minimally invasive therapy for tissue injury and successfully treatment for wounds refractory to first-line therapies. Comminution of ECM and fabrication of powder-derived constructs, however, may compromise the biological integrity of the ECM. The current lack of optimized fabrication protocols prevents a more extensive and effective clinical application of ECM powders. Further study on methods of ECM powder fabrication and modification is needed.

Beta cell replacement has the potential to restore euglycemia in patients with insulin dependent diabetes. While great progress has been made in establishing allogeneic islet transplantation from deceased donors as the standard of care for those with the most labile diabetes, it is also clear that the deceased donor organ supply cannot possibly treat all those who could benefit from restoration of a normal beta cell mass, especially if immunosuppression were not required. Against this background, the International Pancreas and Islet Transplant Association (IPITA) in collaboration with the Harvard Stem Cell Institute (HSCI), the Juvenile Diabetes Research Foundation (JDRF), and the Helmsley Foundation held a 2-day Key Opinion Leaders Meeting in Boston in 2016 to bring together experts in generating and transplanting beta cells derived from stem cells. The following summary highlights current technology, recent significant breakthroughs, unmet needs and roadblocks to stem-cell-derived beta cell therapies, with the aim of spurring future preclinical collaborative investigations and progress toward the clinical application of stem cell-derived beta cells.

Objective To test the hypothesis that gene expression profiling in peripheral blood from patients who have undergone kidney transplantation (KT) will provide mechanistic insights regarding graft repair and regeneration. Background Renal grafts obtained from living donors (LD) typically function immediately, whereas organs from donation after cardiac death (DCD) or acute kidney injury (AKI) donors may experience delayed function with eventual recovery. Thus, recipients of LD, DCD, and AKI kidneys were studied to provide a more complete understanding of the molecular basis for renal recovery. Methods Peripheral blood was collected from LD and DCD/AKI recipients before transplant and throughout the first 30 days thereafter. Total RNA was isolated and assayed on whole genome microarrays. Results Comparison of longitudinal gene expression between LD and AKI/DCD revealed 2 clusters, representing 141 differentially expressed transcripts. A subset of 11 transcripts was found to be differentially expressed in AKI/DCD versus LD. In all recipients, the most robust gene expression changes were observed in the first day after transplantation. After day 1, gene expression profiles differed depending upon the source of the graft. In patients receiving LD grafts, the expression of most genes did not remain markedly elevated beyond the first day post-KT. In the AKI/DCD groups, elevations in gene expression were maintained for at least 5 days post-KT. In all recipients, the pattern of coordinate gene overexpression subsided by 28 to 30 days. Conclusions Gene expression in peripheral blood of AKI/DCD recipients offers a novel platform to understand the potential mechanisms and timing of kidney repair and regeneration after transplantation.

No field in health sciences has more interest than organ transplantation in fostering progress in regenerative medicine (RM) because the future of no other field more than the future of organ transplantation will be forged by progress occurring in RM. In fact, the most urgent needs of modern transplant medicine, namely, more organs to satisfy the skyrocketing demand and immunosuppression-free transplantation, cannot be met in full with current technologies and are at risk of remaining elusive goals. Instead, in the past few decades, groundbreaking progress in RM is suggesting a different approach to the problem. New, RM-inspired technologies among which decellularization, 3-dimensional printing and interspecies blastocyst complementation, promise organoids manufactured from the patients' own cells and bear potential to render the use of currently used allografts obsolete. Transplantation, a field that has traditionally been immunology-based, is therefore destined to become a RM-based discipline. However, the contours of RM remain unclear, mainly due to the lack of a universally accepted definition, the lack of clarity of its potential modalities of application and the unjustified and misleading hype that often follows the reports of clinical application of RM technologies. All this generates excessive and unmet expectations and an erroneous perception of what RM really is and can offer. In this article, we will (1) discuss these aspects of RM and transplant medicine, (2) propose a definition of RM, and (3) illustrate the state of the art of the most promising RM-based technologies of transplant interest.

Introduction: Human ear reconstruction is recognized as the emblematic enterprise in tissue engineering. Up to now, it has failed to reach human applications requiring appropriate tissue complexity along with an accessible vascular tree. We hereby propose a new method to process human auricles in order to provide a poorly immunogenic, complex and vascularized ear graft scaffold. Methods: 12 human ears with their vascular pedicles were procured. Perfusion-decellularization was applied using a SDS/polar solvent protocol. Cell and antigen removal was examined by histology and DNA was quantified. Preservation of the extracellular matrix (ECM) was assessed by conventional and 3D-histology, proteins and cytokines quantifications. Biocompatibility was assessed by implantation in rats for up to 60 days. Adipose-derived stem cells seeding was conducted on scaffold samples and with human aortic endothelial cells whole graft seeding in a perfusion-bioreactor. Results: Histology confirmed cell and antigen clearance. DNA reduction was 97.3%. ECM structure and composition were preserved. Implanted scaffolds were tolerated in vivo, with acceptable inflammation, remodeling, and anti-donor antibody formation. Seeding experiments demonstrated cell engraftment and viability. Conclusions: Vascularized and complex auricular scaffolds can be obtained from human source to provide a platform for further functional auricular tissue engineered constructs, hence providing an ideal road to the vascularized composite tissue engineering approach. Statement of Significance The ear is emblematic in the biofabrication of tissues and organs. Current regenerative medicine strategies, with matrix from donor tissues or 3D-printed, didn’t reach any application for reconstruction, because critically missing a vascular tree for perfusion and transplantation. We previously described the production of vascularized and cell-compatible scaffolds, from porcine ear grafts. In this study, we ---- applied findings directly to human auricles harvested from postmortem donors, providing a perfusable matrix that retains the ear’s original complexity and hosts new viable cells after seeding. This approach unlocks the ability to achieve an auricular tissue engineering approach, associated with possible clinical translation.

In the past, type 2 diabetes mellitus (T2DM) was a contraindication for simultaneous pancreas-kidney transplantation (SPKT) even though it was generally accepted to be an effective treatment option for selected patients with type 1 DM (T1DM) and advanced chronic kidney disease. However, because there may be tremendous overlap in the clinical presentations of T1DM versus T2DM, the presence of detectable C-peptide is no longer considered reliable in determining DM “type.” Experiences with SPKT in uremic patients with detectable pretransplant C-peptide levels with a type 2 diabetes phenotype (older age of onset of DM and older age at transplant, shorter duration of insulin-requiring DM, higher body weight/BMI, higher proportion of African-Americans) have demonstrated outcomes equivalent to those with T1DM although clearly a more robust selection bias exists for patients with presumed T2DM. The success of SPKT in this setting provides evidence that the pathophysiology of T2DM is heterogeneous and not related exclusively to insulin resistance. The purpose of this review is to summarize evidence that appropriately selected uremic patients with T2DM may benefit from SPKT, with a focus on recipient selection in order to optimize outcomes.

Purpose of review Solitary deceased donor kidney and simultaneous pancreas and kidney (SPK) transplantation are the two most common transplant procedures performed for patients with diabetes and uremia, vastly outnumbering all other organ replacement options. Given the improvement in outcomes for solitary pancreas transplantation, the higher mortality for diabetic patients on the waiting list, and the growing shortage of organs (particularly kidneys) for transplantation, the use of living donors for this complex patient population should be more common. Recent findings Yet, despite some clear advantages, sequential pancreas after live donor kidney transplant and especially the combined procedure, simultaneous pancreas (from a deceased donor) and living donor kidney transplantation are relatively uncommon. Summary Possible reasons for the infrequent use of these options and methods for increasing the use of living donor kidneys for the diabetic and uremic patient are presented.

Background The value of importing expanded criteria donor (ECD) kidneys is uncertain. Methods We retrospectively reviewed our single-center experience with ECD kidney transplants (KT). Results Over 12.8 years, we performed 497 ECD KTs including 247 local and 250 imported from other donor service areas. The import ECD group had more donors (16% vs 9%) ≥ age 70, more zero human leukocyte antigen mismatches (14% vs 2%), more KTs with a cold ischemia time >30 hours (46% vs 19%), and fewer kidneys managed with pump preservation (78% vs 92%, all P≤.05) compared to the local ECD group. Mean Kidney Donor Profile Index were 80% import vs 84% local. With a mean follow-up of 55 months, actual patient and graft survival rates were 71% and 58% in import vs 76% and 58% in local ECD KTs, respectively. Death-censored graft survival rates were 70% in import vs 69% in local ECD KTs. Delayed graft function occurred in 28% import vs 23% local ECD KTs (P=NS) whereas the incidence of primary nonfunction was slightly higher with import ECD kidneys (4.8% vs 2.4%, P=.23). Conclusions Midterm outcomes are remarkably similar for import vs local ECD KTs, suggesting that broader sharing of ECD kidneys may improve utilization without compromising outcomes.

Regenerative medicine promises to meet two of the most urgent needs of modern organ transplantation, namely immunosuppression-free transplantation and an inexhaustible source of organs. Ideally, bioengineered organs would be manufactured from a patient's own biomaterials-both cells and the supporting scaffolding materials in which cells would be embedded and allowed to mature to eventually regenerate the organ in question. While some groups are focusing on the feasibility of this approach, few are focusing on the immunogenicity of the scaffolds that are being developed for organ bioengineering purposes. This review will succinctly discuss progress in the understanding of immunological characteristics and behavior of different scaffolds currently under development, with emphasis on the extracellular matrix scaffolds obtained decellularized animal or human organs which seem to provide the ideal template for bioengineering purposes.

In recent decades, organ transplantation has proven itself a landmark success for the treatment of end-stage organ failure. In light of such dramatic success, the demand for transplantable organs continues to rise at an extraordinary rate while the supply has reached a virtual plateau. Waiting lists have reached alarming levels with patients enduring significant morbidity and mortality in hopes of eventually receiving a transplant. On the other hand, patients who do go on to receive life-saving transplants are consigned to a lifelong regimen of brutal immunosuppressive protocols, which themselves carry harmful side-effect profiles. The present trajectory of organ bioengineering and regeneration (OBR) indicates a potential to dramatically alter the discipline of organ transplantation. Modern techniques in OBR allow for the manufacture of relatively simple organs using autologous cellular material, which would avoid evoking immune response and thereby bypass the need for immunosuppressive protocols. The ideal end product of current investigations would be the fabrication of an autograft-equivalent for clinical application by using cells obtained from the patient in need of a transplant. Such an achievement would represent an immunosuppression-free state, a laborious yet fruitless pursuit that has persisted since the early days of the transplant era. Furthermore, an optimized protocol for the biofabrication of transplantable organs using methods in OBR could theoretically generate an inexhaustible supply and thus provide a solution to the chronic shortage suffered by end-stage patients on the waiting list today. The incorporation of OBR approaches and methodologies into the modern practice of transplantation could plausibly represent a major paradigm shift for the field given the advantages described above.

Numerous technical vascular complications may occur during and following renal transplant that may impact graft survival and patient morbidity, but renal arterial thrombosis is perhaps the most devastating, as it is often difficult to identify vascular occlusion in sufficient time to prevent infarction and loss of the allograft. This chapter will focus on arterial thrombosis because the subject is extremely pertinent to the field of regenerative medicine and the attempts to fabricate organoids for transplant purposes.

Organ transplantation has emerged in recent decades as one of the most effective modalities for the treatment of end-stage organ disease. Over 100,000 transplants are performed worldwide each year; however, the supply has not been able to keep up with increasing demand. Furthermore, transplant recipients are committed to a lifelong regimen of brutal immunosuppressive medications that themselves carry significant side effect profiles, influencing clinical outcomes. Recent advances in the fields of tissue engineering and regenerative medicine are beginning to offer alternative solutions that could potentially improve the longevity, functionality, and biocompatibility profiles of transplants. Decellularization technology to produce extracellular matrix scaffolds represents one of the most promising strategies currently under investigation. Such methods can produce bioengineered, transplantable organs using autologous cells that would bypass the need for immunosuppression and its associated side effects. Furthermore, bioengineering strategies in general are not bound by supply constraints imposed by organ donation.