Progress in pancreas transplantation and combined pancreas-kidney transplantation

BACKGROUND: Pancreas transplantation (PT) has proved effective but it is associated with a high risk of surgical complications and technical failure. Duct management and venous drainage are identified as major issues. Improvements in immunosuppression and prophylaxis greatly have contributed to surgical progress. DATA SOURCES: A literature search of the PubMed database (1996-2005) was conducted and research articles on PT reviewed. RESULTS: More than 23 000 PTs have been performed throughout the world. The majority (83%) were performed in combination with kidney transplantation [simultaneous pancreas-kidney transplantation (SPK)]. Pancreas graft survival rates at one year were 85% for 2001-2003 SPK cases, 79% for pancreas after kidney transplantation (PAK) cases, and 76% for pancreas transplantation alone (PTA) cases. For the 1999-2003 cases, enteric drainage was done in 79% of the SPK cases and bladder drainage in 21%. Patient survival rates, pancreas and kidney graft survival rates, and pancreas graft immunological failure rates did not differ significantly in enteric versus bladder drainage cases. All the available data fail to demonstrate a definitive advantage of portal drainage over systemic drainage. From 1993 to 2002, the use of rabbit antithymocyte globulin increased from 0 to 37%; the use of daclizumab increased from 0 to 16%; and the use of basiliximab increased from 0 to 25%. In 1993, 98% of SPK recipients received cyclosporine; but this was decreased to 9% in 2002. Tacrolimus (FK506) usage has increased from 0 (1993) to 87% (2002) of SPK recipients. Sirolimus (SIR) usage has increased from 0 (1993) to 18% (2002) of SPK recipients. CONCLUSIONS: PT remains an effective therapy for treatment of type I diabetes mellitus. Enteric drainage is currently predominant in SPK, but bladder drainage is still largely used. Portal drainage is as safe as systemic drainage, but there is still no convincing evidence about whether it is immunologically or metabolically convenient. The combined of FK506 and mycophenolate mophetil (MMF) is the preferred maintenance immunosuppression in PT. Sirolimus may be a good alternative as a second agent in recipients of PT under FK506 therapy.

Use of surgical techniques in the rat pancreas transplantation model

BACKGROUND: Pancreas transplantation is currently considered to be the most reliable and effective treatment for insulin-dependent diabetes mellitus (also called type I diabetes). With the improvement of microsurgical techniques, pancreas transplantation in rats has been the major model for physiological and immunological experimental studies in the past 20 years. We investigated the surgical techniques of pancreas transplantation in rats by analysing the difference between cervical segmental pancreas transplantation and abdominal pancreaticoduodenal transplantation. METHODS: Two hundred and forty male adult Wistar rats weighing 200-300 g were used, 120 as donors and 120 as recipients. Sixty cervical segmental pancreas transplants and 60 abdominal pancreaticoduodenal transplants were carried out and vessel anastomoses were made with microsurgical techniques. RESULTS: The time of donor pancreas harvesting in the cervical and abdominal groups was 31 6 and 37.6 +/- 3.8 min, respectively, and the lengths of recipient operations were 49.2 +/- 5.6 and 60.6 +/- 7.8 min. The time for donor operation was not significantly different (P > 0.05), but the recipient operation time in the abdominal group was longer than that in the cervical group (P < 0.05). In isograft transplantation without any preconditioning, I-week survival rates were 93.6% and 86.2% in the cervical and abdominal groups, respectively, and were not significantly different (P > 0.05). CONCLUSIONS: Both pancreas transplantation methods are stable models for immunological and physiological studies in pancreas transplantation. Since each has its own advantages and disadvantages, the designer can choose the appropriate method according to the requirements of the study.

Anatomical basis for pancreas transplantation via isolated splenic artery perfusion:A literature review

The variability of vascular anatomy of the pancreas underlines the difficulty of its transplantation.Research regarding the consistency of anatomical variations shows splenic arterial dominance in most cases.This can significantly improve transplantation success.A systematic literature review was performed according to the quality standards described in the AMSTAR measurement tool and the PRISMA guidelines.We valuated existing literature regarding the vascularization and blood perfusion patterns of the pancreas in terms of dominance and variability.The collected data was independently analyzed by two researchers.Variance of vascular anatomy was seen to be underreported in literature,though significant findings have been included and discussed in this study,providing valuable insight into the dynamics of pancreatic perfusion and feasibility of transplantation on several different supplying arteries.The splenic artery(SA)has a high percentage of consistency in all found studies(over 90%).High frequency of anastomoses between arterial pools supplying the pancreas can mediate sufficient blood supply through a dominant vessel,such as the SA,which is present in most cases.Pancreatic transplantation with isolated SA blood supply can provide sufficient arterial perfusion of the pancreas for stable transplant viability due to high anatomical consistency of the SA and vast communications with other arterial systems.

Pancreas transplantation in the mouse

BACKGROUND: Pancreas transplantation is the only established treatment to achieve long-term normoglycemia and insulin independence in patients with insulin-dependent diabetes mellitus. However, many complications both during and post-transplantation have limited the progress of pancreas transplantation. Mice are the widely used laboratory animals that have been used to establish pancreas transplant models. The pathogenesis and the treatment of pancreas allograft rejection have been studied during the last twenty years. This review introduces four different mouse pancreas transplantation models established by different centers. DATA SOURCES: We reviewed the three mostly reported mouse pancreas transplantation models in the literature (Pub Med), and compared them with a novel mouse model established at our center. RESULTS: In this review, four different models of mouse pancreas transplantation were compared in terms of surgical technique, immediate success rate, advantages and disadvantages. CONCLUSIONS: The mouse model is a useful tool to study pancreas transplantation-related diseases and their treatment. The findings from this model help to improve human pancreas transplantation in the future. (Hepatobilinty Pancreat Dis Int 2010; 9:254-258)

Studies of CTLA4Ig in acute rejection of pancreas transplantation in rats

Objective： To investigate the protective effect of CTLA4Ig in rejection of pancreaticoduodenal transplantation model of rat. Methods ： Pancreaticoduodenal transplantion models were established from the donor F344 rats to the Lewis recipients. The models were divided into 2 groups： Group A and B with 12 rats in each group.2 days after transplantation, reciepients in group A were treated with i.p. injection of sailine, and those in group B CTLA41 were injected（200μg）. On day 1,4,7, 10 after transplantation, the grafts were harvested for histopathological examination. On day 4 after transplantation, the CD4^＋CD25^＋ T cells in the grafts were detected by Flow Cytometry. Results： Compared with group A： the degree of the rejection of grafts in group B was lower. The number of CD4^CD25^＋ T cells of graft was （7.91±1.26）% in group A and （13.81±1.71）% in group B, which had significant difference （P〈0.01）. Conclusion： CTLA4Ig could inhibit T cell costimulatory pathway, prevent acute rejection, which might be mediated bv increasing the number of CD4^＋CD25^＋ regulatory T cells.

Donor risk factors in pancreas transplantation

The aim of the work was to analyze and expose the donor and recipient riskfactors in pancreas transplantation. In the following paper, we exposed the 2018Spanish Consensus Document on Donor and Recipient Selection Criteria forPancreas Transplantation. An assessment of the previous Selection Criteria forDonors and Recipients of Pancreas Transplantation, published in 2005 by theSpanish Pancreas Transplant Group (GETP) and the National TransplantOrganization (ONT) was performed. A literature review was performed usingCochrane Library, PubMed and Google Scholar databases. Some of the followingterms were used for the literature search: “Diabetes Mellitus,” “PancreasTransplantation,” “Insulin-Secreting Cells,” “Pancreas Allograft Thrombosis,”“Allograft Pancreatitis,” “Donors’ Risk Factors,” “Recipients’ Risk Factors,”“Pancreas Allograft Rejection” and “Pancreas Allograft Survival.” After anextended search, different inclusion criteria were established. Articles anddocuments with abstracts of full text and in English or Spanish language wereselected. Subsequently, different scientific meetings took place during 2015 and2016 by the GETP. Finally, the updated criteria were published by the GETP andONT in 2018. Several risk factors have been described in pancreas transplantationthat can be divided into donor risk factors: Advanced age (> 50 years);high bodymass index (BMI) (> 30 kg/m2);cause of death (e.g., stroke);previoushyperglycemia;hyperamylasemia;cold ischemia time (greater than 8 or 12 h,depending on the type of donation);the use of vasopressors in the intensive careunit or cardiac arrest;and the macroscopic aspect of the pancreas allograft. Thefollowing are recipient risk factors: Advanced age (> 50 years);active smoking;high BMI (> 30 kg/m2);and peripheral artery disease or sensorimotorpolyneuropathy. Based on the aforementioned parameters, different selectioncriteria have been established for the recipients depending on the type of pancreastransplantation. Knowledge of the risk factors for pancreas transplantation allowsthe establishment of reliable selection criteria for choosing donors and recipients.

Challenges of pancreas transplantation in developing countries,exploring the Turkey example

Pancreas transplantation significantly improves the quality of life for people with type 1 diabetes,primarily by eliminating the need for insulin and frequent blood glucose measurements.Despite the growing numbers of solid organ transplantations worldwide,number of pancreas transplantations in the developing countries`remain significantly low.This difference of pancreas transplantation practices was striking among the participating countries at the 1st International Transplant Network Meeting which was held in Turkey on 2018.In this meeting more than 40 countries were represented.Most of these counties were developing countries located in Africa,Middle East or Asia.The aim of this article is to identify the challenges and limiting factors for pancreas transplantations in these developing countries,by exploring the Turkish example.The challenges faced by the developing countries are broadly classified in four categories;wait-listing,donor pool,team work and follow up.Under these categorical titles,issues are further discussed in detail,giving examples from Turkish practice of pancreas transplantation.Additionally,several solutions to these challenges have been proposed-some of which have already been undertaken by the Turkish Ministry of Health.With the insight and methods presented in this article,pancreas transplantation should be made possible for the potential recipients in the developing countries.

Predicting early graft loss in pancreas transplantation using novel imaging techniques: are we there yet?

Since its inception in 1966 at the University of Minnesota,pancreas transplantation has witnessed major milestones in evolution of surgical techniques,immunosuppression regimen and more recently,machine perfusion for optimising graft utilisation(1).

Human parvovirus B19-associated early postoperative acquired pure red cell aplasia in simultaneous pancreas-kidney transplantation:A case report

BACKGROUND Acquired pure red cell aplasia(aPRCA)related to human parvovirus B19(HPV B19)is rarely reported in simultaneous pancreas-kidney transplantation(SPKT)recipients;there has yet to be a case report of early postoperative infection.In this current study,we report the case of a Chinese patient who experienced the disease in the early postoperative period.CASE SUMMARY A 63-year-old man,with type 2 diabetes and end-stage renal disease,received a brain dead donor-derived SPKT.Immunosuppression treatment consisted of tacrolimus,prednisone,enteric-coated mycophenolate sodium(EC-MPS),and thymoglobulin combined with methylprednisolone as induction.The hemoglobin(Hb)level declined due to melena at postoperative day(POD)3,erythropoietinresistant anemia persisted,and reticulocytopenia was diagnosed at POD 20.The bone marrow aspirate showed decreased erythropoiesis and the presence of giant pronormoblasts at POD 43.Metagenomic next-generation sequencing(mNGS)of a blood sample identified HPV B19 infection at POD 66.EC-MPS was withdrawn;three cycles of intravenous immunoglobulin(IVIG)infusion therapy were administered;and tacrolimus was switched to cyclosporine.The HPV B19-associated aPRCA resolved completely and did not relapse within the 1-year follow-up period.The diminution in mNGS reads was correlated with Hb and reticulocyte count improvements.CONCLUSION HPV B19-associated aPRCA can occur at an early period after SPKT.An effective therapy regimen includes IVIG infusion and adjustment of the immunosuppressive regimen.Moreover,mNGS can be used for the diagnosis and to reflect disease progression.

Anticoagulation in simultaneous pancreas kidney transplantation - On what basis?

BACKGROUND Despite technical refinements,early pancreas graft loss due to thrombosis continues to occur.Conventional coagulation tests(CCT)do not detect hypercoagulability and hence the hypercoagulable state due to diabetes is left untreated.Thromboelastogram(TEG)is an in-vitro diagnostic test which is used in liver transplantation,and in various intensive care settings to guide anticoagulation.TEG is better than CCT because it is dynamic and provides a global hemostatic profile including fibrinolysis.AIM To compare the outcomes between TEG and CCT(prothrombin time,activated partial thromboplastin time and international normalized ratio)directed anticoagulation in simultaneous pancreas and kidney(SPK)transplant recipients.METHODS A single center retrospective analysis comparing the outcomes between TEG and CCT-directed anticoagulation in SPK recipients,who were matched for donor age and graft type(donors after brainstem death and donors after circulatory death).Anticoagulation consisted of intravenous(IV)heparin titrated up to a maximum of 500 IU/h based on CCT in conjunction with various clinical parameters or directed by TEG results.Graft loss due to thrombosis,anticoagulation related bleeding,radiological incidence of partial thrombi in the pancreas graft,thrombus resolution rate after anticoagulation dose escalation,length of the hospital stays and,1-year pancreas and kidney graft survival between the two groups were compared.RESULTS Seventeen patients who received TEG-directed anticoagulation were compared against 51 contemporaneous SPK recipients(ratio of 1:3)who were anticoagulated based on CCT.No graft losses occurred in the TEG group,whereas 11 grafts(7 pancreases and 4 kidneys)were lost due to thrombosis in the CCT group(P=0.06,Fisher’s exact test).The overall incidence of anticoagulation related bleeding(hematoma/gastrointestinal bleeding/hematuria/nose bleeding/re-exploration for bleeding/post-operative blood transfusion)was 17.65%in the TEG group and 45.10%in the CCT group(P=0.05,Fisher’s exact test).The incidence of radiologically confirmed partial thrombus in pancreas allograft was 41.18%in the TEG and 25.50%in the CCT group(P=0.23,Fisher’s exact test).All recipients with partial thrombi detected in computed tomography(CT)scan had an anticoagulation dose escalation.The thrombus resolution rates in subsequent scan were 85.71%and 63.64%in the TEG group vs the CCT group(P=0.59,Fisher’s exact test).The TEG group had reduced blood product usage{10 packed red blood cell(PRBC)and 2 fresh frozen plasma(FFP)}compared to the CCT group(71 PRBC/10 FFP/2 cryoprecipitate and 2 platelets).The proportion of patients requiring transfusion in the TEG group was 17.65%vs 39.25%in the CCT group(P=0.14,Fisher’s exact test).The median length of hospital stay was 18 days in the TEG group vs 31 days in the CCT group(P=0.03,Mann Whitney test).The 1-year pancreas graft survival was 100%in the TEG group vs 82.35%in the CCT group(P=0.07,log rank test)and,the 1-year kidney graft survival was 100%in the TEG group vs 92.15%in the CCT group(P=0.23,log tank test).CONCLUSION TEG is a promising tool in guiding judicious use of anticoagulation with concomitant prevention of graft loss due to thrombosis,and reduces the length of hospital stay.

Two-layer cold storage method for pancreas and islet cell transplantation

The two-layer cold storage method (TLM) was f irst reported in 1988, consisting of a perfluorochemical (PFC) and initially Euro-Collins' solution, which was later replaced by University of Wisconsin solution (UW). PFC is a biologically inert liquid and acts as an oxygen-supplying agent. A pancreas preserved using the TLM is oxygenated through the PFC and substrates are supplied by the UW solution. This allows the pancreas preserved using the TLM to generate adenosine triphosphate during storage, prolonging the preservation time. In a canine model, the TLM was shown to repair and resuscitate warm ischemically damaged pancreata during preservation, improve pancreas graft survival after transplantation, and also improve the islet yield after isolation. Clinical trials using the TLM in pancreas preservation before whole-pancreas transplantation and islet isolation have shown promising outcomes. We describe the role of the TLM in pancreas and islet transplantation.

Back-table surgery pancreas allograft for transplantation:Implications in complications

To describe the main aspects of back-table surgery in pancreatic graft and the problems arising from poor technique.Back-table surgery for pancreatic graft is a complex,meticulous and laborious technique on which the success of implant surgery and perioperative results depends.The technique can be described in the following steps:Preparation of the sterile table,ex-situ inspection of the pancreasspleen block,management of the duodenum,identification of the bile duct,preparation of the portal vein,preparation of the own graft arteries and anastomosis to the arterial graft,spleen management and graft preservation prior to implantation in the recipient.A careful inspection of the pancreas-spleen block should be performed.It is important to identify the stump of the main bile duct,the portal vein cuff,and the arrangement of the superior mesenteric artery and splenic artery.The redundant duodenum must be removed.The availability of a good venous cuff facilitates the portal vein anastomosis and the positioning of the graft,two key points to prevent thrombosis.The section line of the arteries must be clean,without atherosclerosis,to prevent arterial thrombosis.The superior and splenic mesenteric arteries are generally separated by dense fibrolymphatic tissue.The artery can be reconstructed by interposing a"Y"graft from the donor iliac artery;or with an end-to-end anastomosis between the splenic artery and the superior mesenteric artery.An exquisite technique of bench work helps to prevent the most feared complications of pancreas transplantation:Thrombosis and graft pancreatitis.

Surgical complications after pancreatic transplantation:A computed tomography imaging pictorial review

Pancreatic transplantation is considered by the American Diabetes Association and the European Association for the Study of Diabetes an acceptable surgical procedure in patients with type 1 diabetes also undergoing kidney transplantation in pre-final or end-stage renal disease if no contraindications are present.Pancreatic transplantation,however,is a complex surgical procedure and may lead to a range of postoperative complications that can significantly impact graft function and patient outcomes.Postoperative computed tomography(CT)is often adopted to evaluate perfusion of the transplanted pancreas,identify complications and as a guide for interventional radiology procedures.CT assessment after pancreatic transplantation should start with the evaluation of the arterial Y-graft,the venous anastomosis and the duodenojejunostomy.With regard to complications,CT allows for the identification of vascular complications,such as thrombosis or stenosis of blood vessels supplying the graft,the detection of pancreatic fluid collections,including pseudocysts,abscesses,or leaks,the assessment of bowel complications(anastomotic leaks,ileus or obstruction),and the identification of bleeding.The aim of this pictorial review is to illustrate CT findings of surgical-related complications after pancreatic transplantation.The knowledge of surgical techniques is of key importance to understand postoperative anatomic changes and imaging evaluation.Therefore,we first provide a short summary of the main techniques of pancreatic transplantation.Then,we provide a practical imaging approach to pancreatic transplantation and its complications providing tips and tricks for the prompt imaging diagnosis on CT.

Establishment of simultaneous pancreas and kidney transplantation (SPK) model with cuff technique and portal venous drainage in rats

To establish a simultaneous pancreas and kidney transplantation （SPK） model in the rat. Methods： SD rats served as donors and recipients. The donor portal vein and the recipient superior mesenteric vein were anastomosed and the donor renal veins and recipient renal veins were anastomosed by cuff method. Arterial reconstruction was carried out by end to side anastomosis of the donor abdominal aorta to the recipient abdominal aorta. Enteric drainage was performed by side to side anastomosis between donors＇ duodenum and recipients＇ jejunum. The donor ureter -bladder valve was anastomosed to the bladder of recipients. Results： Out of 30 cases of SPK transplantation, 24 had normal serum glucose and serum creatinine after operation. The successful rate was 80 %. Conclusion： This model of SPK in rats is stable and reliable, which could be applied for further scientific research.

Mortality assessment for pancreas transplants in the United States over the decade 2008-2018

BACKGROUND Pancreas transplant is the only treatment that establishes normal glucose levels for patients diagnosed with diabetes.However,since 2005,no comprehensive analysis has compared survival outcomes of:(1)Simultaneous pancreas-kidney(SPK)transplant;(2)Pancreas after kidney(PAK)transplant;and(3)Pancreas transplant alone(PTA)to waitlist survival.AIM To explore the outcomes of pancreas transplants in the United States during the decade 2008-2018.METHODS Our study utilized the United Network for Organ Sharing Standard Transplant Analysis and Research file.Pre-and post-transplant recipient and waitlist characteristics and the most recent recipient transplant and mortality status were used.We included all patients with type I diabetes listed for pancreas or kidneypancreas transplant between May 31,2008 and May 31,2018.Patients were grouped into one of three transplant types:SPK,PAK,or PTA.RESULTS The adjusted Cox proportional hazards models comparing survival between transplanted and non-transplanted patients in each transplant type group showed that patients who underwent an SPK transplant exhibited a significantly reduced hazard of mortality[hazard ratio(HR)=0.21,95%confidence intervals(CI):0.19-0.25]compared to those not transplanted.Neither PAK transplanted patients(HR=1.68,95%CI:0.99-2.87)nor PTA patients(HR=1.01,95%CI:0.53-1.95)experienced significantly different hazards of mortality compared to patients who did not receive a transplant.CONCLUSION When assessing each of the three transplant types,only SPK transplant offered a survival advantage compared to patients on the waiting list.PKA and PTA transplanted patients demonstrated no significant differences compared to patients who did not receive a transplant.

Protective effects of L-arginine on reperfusion injury after pancreaticoduodenal transplantation in rats

BACKGROUND: Post-transplantation pancreatitis andgraft thrombosis are two major complications of pancreastrans-plantation that contribute to morbidity, mortality, andgraft loss. Nitric oxide (NO) is a potent vasodilator agentformed when L-arginine ( L-Arg) is converted to L-citrul-line by the action of NO synthase (NOS), and plays a ma-jor role in microcirculatory changes. We therefore investi-gated the effect of L-Arg on reperfusion injury followingpancreaticoduodenal transplantation in rats.METHODS: The homologous male Wistar rat model ofheterotopic total pancreaticoduodenal transplantation wasused. The L-Arg-treated rats received the intravenous in-jection of L-Arg 5 minutes before and after reperfusion at adose of 200 mg/kg while the N-Nitro-L-arginine methyl es-ter (L-NAME) -treated rats at a dose of 10 mg/kg. Theamount of NO in the pancreas graft was measured. Serumconcentration of cytokine-induced neutrophil chemoattrac-tant ( CINC) was determined by enzyme-linked immu-nosorbant assay, the expression of CINC mRNA was detect-ed by Northern blot assay in the pancreas graft, and the ac-tivity of myeloperoxidase (MPO) was measured. Histolo-gical examination was performed.RESULTS: The amount of NO was higher in the L-Arggroup than in the control group, while it was lower in theL-NAME group than in the control group (P <0.05). Thepeak of serum CINC concentration occurred 3 hours afterreperfusion with the difference among the groups being sig-nificant. The expression peak of CINC mRNA in the pan-creas graft occurred 3 hours after reperfusion. The expres-sion level in the L-Arg group (7.66 ± 1.53 μg/L) was lowerthan in the control group (26.31±2.01 μg/L), while in theL-NAME group (34.18 ±3.12 μg/L) it was higher than thatin the control group (P <0. 05). The activity of MPO inthe L-Arg group was obviously decreasd as compared within the other groups. The pancreas inflammation was ame-liorated when L-Arg was administered, whereas the panc-reas damage was aggravated when L-NAME was adminis-tered.CONCLUSIONS: L-Arg can increase the amount of NOand inhibit the elevation of CINC, the CINC mRNA ex-pression and early neutrophil accumulation in the pancreas.NO has protective effects on ischemia/reperfusion injury inpancreaticoduodenal transplantation.

Late complications of pancreas transplant

To summarize the long-term complications after pancreas transplantation that affect graft function,a literature search was carried out on the long-term complications of pancreatic transplantation,namely,complications from postoperative 3rd mo onwards,in terms of loss of graft function,late infection and vascular complications as pseudoaneurysms.The most relevant reviews and studies were selected to obtain the current evidence on these topics.The definition of graft failure varies among different studies,so it is difficult to evaluate,a standardized definition is of utmost importance to know the magnitude of the problem in all worldwide series.Chronic rejection is the main cause of long-term graft failure,occurring in 10%of patients.From the 3rd mo of transplantation onwards,the main risk factor for late infections is immunosuppression,and patients have opportunistic infections like:Cytomegalovirus,hepatitis B and C viruses,Epstein-Barr virus and varicella-zoster virus;opportunistic bacteria,reactivation of latent infections as tuberculosis or fungal infections.Complete preoperative studies and serological tests should be made in all recipients to avoid these infections,adding perioperative prophylactic treatments when indicated.Pseudoaneurysm are uncommon,but one of the main causes of late bleeding,which can be fatal.The treatment should be performed with radiological endovascular approaches or open surgery in case of failure.Despite all therapeutic options for the complications mentioned above,transplantectomy is a necessary option in approximately 50%of relaparotomies,especially in lifethreatening complications.Late complications in pancreatic transplantation threatens long-term graft function.An exhaustive follow-up as well as a correct immunosuppression protocol are necessary for prevention.

Alternative therapeutic strategies in diabetes management

Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreaticβcells,insulin resistance in peripheral tissues,or both,and results in a non-sufficient production of insulin.To adjust blood glucose levels,diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity.With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities,different strategies have been investigated.The first approaches included enhancing endogenousβcell activity or transplanting new islets.The protocol for this kind of intervention has recently been optimized,leading to standardized procedures.It is indicated for diabetic patients with severe hypoglycemia,complicated by impaired hypoglycemia awareness or exacerbated glycemic lability.Transplantation has been associated with improvement in all comorbidities associated with diabetes,quality of life,and survival.However,different trials are ongoing to further improve the beneficial effects of transplantation.Furthermore,to overcome some limitations associated with the availability of islets/pancreas,alternative therapeutic strategies are under evaluation,such as the use of mesenchymal stem cells(MSCs)or induced pluripotent stem cells for transplantation.The cotransplantation of MSCs with islets has been successful,thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms,including exosome release.The use of induced pluripotent stem cells is recent and requires further investigation.The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities,such as wound healing.Despite the number of advantages of the direct injection of MSCs,new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results.In conclusion,this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.

Machine perfusion in abdominal organ transplantation: Current use in the Netherlands

Scarcity of donor organs and the increment in patients awaiting a transplant increased the use of organs from expanded criteria donors or donation after circulatory death.Due to the suboptimal outcomes of these donor organs,there is an increased interest in better preservation methods,such as ex vivo machine perfusion or abdominal regional perfusion to improve outcomes.This state-ofthe-art review aims to discuss the available types of perfusion techniques,its potential benefits and the available evidence in kidney,liver and pancreas transplantation.Additionally,translational steps from animal models towards clinical studies will be described,as well as its application to clinical practice,with the focus on the Netherlands.Despite the lack of evidence from randomized controlled trials,currently available data suggest especially beneficial effects of normothermic regional perfusion on biliary complications and ischemic cholangiopathy after liver transplantation.For ex vivo machine perfusion in kidney transplantation,hypothermic machine perfusion has proven to be beneficial over static cold storage in a randomized controlled trial,while normothermic machine perfusion is currently under investigation.For ex vivo machine perfusion in liver transplantation,normothermic machine perfusion has proven to reduce discard rates and early allograft dysfunction.In response to clinical studies,hypothermic machine perfusion for deceased donor kidneys has already been implemented as standard of care in the Netherlands.

Complications during multiorgan retrieval and pancreas preservation

In pancreas transplantation, complications can arise at each step of the process,from the initial selection of donors and recipients through the surgical techniqueitself and the post-operative period, when lifelong immunosuppression isrequired. In the early steps, careful retrieval and preservation of the pancreas arecrucial for the viability of the organ and ultimate success of the transplant. Thepancreas is a low-flow gland, making it highly sensitive to transplantationconditions and presenting risk of pancreatitis due to periods of ischemia. The twogroups of donors - after brain death (DBD) or after cardiac arrest (DCD) - requiredifferent strategies of retrieval and preservation to avoid or reduce the risk ofcomplications developing during and after the transplantation. For DBD donortransplantation, multiorgan retrieval and cold preservation is the conventionaltechnique. Asystole donor (DCD) transplantation, in contrast, can benefit from thenewest technologies, such as hypothermic and especially normothermicpreservation machines (referred to as NECMO), to optimize organ preservation.The latter has led to an increase in the pool of donors by facilitating recuperationof organs for transplantation that would have been discarded otherwise.