Pancreas and Islet Transplantation in Diabetes
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Abstract:
Bcell replacement, either by the intact whole pancreas or by an isolated pancreas islet, has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependent diabetes mellitus or some of type 2 diabetes. Between the two treatment options, the pancreas transplantation has been shown to be very effective at maintaining an euglycemic state for a sustained period of time providing the recipient with a normal life. The graft survival has been improved due to a current combination of immunosuppressants, refined surgical techniques, and a better postoperative patient care. However, it is associated with a risk of surgical and postoperative complications. The islet transplantation has been considered to be an attractive treatment modality as a less invasive and easily applicable procedure in lieu of whole organ pancreas transplantation. In spite of its many advantages, the islet transplantation has not always achieved the sustained level of normoglycemia without insulin. A poor early or long term graft survival is considered to be caused by inconsistent low islet yield, initial considerable amount of graft loss during engraftment period, rejection of islet in hepatic environment, and absence of monitoring tool for islet graft function. Although current clinical reports have led to a promising result, further improvements are needed to get the long term successful results. Now the current status of pancreas and islet transplantations is reviewed and perspectives of these treatments are discussed.Keywords:
Pancreas transplantation
The aim of this study was to evaluate Exendin-4 (EX-4) effect on islet volume and number in the mouse pancreas.Thirty-two healthy adult male NMRI mice were randomly divided into control and experimental groups.EX-4 was injected intraperitoneally (i.p.) at the doses of 0.25 (E1 group), 0.5 (E2 group), and 1 μg/kg (E3 group), twice a day for seven consecutive days.One day after the fi nal injection, the mice were sacrifi ced, and pancreas from each animal was dissected out, weighed, and fi xed in 10 % formalin for measurement of pancreas, and islet volume and islet number by stereological assessments.There was a signifi cant increase in the weight of pancreases in E3 groups.Islet and pancreas volumes in E1 and E2 groups were not changed compared to control group.E3 group showed a signifi cant increase in islet and pancreas volume (p < 0.05).There were no signifi cant changes in the total number of islets in three experimental groups.The results revealed that EX-4 increased pancreas and islet volume in non-diabetic mice.The increased total islet mass is probably caused by islet hypertrophy without the formation of additional islets (Fig. 5, Ref. 35).
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Objective Length of hospital stay is a sensitive indicator of short-term prognosis. In this retrospective study, we investigated how pancreas preservation time affects length of hospital stay after pancreas transplantation. Methods Patients receiving pancreas transplantation (1998.7–2018.6) were identified from the Scientific Registry of Transplant Recipients database and grouped according to pancreas preservation time. We analyzed the relationship of pancreas preservation time with graft and patient survival and prolonged length of stay (PLOS; i.e., hospital stay ≥20 days). Results We included 18,099 pancreas transplants in the survival analysis. Pancreas preservation time >20 hours had a significantly higher risk of graft failure than 8 to 12 hours. Pancreas preservation time was not significantly associated with patient survival. We included 17,567 pancreas transplants in the analysis for PLOS. Compared with 8 to 12 hours, pancreas preservation time >12 hours had a significantly higher PLOS risk, which increased with increased pancreas preservation time. In simultaneous pancreas–kidney transplantation, we also found that pancreas preservation time was positively associated with PLOS risk with pancreas preservation time >12 hours. Conclusion Pancreas preservation time is a sensitive predictor of PLOS. Transplant centers should minimize pancreas preservation time to optimize patient outcomes.
Pancreas transplantation
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Introduction: The early diagnosis of pancreas allograft rejection after single pancreas or simultaneous pancreas/kidney transplantation is essential for adequate anti-rejection therapy and long term graft survival. In simultaneous pancreas/kidney transplantation it has been shown that the absence of histological rejection in kidney biopsies is not always indicative for absence of rejection in the pancreas. Due to the potential spectrum of complications, pancreas allograft biopsies are performed reluctantly. Here, we report on our results on cause-biopsies of the pancreas and kidney allografts. Methods: All allografts were monitored during follow up after transplantation by contrast-enhanced ultrasound using a Acuson Sequoia (Siemens Medical Solutions) and 1ml of SonoVue® (BRACCO). The indication to biopsy was given if organ function deteriorated (elevated fasting blood-glucose and/or increased pancreas enzymes or impaired kidney function) and no other underlying cause was detected. Causebiospies of the pancreas graft were performed under ultrasound- or computertomography (CT) guidance. The kidney graft was biopsized exclusively by ultrasound due to its easy accessibility. Histopathologic evaluation was performed at an external reference center. Results: A total of 13 pancreas transplantations have been performed at our center since 2008, thereof 1 patient with pancreoprive diabetes and 12 patients with type 1 diabetes and end-stage renal disease (10 simultaneous pancreas/kidney, 1 pancreas after kidney and 1 pancreas re-transplantation). During follow up 12 cause-biopsies of pancreasallografts were indicated in 7 patients due to elevated fasting blood glucose or increased pancreas enzymes. In 5 patients biopsies were performed under ultrasound guidance, in 2 patients via CT-monitoring. Two biopsies resulted in insufficient material and had to be repeated. By histopathological examination, 5 rejection episodes of different degree (BANFF III, IIa, II, I) were found in 4 patients and treatment with Predisone- or Thymoglobulin pulse-therapy was initiated. An exclusive kidney-allograft rejection was diagnosed in 1 patient that was previously treated for pancreas-allograft rejection. No complications occured, neither after ultrasound- nor computertomography guidance occurred. Conclusion: Cause-biospies of pancreas-allografts can be performed safely under contrast-enhanced ultrasound or computertomography guidance. Especially contrast-enhanced ultrasound appears to be an excellent method for pancreas allograft surveillance and biopsy in experienced hands. Even though the cohort is relatively small, our results suggest that a simultaneous rejection of the pancreas and kidney allograft is a rare event.
Pancreas transplantation
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Purpose. A comparative morphological analysis of adult pancreas and newborn rabbits as acceptable model for obtaining of islet cell cultures having a low immunogenicity was agoal of this study. Materials and methods. Pancreas from adult and newborn rabbits and islet cell culture was examined by histological and immunohistochemical techniques. Results. Shown, the pancreas of adult rabbits contains great amount of exocrine tissue and culturing it does not allow to obtain the puri fi ed islets of impurities. By contrast, pancreas of newborn rabbits in which the ratio of the islets and the exocrine tissue is much higher, it is possible to obtain highly puri fi ed cultures of islet cells. Conclusion. Morphological features of newborn rabbit pancreas can use it as a model for obtaining cultures of islet cells having low immunogenicity.
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Ahistological survey of the pancreas in a large series of unselected cases quickly discloses the fact that the amount of islet tissue varies a great deal from case to case. Heilberg (1), and later, Ogilvie (2), devised methods for estimating the weight of an average islet and also the number of islets in a given pancreas. From these data it was possible, too, to calculate by weight, the proportion of islet tissue in the pancreas. These figures were arrived at through area readings. Ogilvie's work has been confined to the creation of normal standards, and to the age variations. In the present series, however, the chief consideration is the possible effects of disease on the amount of islet tissue present. The amount of islet tissue in each section was estimated by area readings made with a planimeter. In a number of cases readings were made on sections from several parts of the same pancreas; these readings corresponded so closely as to confirm the view that islet tissue is distributed fairly uniformly, and that readings from any one section were representative.
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The aim of this study was to evaluate Exendin-4 (EX-4) effects on islet volume and number in the mouse pancreas. Thirty-two healthy adult male NMRI mice were randomly divided into control and experimental groups. EX-4 was injected intraperitoneally (i. p.) at doses of 0.25 (E1 group), 0.5 (E2 group), and 1 µg/kg (E3 group), twice a day for 7 consecutive days. One day after the final injection, the mice were sacrificed, and the pancreas from each animal dissected out, weighed, and fixed in 10% formalin for measurement of pancreas and islet volume, and determination of islet number by stereological assessments. There was a significant increase in the weight of pancreases in the E3 group. Islet and pancreas volumes in E1 and E2 groups were unchanged compared to the control group. The E3 group showed a significant increase in islet and pancreas volume (P < 0.05). There were no significant changes in the total number of islets in all three experimental groups. The results revealed that EX-4 increased pancreas and islet volume in non-diabetic mice. The increased total islet mass is probably caused by islet hypertrophy without the formation of additional islets.
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Abstract Islets of Langerhans are fundamental in understanding diabetes. A healthy human pancreas from a donor has been used to asses various islet parameters and their three-dimensional distribution. Here we show that islets are spread gradually from the head up to the tail section of the pancreas in the form of contracted or dilated islet routes. We also report a particular anatomical structure, namely the cluster of islets. Our observations revealed a total of 11 islet clusters which comprise of small islets that surround large blood vessels. Additional observations in the peripancreatic adipose tissue have shown lymphoid-like nodes and blood vessels captured in a local inflammatory process. Our observations are based on regional slice maps of the pancreas, comprising of 5,423 islets. We also devised an index of sphericity which briefly indicates various islet shapes that are dominant throughout the pancreas.
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Pancreas transplantation provides the only proven method to restore long-term normoglycemia in patients with insulin-dependent diabetes mellitus. Although many studies describe the most important risk factors for short-term survival of a pancreas transplant, more information about factors that distinguish short-term from long-term graft function is needed.Analysis of 21 328 pancreas transplants from the International Pancreas Transplant Registry, performed from 1984 to 2009 (minimum 5-year follow-up), shows a significant improvement in long-term patient survival and pancreas graft function. Total 5-and 10-year pancreas graft function rates are 73 and 56%, respectively, for simultaneous pancreas-kidney transplants; 64 and 38%, respectively, for pancreas after kidney; and 53 and 36%, respectively, for pancreas transplants alone. The most influential period is the first year posttransplant. Recipients who reach this time point with a functioning graft have a much higher probability for excellent long-term graft function. Important factors influencing long-term function were features that described the quality of the deceased donor. Pancreas transplants in younger, high panel reactive antibody, or African-American recipients also showed an increased risk of early graft failure. Anti-T-cell induction therapy had a significant impact on long-term survival in solitary transplants.With careful recipient and donor selection and close follow-up in the first year posttransplant, not only good short-term but also long-term pancreas graft function and, therefore, durable metabolic control can be achieved for the diabetic patient.
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In the eight years since the initiation of pancreas transplantation at our center, 36 patients have received either segmental or whole pancreas grafts. Seventeen patients had segmental pancreas allografts, with eight of these receiving simultaneous kidney allografts from the same donor. Nineteen patients received whole pancreas and kidney allografts. Thirty five of the pancreases were preserved using hypothermic storage for up to 43 hours and 45 minutes, using either albumin-augmented crystalloid or hyperosmolar colloid preservation solution. The one-year actuarial graft survival was 12 per cent for segmental pancreas transplants and 42 per cent for whole pancreas grafts. The use of cyclosporine after whole pancreas transplantation as well as improved surgical techniques for exocrine drainage contributed to the improvement in graft survival in the whole pancreas graft group.
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