The History of Pancreas Transplantation: Past, Present and Future
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The first attempt to cure type 1 diabetes by pancreas transplantation was done at the University of Minnesota, in Minneapolis, on December 17, 1966, followed by a series of whole pancreas transplantation. Due to the lack of potent immunosuppressive drugs, rejections and infections, it was concluded that pancreas was less antigenic than the kidney which was less antigenic than the duodenum. It opened the door to a period, between the mid 70's to mid 80's where only segmental pancreatic grafts were used in the recipient. Numerous techniques for diverting or dealing with the pancreas juice secretion were described, none of them being satisfactory. In the late 70ȉs - early 80's, three major events happened and boosted the development of pancreas transplantation: firstly the introduction of Cyclosporine A in the clinical field, secondly the organization on March 1980, of the first international meeting on Pancreas Transplantation with the first report of the International Pancreas Transplantation Registry (IPTR) and finally in 1982, the organization of the first informal so-called Spitzingsee meetings where pancreas transplantation successes but mainly failures were discussed which precluded the onset of IPITA (International Pancreas and Islet Transplantation Association), EuroSPK (European Study Group for simultaneous Pancreas and Kidney Transplantation) and EPITA (European Pancreas and Islet Transplantation Association).During one of the Spitzingsee meetings, participants had the idea to renew the urinary drainage technique of the exocrine secretion of the pancreatic graft with segmental graft and eventually with whole pancreaticoduodenal transplant. That was clinically achieved during the mid 80's and remained the mainstay technique during the next decade. In parallel, the Swedish group developed the whole pancreas transplantation technique with enteric diversion. It was the onset of the whole pancreas reign. The enthusiasm for the technique was rather moderated in its early phase due to the rapid development of liver transplantation and the need for sharing vascular structures between both organs, liver and pancreas. During the modern era of immunosuppression, the whole pancreas transplantation technique with enteric diversion became the gold standard for simultaneous pancreas and kidney transplantation (SPK), with portal drainage of the venous effluent of the pancreas, even for pancreas after kidney (PAK) or pancreas transplantation alone (PTA). Today, there remains room for improvement: safety of using the duodeno-duodenal anastomosis technique must be confirmed by prospective analysis while preventing ischemic reperfusion injuries, using specific drugs; that must be assessed in new trials.Keywords:
Pancreas transplantation
Exocrine secretion
Islet and pancreas transplantation may compete for a limited number of organs. We analyzed records from the national Swiss transplant registry during a 4-year period to investigate the proportion of donors that are suitable for islet and pancreas transplantation. Suitability for pancreas transplantation was mainly defined as: age 10-45 years; weight
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Pancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor pancreata relative to the number of patients needing a transplant. The aim of this thesis was to further optimize pancreas graft survival in pancreas transplantation and to optimize islet isolation outcomes in islet of Langerhans transplantation, leading to better use of available organs.
The focus in pancreas transplantation should be on optimizing recipients to improve graft survival and on improving quality of pancreata procured by centers not performing pancreas transplantation (for example, by training procurement surgeons to optimize pancreas procurement, thereby increasing the number of transplantable organs.
In islets transplantation, it is recommended that the reporting of donor, pancreas and isolation factors should become more standardized, which would enable us to determine more accurately which factors are important predictors for islet isolation outcome. Furthermore, if more biomedical factors (e.g. the presence of hyperemic islets) would be reported in addition to the other factors, we would be able to assess the independent effect of these biomedical factors for islet isolation outcome and eventually the effect on islet transplantation in the clinical setting.
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Although endocrine function could be established and rejection was usually prevented after pancreas or pancreaticoduodenal transplantation, most of the grafts failed because of complications arising from the obligatory transplantation of the duodenum or exocrine pancreas. In the area of vascularized pancreas and pancreaticoduodenal transplantation, the number of experimental studies in rats has been limited and mainly restricted to surgical procedures. For pancreas and pancreaticoduodenal transplantation, rats of about 250 to 300 g are of a suitable size to enable the surgical procedure to be performed. The technique to be described permits a one-stage transplantation of the pancreas without duodenum, preserving endocrine and exocrine function. In our experiments about 60% of the pancreas transplantations appeared to be successful. Pancreatitis is the most common cause of graft failure. Using non-touch techniques the incidence of pancreatitis can be reduced markedly. The functional and histopathological aspects of pancreas transplantation are discussed briefly.
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Up to now we registered all over the world 485 transplantations of the pancreas. The partial donation of organs of relatives was performed in forty cases. On August 1st 1984 297 patients (70%) survived after a transplantation of the pancreas; of them 131 had a functioning transplant (30%). 54 transplanted organs (13%) had a good function for longer than 1 year. The most frequent complications were the thrombosis of the transplant, the pancreatitis, the fistulae of the pancreas and the rejection. Of 166 human allogenic islet transplantations at present none is functioning. Early rejections were the causes for the short function times. There were no cases of death by an islet transplantation. The present research concentrates to new methods of the islet isolation from the human pancreas and the immunological influence on the isolated islets.
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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.
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Background. Previous small clinical trials indicate that the two-layer method (TLM) for pancreas preservation improves islet isolation outcome. However, the effect of TLM has not been evaluated in large-scale study. In addition, a direct benefit of TLM on islet transplantation outcome has not been addressed in the setting of any randomized controlled trials. Methods. Between April 2003 and October 2005, human pancreata from brain-dead donors were preserved by TLM using preoxygenated perfluorocarbon (n=75) or in University of Wisconsin (UW) solution (n=91) prior to islet isolation. Islet isolation and transplantation outcomes were compared between the two groups. Results. We did not find any significant differences in adenosine triphosphate content in pancreatic tissue after preservation, pre and postpurification islet yields, in vitro insulin secretory function, or utilization ratio of transplantation between the two groups. Transplanted mass and functional viability of islet isolated from TLM-preserved pancreas were similar to those from UW-preserved pancreas. Patients receiving the TLM-islet or the UW-islet showed a marked decrease in insulin requirement after transplantation. However, no significant difference was observed in a decrease in insulin requirement between patients receiving the TLM-islet and the UW-islet. Conclusions. No beneficial effect of TLM on islet isolation and transplantation outcomes was observed. Our findings bring into question the true merit of routine use of TLM prior to islet isolation.
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