Clinical Pancreas Transplantation Research Articles

Endoscopic control after retroperitoneal pancreas transplantation with a Roux-en-Y duodenojejunostomy for exocrine drainage

Background. Simultaneous pancreas and kidney transplantation is a gold standard in the treatment of diabetes mellitus complicated by stage 5 chronic kidney disease as a result of diabetic nephropathy. One of the main problems of clinical pancreas transplantation is the pancreas graft exocrine drainage. In order to preserve the advantages of the retroperitoneal graft location and avoid the main disadvantage of duodenal drainage, namely, fatal complications potentially arising in case of necessary graft removal, we have proposed a modified method of retroperitoneal pancreatic transplantation with exocrine drainage via a modified Roux-en-Y duodenojejunostomy. It reduces the number of severe surgical complications and increases the recipient survival rate. When this method was used in previous years, it was not possible to assess the condition of donor duodenum mucosa and interintestinal anastomoses.Objective. To demonstrate the possibility of endoscopic assessment of interintestinal anastomoses when performing retroperitoneal pancreas transplantation with small intestine drainage of exocrine secretions.Results. The article presents the initial experience of endoscopic assessment of the interintestinal anastomoses and the mucous membrane of the donor duodenum after retroperitoneal pancreas transplantation with exocrine drainage via a Roux-en-Y duodenojejunostomy.Conclusion. The presented case demonstrates the feasibility of diagnostic endoscopic interventions when performing retroperitoneal pancreas transplantation with small intestine drainage of pancreatic secretions.

Current Trends in Organ Preservation Solutions for Pancreas Transplantation: A Single-Center Retrospective Study.

Due to the high vulnerability of the pancreas to ischemia-reperfusion injury, choices regarding preservation solution markedly affect pancreas transplant success. A retrospective single-center analysis of 380 pancreas transplants (2000-2019) was performed to correlate current preservation solutions with transplant outcomes. Early graft failure requiring transplantectomy within 30days post-transplant occurred in 7.5% for University of Wisconsin (UW) group (n = 267), 10.8% of Celsior (CS) group (n = 83), 28.5% of Histidine-Tryptophan-Ketoglutarate (HTK) group (n = 7), and none for Institut Georges Lopez-1 (IGL-1) group (n = 23). The most common causes of technical failures in this cohort included abdominal hemorrhage (8.4%); graft pancreatitis (3.7%); fluid collections (2.6%); intestinal complications (6.6%); and vascular thrombosis (20.5%). Although IGL-1 solution provided lower surgical complication rates, no significant differences were found between studied groups. Nevertheless, HTK solution was associated with elevated pancreatitis rates. The best graft survival was achieved at 1year using UW and IGL-1, and at 3 and 5years using IGL-1 (p = 0.017). There were no significant differences in patient survival after a median follow-up of 118.4 months. In this setting therefore, IGL-1 solution appears promising for perfusion and organ preservation in clinical pancreas transplantation, compared to other commonly used solutions.

Felix dies natalis, insulin… ceterum autem censeo "beta is better".

One hundred years after its discovery, insulin remains the life-saving therapy for many patients with diabetes. It has been a 100-years-old success story thanks to the fact that insulin therapy has continuously integrated the knowledge developed over a century. In 1982, insulin becomes the first therapeutic protein to be produced using recombinant DNA technology. The first "mini" insulin pump and the first insulin pen become available in 1983 and 1985, respectively. In 1996, the first generation of insulin analogues were produced. In 1999, the first continuous glucose-monitoring device for reading interstitial glucose was approved by the FDA. In 2010s, the ultra-long action insulins were introduced. An equally exciting story developed in parallel. In 1966. Kelly et al. performed the first clinical pancreas transplant at the University of Minnesota, and now it is a well-established clinical option. First successful islet transplantations in humans were obtained in the late 1980s and 1990s. Their ability to consistently re-establish the endogenous insulin secretion was obtained in 2000s. More recently, the possibility to generate large numbers of functional human β cells from pluripotent stem cells was demonstrated, and the first clinical trial using stem cell-derived insulin producing cell was started in 2014. This year, the discovery of this life-saving hormone turns 100 years. This provides a unique opportunity not only to celebrate this extraordinary success story, but also to reflect on the limits of insulin therapy and renew the commitment of the scientific community to an insulin free world for our patients.

The Future of Islet Transplantation Is Now.

Milestones in the history of diabetes therapy include the discovery of insulin and successful methods of beta cell replacement including whole pancreas and islet cell transplantation options. While pancreas transplantation remains the gold standard for patients who have difficulty controlling their symptoms with exogenous insulin, islet allotransplantation is now able to provide similar results with some advantages that make it an attractive potential alternative. The Edmonton Protocol, which incorporated a large dose of islets from multiple donors with steroid-free immunosuppression helped to establish the modern era of islet transplantation almost 20 years ago. While islet allotransplantation is recognized around the world as a powerful clinical therapy for type 1 diabetes it is not yet recognized by the Federal Drug Administration of the United States. Large-scale clinical trials administered by the Clinical Islet Transplantation Consortium have recently demonstrated that the well-regulated manufacture of a human islet product transplanted into patients with difficult to control type 1 diabetes and with a history of severe hyperglycemic episodes can safely and efficaciously maintain glycemic balance and eliminate the most severe complications associated with diabetes. The results of these clinical trials have established a strong basis for licensure of clinical islet allotransplantation in the US. Recognition by the Federal Drug Administration would likely lead to third party reimbursement for islet allotransplantation as a therapeutic option in the United States and would make the treatment available to many more patients. The high costs of rampant diabetes justify the expense of the treatment, which is in-line with the costs of clinical pancreas transplantation. While much enthusiasm and hope is raised toward the development and optimization of stem cell therapy, the islet transplantation community should push toward licensure, if that means broader access of this procedure to patients who may benefit from it. Even as we prepare to take the first steps in that direction, we must acknowledge the new challenges that a shift from the experimental to clinical will bring. Clinical islet allotransplantation in the United States would be a game-changing event in the treatment of type 1 diabetes and also generate enthusiasm for continued research.

Integration of a Massive Open Online Course on Clinical Kidney, Pancreas and Islet Transplantation into a Regular Medical Science Curriculum

Integration of a Massive Open Online Course on Clinical Kidney, Pancreas and Islet Transplantation into a Regular Medical Science Curriculum

Extracorporeal machine perfusion of the pancreas: technical aspects and its clinical implications--a systematic review of experimental models.

Pancreas or pancreatic islet transplantation is an important treatment option for insulin-dependent diabetes and its complications. However, as the pancreas is particularly susceptible to ischaemic-reperfusion injury, the criteria for pancreas and islet donation are especially strict. With a chronic shortage of donors, one critical challenge is to maximise organ availability and expand the donor pool. To achieve that, continuous improvement in organ preservation is required, with the aims of reducing ischaemia-reperfusion injury, prolong preservation time and improve graft function. Static cold storage, the only method used in clinical pancreas and islet cell transplant currently, has likely reached its plateau. Machine perfusion, hypothermic or normothermic, could hold the key to improving donor pancreas quality as well as quantity available for transplant. This article reviews the literature on experimental models of pancreas machine perfusion, examines the benefits of machine perfusion, the technical aspects and their clinical implications.

A Role for Transplant Endocrinologists - It's About Time

Since the introduction of clinical pancreas transplantation as a treatment for type 1 diabetes in the United States in the 1980s, endocrinologists, save the few conducting mechanistic investigations into the consequences of restoring endocrine function on metabolism and the complications of diabetes ( 1. Morel P. Goetz F.C. Moudry-Munns K. Freier E. Sutherland D.E. Long-term glucose control in patients with pancreatic transplants. Ann Intern Med. 1991; 115: 694-699 Crossref PubMed Scopus (66) Google Scholar ), have been largely uninvolved in the evaluation for or subsequent care and monitoring of pancreas transplant recipients. Historically, this may have been appropriate, since a pancreas transplant is usually added to a kidney transplant for a type 1 diabetic patient with end-stage nephropathy. Moreover, as kidney transplantation was established first, referral to a transplant center with medical determination for the indication of adding a pancreas and monitoring its function was handled by the transplant nephrologist. Finally, because the benefits of near-normal glycemic control in type 1 diabetes were not yet appreciated, success of a pancreas transplant was measured only by the postoperative insulin requirement, with a return to insulin therapy indicating graft failure.

Editorial introductions

Editorial introductions

Systematic Protocol Biopsy of the Duodenal Graft for Surveillance after Pancreas Transplantation

Introduction: We present data on serial protocol biopsies (px) of the duodenal graft by double-balloon enteroscopy (DBE) for surveillance of rejection and local CMV infection in patients undergoing either single pancreas (SPT) or combined pancreas and kidney transplantation (SPK). Methods: Between August 2009 and December 2011, 39 pancreas transplantations (SPK n= 31; SPT n= 8) were performed. All patients underwent consecutive px of the duodenal graft at 1, 3, 6 and 12-month post-transplant. Thereafter, duodenal-px was continued yearly and/or on-demand basis. Rejection was evaluated according to the Banff criteria for small bowel allografts. All samples were immunostained for focal cytomegalovirus (CMV) infection. Results: Patient and survival rate for the study cohort were 100%. Overall 86 mucosal px of the duodenal graft were obtained in 36 patients. No procedure-related complications were observed. DBE was feasible in 90% of the study cohort. In 7 out of 39 patients (17.9%) (SPK n= 4; SPT n=3) rejection was diagnosed in the duodenal graft. All patients in the SPK group presented also rejection in the kidney graft, either simultaneously (n= 2) or previous to the duodenal px (n= 2, 14 and 50 days pre-duodenal-px). In SPT group, subclinical rejection was diagnosed in 3 of 8 patients. Local CMV-infection was detected in 5 patients (13%) (SPK n= 3; SPT n= 2). In 1 patient with focal CMV infection, spontanuous perforation of the duodenal graft was observed at 1-month. Subsequent duodenal px at 1-month post-treatment showed reversal of both rejection episodes and focal CMV-infections. Conclusion: Serial protocol px of the duodenal segment of the pancreas graft by DBE is safe and might represent an effective method for surveillance of both rejection and focal CMV-infection after clinical pancreas transplantation.

Update on Islet Cell Transplantation for Type 1 Diabetes

Despite modern medical breakthroughs, diabetes mellitus is a worldwide leading cause of morbidity and mortality. Definitive surgical treatment of diabetes mellitus was established with the advent and refinement of clinical pancreas transplantation in the 1960s. During the following decades, critical discoveries involving islet isolation and engraftment took place. Clinical islet cell transplantation represents the potential for reduced insulin requirements and debilitating hypoglycemic episodes without the morbidity of surgery. Unfortunately, islet cell transplantation was unable to achieve comparable results with solid organ transplantation. This was until the Edmonton protocol (steroid-free immunosuppression) was described, which demonstrated that islet cell transplantation could be a viable alternative to pancreas transplantation. Significant advances in islet purification techniques and novel immunomodulatory agents have since renewed interest in islet cell transplantation. Yet the field is still challenged by a limited supply of islet cells, inadequate engraftment, and the deleterious effects of chronic immunosuppression. This article discusses the history and the current status of clinical islet cell transplantation.

Richard Carlton Lillehei Transplant and Shock Surgical Pioneer

ABSTRACTRichard Carlton Lillehei (1927–1981) was a trainee of the Minnesota School of Surgery under Owen H. Wangensteen in the early 1950s, when great advances were being accomplished in cardiac surgery. His mentors besides Wangensteen included his brother C. Walton Lillehei, Richard L. Varco, and several others in the Department of Surgery. His interest in surgical research was evident since the early part of his training. The understanding of the nature and management of shock occupied his attention and persisted all his life. Equally, his studies on organ preservation and intestinal and pancreatic transplantation were classic in the evolution of surgery. In fact, Rich Lillehei, together with William Kelly, performed the world's first clinical pancreas transplant in 1966 and with his own team, the world's first clinical small bowel transplantation in 1967. Following that, these two areas of transplantation progressively advanced to be applied to thousands of patients worldwide. Lillehei was also a committed teacher and many of his students are disseminated throughout the globe. Unfortunately, his enormous contributions were cut short with his premature death at age 53. However, his surgical legacy remains alive!

Anti-CD25 Antibody (Daclizumab) Maintenance Therapy in Pancreas Transplantation

Background Calcineurin inhibitors (CNI) are the basis of contemporary immunosuppression in clinical pancreas transplantation (PT). Nevertheless, CNI toxicities, especially nephrotoxicity, have stimulated the search for CNI-sparing protocols. We performed a retrospective analysis of 25 PT patients with progressive CNI toxicities that were switched to a daclizumab (DAC)–based maintenance regimen. Methods From 2003 to 2007, 25 PT patients with progressive CNI toxicity (predominantly nephrotoxicity) were identified and switched from CNI to monthly DAC maintenance therapy. The DAC group was compared with matched control subjects (1:1) by transplant type and number, age, year of transplant, and duct management. Results and conclusions Results showed improved graft survival rates and decreased immunologic loss rates at 1, 3, and 5 years in the DAC group compared with the control group. There was no difference in patient survival rate between the 2 groups. Analysis demonstrates that DAC maintenance therapy is safe and effective for PT patients experiencing CNI toxicities. A randomized trial to compare DAC- and CNI-based regimens is needed in CNI-intolerant patients, with particular attention to the impact on renal function and patient morbidity (eg, infection rates).

Transplante de pâncreas

Diabéticos insulino-dependentes são susceptíveis a altas taxas de complicações secundárias. O transplante de pâncreas teve início na Universidade de Minesota em 1966, com altas taxas de insucessos. Porém, recentemente, este procedimento tem obtido melhores resultados, conjuntamente com outros transplantes de órgãos. Os autores analisam, retrospectivamente, os fatores associados a melhora nos resultados do transplante de pâncreas, entre eles a seleção dos doadores, a técnica de retirada do pâncreas, a cirurgia do receptor com drenagem da secreção pancreática exócrina na bexiga ou no jejuno, o protocolo de imunossupressão, as falhas técnicas como tromboses vasculares, hemorragias, rejeição e infecção no Hospital das Clinicas da Universidade de São Paulo. As sobrevidas do enxerto e dos pacientes são analisadas no período de 1997 a 2006.

A prospective randomized multicenter trial comparing histidine-tryptophane-ketoglutarate versus University of Wisconsin perfusion solution in clinical pancreas transplantation

We aimed to evaluate early pancreas transplant graft function after histidine-tryptophan-ketoglutarate (HTK) versus University of Wisconsin (UW) perfusion. Prospective randomized multicenter study including 68 pancreas transplantations stratified according to preservation fluid used (27 HTK vs. 41 UW). Primary endpoint was pancreas graft survival at 6 months. Serum alpha-amylase, lipase, C-peptide, HbA1C and exogenous insulin requirement were compared at several time points. Mean pancreas cold ischemia time was 10.8 +/- 3.7 (HTK) vs. 11.8 +/- 3.4 h (UW) (P = 0.247). Simultaneous pancreas-kidney transplantation was performed in 95.6% of the patients, pancreas transplantation alone in 2.9%, and pancreas after kidney transplantation in 1.5%. Six months graft survival was 85.2% (HTK) vs. 90.2% (UW) (P = 0.703). Serum amylase and lipase values did not differ between both the groups during the observation period. C-peptide levels were elevated in both the groups without significant differences at each time point. Higher exogenous insulin requirement early after transplantation in the UW group had resolved at 3 months. Six month patient survival was 96.3% (HTK) vs. 100% (UW) (P = 0.397). With a mean cold ischemia time of 10 h in this study, HTK and UW solutions appear to be equally suitable for perfusion and organ preservation in clinical pancreas transplantation.

Advances in immunosuppression for pancreas transplantation

A review of current literature was performed to identify trends and evaluate outcomes with regard to clinical immunosuppression in pancreas transplantation. Through 2006, over 20 000 pancreas transplantations were performed in the US. Since 2000, the 1-year patient survival rates for the three pancreas transplantation categories--simultaneous pancreas-kidney, sequential pancreas after kidney, and pancreas alone--were 95-97% and the 1-year pancreas graft survival (complete insulin independence) rates were 85%, 78%, and 77%, respectively. One-year rates of rejection have steadily decreased and are currently in the 10-20% range depending on case mix and immunosuppressive regimen. At present, 88% of recipients receive antibody induction, 65% receive maintenance therapy with the tacrolimus/mycophenolate mofetil combination, and 40-50% undergo corticosteroid withdrawal without adverse consequences. Limited data with tacrolimus/sirolimus reveal excellent short-term outcomes, whereas initial attempts with calcineurin inhibitor avoidance or minimization are less promising. Antibody induction and either tacrolimus/mycophenolate mofetil or tacrolimus/sirolimus maintenance therapy with steroid withdrawal have become the mainstay of contemporary immunosuppression in clinical pancreas transplantation. The development of a nonnephrotoxic, nondiabetogenic, and nongastrointestinal toxic regimen, however, is highly desirable to improve outcomes and quality of life in recipients.

Comparison of M-Kyoto Solution and Histidine−Tryptophan−Ketoglutarate Solution With a Trypsin Inhibitor for Pancreas Preservation in Islet Transplantation

The use of University of Wisconsin (UW) preservation solution in islet transplantation has some disadvantages, including inhibition of collagenase activity for pancreatic digestion. Histidine-tryptophan-ketoglutarate (HTK) solution has demonstrated an efficacy similar to UW solution for organ preservation in clinical pancreas transplantation. Recently, we reported that islet yield from porcine pancreata was significantly gtreater when they were preserved using M-Kyoto solution compared with UW solution. Here, we compared HTK solution with ulinastatin (M-HTK) and M-Kyoto solution for islet yield. In porcine islet isolation, islet yield after purification was significantly greater in the M-Kyoto/perfluorochemical (PFC) group compared with the M-HTK/PFC group. The M-Kyoto/PFC group had a significantly lower ADP/ATP ratio compared with the M-HTK/PFC group, suggesting that different islet yields might be due to the differences as energy sources of the solutions used. In conclusion, M-Kyoto/PFC solution is better for pancreas preservation before islet isolation than M-HTK/PFC solution.

Sirolimus Improves Early Microcirculation, but Impairs Regeneration After Pancreatic Ischemia-Reperfusion Injury

Ischemia and reperfusion injury remains a relevant problem in clinical pancreas transplantation. We investigated the effect of sirolimus (SRL) in a rodent model of 90-min warm pancreatic ischemia. Four groups were studied: (1) sham surgery and vehicle; (2) sham surgery and SRL; (3) warm ischemia and vehicle; (4) warm ischemia and SRL. SRL (1.5 mg/kg/day) and vehicle were administered intraperitoneally for 3 days prior to surgery until the animals were killed. Microcirculation was assessed immediately after reperfusion by means of intravital fluorescence microscopy. Histopathological injury, apoptosis, proliferation and biochemical parameters were analyzed at 2 h, 1 day and 5 days after surgery. Ninety minutes after ischemia, intravital microscopy revealed an improved functional capillary density (p < 0.05) and reduction of adherent leucocytes (p < 0.01) and platelets (p < 0.05) in the SRL-treated group compared to the vehicle-treated controls. In contrast, on day 5 after ischemia, the pancreatic tissue of SRL-treated animals showed a higher grade of histological injury (p < 0.05) and higher rate of apoptotic cells (p < 0.05) than the vehicle controls. In summary, our data indicate that administration of SRL improves microcirculation at a very early stage, but results in an impairment of the recovery phase after pancreatic ischemia-reperfusion injury.

What is Successful Islet Transplantation in 2006?

Pre-Edmonton Era—The PastDuring the past six years, transplant teams have been intensely focused on improving the rather dismal history of pancreatic islet allograft transplantation in humans. This short review will consider the status of islet transplantation in 2006 in the context both of success rates of islet transplantation prior to 2000 and current success with whole pancreas transplantation.Successful clinical pancreas transplantation for type 1 diabetes was first reported by the University of Minnesota in 1966 (see Figure 1). In the ensuing years, operative techniques and immunosuppressive drug regimens improved significantly.

University of Wisconsion Solution Versus Celsior Solution in Clinical Pancreas Transplantation

Introduction This study compared the safety and efficacy of University of Wisconsin solution (UW) and Celsior solution (C) in pancreas transplantation (PTx). Methods A retrospective review of 154 PTx performed over a 61-month period included 77 grafts preserved with UW and 77 with C. The two groups were comparable for both donor and recipient characteristics. Results After a mean cold ischemia time of 624 minutes (range 360 to 945 minutes) for UW versus 672 minutes (range 415 to 1005 minutes) for C ( P = NS), no primary endocrine nonfunction occurred. Delayed endocrine function was diagnosed in two grafts in the UW group (2.6%) versus none in the C group ( P = NS). After a minimum follow-up of 4 months (mean 26.5 ± 15.2 months), 22 recipients (UW = 11 vs C = 11; P = NS) required relaparotomy. Overall, 18 pancreata were lost due to either patient death with functioning graft (UW = 4 vs C = 1; P = NS) or graft loss due to other reasons (UW = 8 vs C = 5; P = NS). Actuarial 1- and 5-year patient survival rates were 93.5% and 86.8% for UW compared with 98.7% and 98.7% for C ( P = .04). Actuarial graft survival rates at the same times were 88.3% and 75.0% for UW compared with 90.4% and 90.4% for C ( P = NS). Conclusions Within the range of cold ischemia times reported in this study, UW and C show similar safety and efficacy profiles for PTx.

In Vivo Imaging of Human Pancreatic Microcirculation and Pancreatic Tissue Injury in Clinical Pancreas Transplantation

Pancreatitis remains to be a major complication following clinical pancreas transplantation. We performed orthogonal polarized spectral (OPS) imaging for direct in vivo visualization and quantification of human pancreatic microcirculation in six healthy donors for living donor liver transplantation and 13 patients undergoing simultaneous pancreas-kidney transplantation. We further determined the impact of microvascular dysfunction during early reperfusion on pancreatic graft injury. Exocrine and endocrine pancreatic impairment was determined by analysis of serum lipase, amylase and C-peptide levels. Compared to normal pancreas in liver donors (homogeneous acinar perfusion) functional capillary density (FCD) and capillary red blood flow velocity of reperfused grafts were significantly decreased. Elevated CRP concentrations on day 2 post-transplant and serum lipase and amylase levels determined on days 4-5 significantly correlated with microvascular dysfunction during the first 30 min of graft reperfusion. Post-transplant serum C-peptide also correlated significantly with pancreatic capillary perfusion. OPS imaging allows to intra-operatively assess physiologic pancreatic microcirculation and to determine microcirculatory impairment during early graft reperfusion. This impairment correlated with the manifestation of post-transplant dysfunction of both exocrine and endocrine pancreatic tissue. OPS imaging may be used clinically to determine the efficacy of interventions, aiming at attenuating microcirculatory impairment during the acute post-transplant reperfusion phase.