Whole-pancreas Transplantation Research Articles

Pancreatic islet transplantation in type 1 diabetes: 20-year experience from a single-centre cohort in Canada

Islet transplantation offers an effective treatment for selected people with type 1 diabetes and intractable hypoglycaemia. Long-term experience, however, remains limited. We report outcomes from a single-centre cohort up to 20 years after islet transplantation. This cohort study included patients older than 18 years with type 1 diabetes undergoing allogeneic islet transplantation between March 11, 1999, and Oct 1, 2019, at the University of Alberta Hospital (Edmonton, AB, Canada). Patients who underwent islet-after-kidney transplantation and islet transplantation alone or islet transplantation before whole-pancreas transplantation (follow-up was censored at the time of whole-pancreas transplantation) were included. Patient survival, graft survival (fasting plasma C-peptide >0·1 nmol/L), insulin independence, glycaemic control, and adverse events are reported. To identify factors associated with prolonged graft survival, recipients with sustained graft survival (≥90% of patient follow-up duration) were compared with those who had non-sustained graft survival (<90% of follow-up duration). Multivariate binary logistic regression analyses were done to determine predictors of sustained graft survival. Between March 11, 1999, and Oct 1, 2019, 255 patients underwent islet transplantation and were included in the analyses (149 [58%] were female and 218 [85%] were White). Over a median follow-up of 7·4 years (IQR 4·4-12·2), 230 (90%) patients survived. Median graft survival was 5·9 years (IQR 3·0-9·5), and graft failure occurred in 91 (36%) patients. 178 (70%) recipients had sustained graft survival, and 77 (30%) had non-sustained graft survival. At baseline, compared with patients with non-sustained graft survival, those with sustained graft survival had longer median type 1 diabetes duration (33·5 years [IQR 24·3-41·7] vs 26·2 years [17·0-35·5]; p=0·0003), median older age (49·4 years [43·5-56·1] vs 44·2 years [35·4-54·2]; p=0·0011), and lower median insulin requirements (0·53 units/kg per day [0·45-0·67] vs 0·59 units/kg per day [0·48-0·70]; p=0·032), but median HbA1c concentrations were similar (8·2% [7·5-9·0] vs 8·5% [7·8-9·2]; p=0·23). 201 (79%) recipients had insulin independence, with a Kaplan-Meier estimate of 61% (95% CI 54-67) at 1 year, 32% (25-39) at 5 years, 20% (14-27) at 10 years, 11% (6-18) at 15 years, and 8% (2-17) at 20 years. Patients with sustained graft survival had significantly higher rates of insulin independence (160 [90%] of 178 vs 41 [53%] of 77; p<0·0001) and sustained improvements in glycaemic control mixed-main-effects model group effect, p<0·0001) compared with those with non-sustained graft survival. Multivariate analyses identified the combined use of anakinra plus etanercept (adjusted odds ratio 7·5 [95% CI 2·7-21·0], p<0·0001) and the BETA-2 score of 15 or higher (4·1 [1·5-11·4], p=0·0066) as factors associated with sustained graft survival. In recipients with sustained graft survival, the incidence of procedural complications was lower (23 [5%] of 443 infusions vs 17 [10%] of 167 infusions; p=0·027), whereas the incidence of cancer was higher (29 of [16%] of 178 vs four [5%] of 77; p=0·015) than in those with non-sustained graft survival; most were skin cancers (22 [67%] of 33). End-stage renal disease and severe infections were similar between groups. We present the largest single-centre cohort study of long-term outcomes following islet transplantation. Although some limitations with our study remain, such as the retrospective component, a relatively small sample size, and the absence of non-transplant controls, we found that the combined use of anakinra plus etanercept and the BETA-2 score were associated with improved outcomes, and therefore these factors could inform clinical practice. None.

Beta-cell function and human islet transplantation: can we improve?

Islet transplantation, a therapeutic option to treat type 1 diabetes, is not yet as successful as whole-pancreas transplantation as a treatment for diabetes. Mouse models are commonly used for islet research. However, it is clear disparities exist between islet transplantation outcomes in mice and humans. Given the shortage of transplant-grade islets, it is crucial that we further our understanding of factors that determine long-term islet survival and function post-transplantation. In turn, this may lead to new therapeutic targets and strategies that will improve transplant outcomes. Here, we summarise the current landscape in clinical transplantation, highlight underlying similarities and differences between mouse and human islets, and review interventions that are being considered to create a new pool of β-cells for clinical application.

Tissue-engineering approaches in pancreatic islet transplantation.

Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.

Human Pancreatic Islet Production: From Research Protocols to Standardized Multicenter Manufacturing.

Transient function following human pancreatic islet allotransplantation in a subject with type 1 diabetes was first reported over 25 years ago (1). Since then, clinical outcomes have been progressively improving, and nowadays islet transplantation represents a largely applied procedure that in experienced centers has a success rate similar to that of whole-pancreas transplantation (2,3). It might appear of little interest to discuss again the technical aspects of human islet manufacturing and to ask, is it justified to spend much time and many resources to further improve these procedures? The answer is yes, of course. Islet isolation and purification, that is islet manufacturing, are key elements in any islet transplant program. The ability to retrieve most of the islets from a human pancreas is the obvious prerequisite for the success of an islet transplant, as in vivo islet graft function significantly correlates with the number of transplanted islets (4). In addition, islet isolation procedures greatly affect islet quality in terms of viability, function, and proinflammatory conditions, all factors associated with in vivo islet graft function (5,6). The optimization of islet production will also lead to an improved cost efficacy of the overall islet transplant programs, which is now among the major limiting factors for the wider application of this procedure. A detailed …

PDB42 - COST EFFECTIVENESS OF ALLOGENIC PANCREATIC ISLET TRANSPLANTATION VERSUS WHOLE PANCREAS TRANSPLANTATION IN THE UNITED KINGDOM

The study objective was to evaluate the cost-effectiveness of allogenic pancreatic islet transplantation (PIT) compared to whole pancreas transplantation (WPT) in adult patients with brittle type 1 diabetes (T1DM) and eligible for β-cell replacement in UK. A life-time horizon Markov model was developed to reflect the progression of patients who undergo β-cell replacement. The cohort moves across 8 health states: transplant, insulin independent, insulin dependent without and with complete graft function loss, macrovascular complications, microvascular complications, macro- and microvascular complications, death. Acute adverse events were also considered. Parametric extrapolations of insulin independence and graft survival were performed based on data from the Collaborative Islet Transplantation Registry (CITR) and the International Pancreas Transplant Registry (IPTR). All other clinical and quality of life data were derived from literature. Costs from the 3rd party payer perspective were obtained from official sources and from the literature. Both costs and health outcomes, life years (LYs) and quality adjusted LYs (QALYs), were annually discounted at 3.5%. As expected, better overall survival and lower complication rates increased both LYs and QALYs gained in PIT vs WPT, resulting in incremental values of 1.15 and 0.62 respectively. PIT was also associated with an incremental cost of £18,132 vs WPT. The resulting cost per LY and QALY gained with PIT vs WPT were £15,784 and £29,281 respectively. Deterministic and probabilistic sensitivity analysis showed overall robustness of the basecase results, with 74% of simulations located below the threshold of £100,000/QALY, usually considered for the assessment of orphan drugs in UK. To our knowledge, this is the first model to assess PIT against WPT for the treatment of brittle T1DM. Recognizing limitations, mainly due to the lack of direct comparative evidence, PIT seems to represent a cost-effective option to WPT in UK.

Liraglutide in whole-pancreas transplant patients with impaired glucose homoeostasis: A case series

Hyperglycaemia may develop after whole-pancreas transplantation (PTX) in patients with type 1 diabetes mellitus (T1DM), but the efficacy and tolerability of GLP-1 receptor agonists have not been assessed in this population. This report is a 6-month prospective follow-up of six T1DM recipients of PTX (mean time after PTX: 68.8±45.7 months), all of whom had an HbA1c>6.5% (48mmol/mol) [mean: 7.1% (54mmol/mol)] after initiation of liraglutide alone at 0.6mg once daily titrated to 1.2mg once daily at week 1. Gastrointestinal disorders were reported in three of the six patients, with discontinuation of liraglutide in only one patient. HbA1c improved in the five remaining patients, with a median decrease of 0.8% (0.0–2.7%) at 6 months, and the median decrease in body weight was 2.0kg. Immunosuppressive treatments remained unchanged with liraglutide. Thus, liraglutide appears to be an effective and well-tolerated option in PTX patients with impaired glucose homoeostasis, regardless of the cause.

Pancreas transplantation: a treatment option for people with diabetes

Since the first pancreas transplants in the early 1960s, whole-organ pancreas transplantation, either alone or combined with kidney transplantation, has become commonplace in many countries around the world. Whole-organ pancreas transplantation is available in the UK, with ~200 transplants currently carried out per year. Patient survival and pancreas graft outcome rates are now similar to other solid organ transplant programmes, with high rates of long-term insulin independence. In the present review, we will discuss whole-pancreas transplantation as a treatment for diabetes, focusing on indications for transplantation, the nature of the procedure performed, graft survival rates and the consequences of pancreas transplantation on metabolic variables and the progression of diabetes-related complications.

The Incretin Response After Successful Islet Transplantation

The Incretin Response After Successful Islet Transplantation

A Low-Oxygenated Subpopulation of Pancreatic Islets Constitutes a Functional Reserve of Endocrine Cells

OBJECTIVEThe blood perfusion of pancreatic islets is highly variable and tightly regulated by the blood glucose concentration. Thus, oxygen levels are considered crucial for islet metabolism and function. Although islet oxygenation has been extensively studied in vitro, little is known about it in vivo. The current study aimed to investigate the oxygenation of the endocrine pancreas in vivo.RESEARCH DESIGN AND METHODSThe reductive metabolism of 2-nitroimidazoles, such as pimonidazole, has previously been extensively used in studies of oxygen metabolism both in vitro and in vivo. At tissue oxygen levels <10 mmHg, pimonidazole accumulates intracellularly and may thereafter be detected by means of immunohistochemistry. Islet oxygenation was investigated in normal, 60% partially pancreatectomized, as well as whole-pancreas–transplanted rats. Moreover, leucine-dependent protein biosynthesis was performed using autoradiography to correlate islet oxygenation with metabolic activity.RESULTSIn vivo, 20–25% of all islets in normal rats showed low oxygenation (pO2 <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low-oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Moreover, oxygenation was related to metabolism, since well-oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis.CONCLUSIONSThe current study suggests a novel subpopulation of dormant low-oxygenated islets, which seems to constitute a functional reserve of endocrine cells. This study establishes a novel perspective on the use of the endocrine pancreas in glucose homeostasis.

Improved Second Phase Insulin Secretion and Preserved Insulin Sensitivity After Islet Transplantation

Improved Second Phase Insulin Secretion and Preserved Insulin Sensitivity After Islet Transplantation

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

The two-layer cold storage method (TLM) was first 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.

Immunological aspects of pancreatic islet cell transplantation

Type 1 diabetes mellitus (T1DM) is one of the most common diseases of childhood. Insulin discovery changed the clinical course of T1DM from an acutely fatal disease to a chronic disease, but this discovery was later found to be inefficient to control its long-term complications. Whole-pancreas and islet cell transplantation seem to provide a potential solution by restoring the normal physiology of glucose–insulin homeostasis. Although islet transplantation is less invasive than whole-pancreas transplantation, the insulin-free state after islet transplantation remained low (10%) at 5 years after surgery. Here, we will present the specific immunologic challenges that are specific to islet cell transplantation, including instant blood-mediated inflammatory reaction and the recurrence of autoimmunity. We will also briefly discuss the immunosuppressive regimens used and the recent radiologic techniques in the detection of engraftment and early rejection of islet cells.

Kidney and pancreas transplantation in type 1 diabetes mellitus

Type 1 diabetes mellitus is characterized by autoimmune destruction of pancreatic beta cells, leading to a state of absolute insulin deficiency. Glycemic control via the use of exogenous insulin injections is often imperfect, resulting in multiple long-term complications, such as retinopathy, neuropathy, vasculopathy, and nephropathy. The Diabetes Control and Complications Trial has provided conclusive evidence that better glycemic control by intensive insulin treatment effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes mellitus. At this moment, the only reliable option for achieving long-term insulin independence is whole-pancreas transplantation. The proposed benefits of pancreas transplantation are clear: improved quality of life, prevention of recurrent diabetic nephropathy, freedom from exogenous insulin with euglycemia and normalization of glycosylated hemoglobin, less stringent dietary restrictions, less frequent blood glucose monitoring, and stabilization of or improvement in secondary complications. The trade-offs to the patient are the operative risk, the need for chronic immunosuppression, and the inherent side effects of chronic immunosuppression.

Simultaneous kidney-pancreas transplantation: The preferred option for patients with type I diabetes mellitus and approaching end-stage renal disease

Diabetes mellitus is a chronic disease often leading to disabling microvascular and macrovascular complications. Intensive treatment with insulin can only delay the progression of these complications. Normalization of the glucose homeostasis will reduce the cardiovascular morbidity and mortality. At this time, whole-pancreas transplantation is the only option to achieve long-term insulin independence, resulting in an improvement or stabilization of the microvascular and, at least partly, the macrovascular lesions. Therefore, simultaneous kidney-pancreas transplantation has become the preferred treatment option for selected patients with type I diabetes mellitus and approaching end-stage renal disease. With the improving results of isolated pancreas transplantation, this procedure may be offered with increasing frequency to diabetics with a good functioning kidney transplant or to diabetics with overt diabetic nephropathy but preserved renal function. In this review we describe recipient and donor selection criteria, some surgical techniques, survival rates, and the currently used immunosuppressive protocols, and at the end we propose a treatment strategy.

Perfluorocarbon for organ preservation before transplantation.

Perfluorocarbons (PFC) are hydrocarbons in which all or most of the hydrogen atoms have been replaced with fluorine. PFC have a very high capacity for dissolving oxygen (O2 ), and a negligible oxygen-binding constant allows them to release O2 more effectively than hemoglobin into the surrounding tissue. As a result of this unique property, PFC-based solutions have been examined as oxygen carriers. PFC was first used for organ preservation as a component of the two-layer method (TLM) (University of Wisconsin [UW] solution-perfluorochemical plus oxygen) of pancreas preservation. Pancreata preserved in the TLM are oxygenated through the PFC and substrates are supplied by the UW solution. This allows pancreata stored in the TLM to generate adenosine triphosphate during storage and prolong the preservation period. In the canine model, TLM has been shown to repair and resuscitate warm ischemically injured pancreata during preservation, improve pancreas graft survival after transplantation, and improve islet yields after isolation. Current clinical trials using the TLM of pancreas preservation before whole-pancreas transplantation and islet isolation show promising results. The TLM has also been shown to be beneficial for preserving other difficult organs, such as heart and small bowel.

Islet/pancreas transplantation: challenges for pediatrics.

Beta cell replacement is a valid alternative to exogenous insulin injections to treat type 1 diabetic patients. The rate of success obtained after whole-pancreas transplantation, performed alone or in combination with kidney, and, as shown recently, by islet transplantation, justifies optimism and sets the stage for a larger clinical application of these approaches. Lifetime immunosuppression, however, required to protect the graft against recurrent autoimmune destruction and allorejection, raises serious doubts about the safety of its employment in children. While it is evident that children may be helped even more than adults by the possibility to correct diabetic metabolic disorders without exogenous insulin, and to lower in a more effective way the chance to develop secondary complications, the drawbacks of the currently used immunosuppressive drugs largely overcome the potential benefits. A great step forward for immediate applicability of transplantation to children involves the optimization of tolerogenic protocols and a better understanding of the concept of immune ignorance. Functional tolerance should be sufficient to entail the absence of immune reactivity against self- and graft antigens, while maintaining immune reactivity against other non-self, non-donor antigens. In addition, novel strategies aimed at utilizing surrogate beta cells obtained from non-islet cells, or by genetic manipulation of beta-cell precursors merit consideration as the use of xenogeneic donors. However, much work is still needed for their safe clinical implementation.

Oxygen tension in isolated transplanted rat islets and in islets of rat whole-pancreas transplants.

Despite similar immunosuppressive protocols having been applied, the success rate of pancreatic islet transplantation has been much lower than that of whole-pancreas transplantation. We compared the oxygen tension in syngeneically transplanted isolated rat islets and islets of syngeneic rat whole-pancreatic grafts, with native islets, using Clark-type microelectrodes. An oxygen tension of approximately 40 mmHg was recorded in both native islets and in islets of the whole-pancreas graft. Isolated islets transplanted under the renal capsule had a markedly lower oxygen tension ( approximately 6 mmHg). The exocrine parenchyma of the native and of the transplanted pancreatic gland had an oxygen tension of approximately 30 mmHg. The lower oxygen tension in transplanted isolated islets may be one explanation for the more frequent failures of transplanted islets compared with the outcome when the whole pancreatic gland is transplanted.

Simultaneous pancreas-kidney and pancreas transplantation.

The discovery of insulin in 1922 changed the treatment of type 1 diabetes mellitus (DM) forever. Insulin was the first effective therapy for type 1 DM; however, its success engendered a terrible paradox for patients with this disease. The use of insulin transformed type 1 DM from a rapidly fatal

Initial Experience With Clinical Islet Transplantation in Argentina

WHOLE pancreas transplantation may be the best therapeutic option for type I diabetic patients in advanced stages of their disease. However, those patients who are not eligible for whole pancreas transplantation may still benefit from pancreatic cell transplantation, which in spite of its lower rate of insulin independence, involves a minor surgical procedure and a lower posttransplant risk. We herein report our initial experience on pancreatic islet transplantation at a kidney and pancreas transplantation program based in Argentina since 1995.

Pancreatic transplantation reverses endothelial dysfunction in experimental diabetes mellitus

<h2>Abstract</h2> <b>Background:</b> There is insufficient evidence whether transplantation of the whole pancreas can reverse vascular complications associated with diabetes. In this study we investigated whether pancreatic transplantation in experimental diabetes reverses established defects in endothelium-dependent relaxation. <b>Methods:</b> Streptozotocin-induced diabetic rats underwent whole-pancreas transplantation after 12 weeks of disease. Endothelial function was evaluated 4 weeks after transplantation and compared with that of control- and age-matched diabetic animals. Blood was taken for analysis of glucose, insulin, total glycosylated hemoglobin, and plasma amino acid levels. Descending thoracic aortas were isolated, sectioned into rings, and mounted in isolated tissue baths. In precontracted rings, endothelium-dependent relaxation to acetylcholine was performed and compared with endothelium-independent relaxation to nitroglycerin as a control. <b>Results:</b> Pancreatic transplantation normalized the increases in glucose and total glycosylated hemoglobin levels and the decrease in serum insulin levels. Diabetes resulted in impaired relaxation to acetylcholine without altering relaxation to nitroglycerin. Pancreatic transplantation completely restored the defective relaxation to acetylcholine without altering the relaxation to nitroglycerin. <b>Conclusions:</b> These results suggest that pancreatic transplantation selectively improved endothelium-dependent relaxation as opposed to a generalized improvement in vascular smooth muscle reactivity. Furthermore, these studies suggest for the first time that one aspect of vascular complications (i.e., endothelial dysfunction) is amenable to this surgical intervention. (Surgery 1998;123:89-95.)