Pancreas Transplantation Research Articles

Endocrine and exocrine function replacement by pancreas transplant alone: a case report on the oldest recipient in Korea

Endocrine and exocrine function replacement by pancreas transplant alone: a case report on the oldest recipient in Korea

The pancreas after kidney transplant is the second-best option, comparable to the simultaneous pancreas and kidney transplant

The pancreas after kidney transplant is the second-best option, comparable to the simultaneous pancreas and kidney transplant

Transforming organ transplantation with regenerative medicine: an interview with Giuseppe Orlando.

Giuseppe Orlando is an Associate Professor of Surgery and a kidney and pancreas transplant surgeon scientist at Wake Forest University School of Medicine (Winston-Salem, North Carolina), and the President Elect of the Cell Transplant and Regenerative Medicine Society. With a research interest in bioengineering and the regeneration of transplantable organs, Giuseppe's work seeks to establish the link between transplant medicine and regenerative medicine.

Impact of the PI3K-alpha inhibitor alpelisib on everolimus resistance and somatostatin receptor expression in an orthotopic pancreatic NEC xenograft mouse model.

The mechanistic target of rapamycin complex 1 (mTORC1) inhibitor everolimus is one of the few approved therapies for locally advanced and metastatic neuroendocrine tumours (NETs). However, after initial disease stabilisation, most patients develop resistance within 1 year. Our aim was to overcome resistance to everolimus by additional treatment with the PI3K-alpha inhibitor alpelisib in an everolimus-resistant orthotopic pancreatic neuroendocrine carcinoma xenograft mouse model. Female SCID mice underwent laparoscopic pancreatic transplantation of everolimus-sensitive (BON1KDMSO) or everolimus-resistant (BON1RR2) NET cells. Both groups were further divided into four treatment groups: placebo, everolimus, alpelisib, and everolimus + alpelisib (combination). Oral treatment was started at a tumour volume of approximately 140 mm3 and continued until 1900-2000 mm3, validated by weekly MRI. Somatostatin receptor expression and tumour viability were analysed by 68Ga-DOTATOC and 18F-FDG PET/CT. Everolimus resistance of the BON1RR2 tumours was confirmed. In the everolimus-sensitive group, everolimus alone, alpelisib alone, and combination treatment significantly prolonged survival, compared to placebo, while in the BON1RR2 group, only combination treatment significantly prolonged survival compared to placebo, but neither everolimus nor alpelisib alone. Placebo-treated everolimus-sensitive tumours grew more rapidly (median survival 45 days), compared to placebo-treated everolimus-resistant tumours (60 days). Within the everolimus-sensitive group, the combination-treated mice showed the longest median survival (52 days). Of all groups, the everolimus-resistant combination-treated group survived longest (69 days). Combination treatment with everolimus and alpelisib seems promising to overcome everolimus resistance in neuroendocrine neoplasms, and should be further examined in a clinical trial.

Abstract 17626: Apolipoprotein A-IV-Associated Cardiac Amyloidosis: A Classic Presentation of a Rare Condition

Introduction: A 65-year-old male with type one diabetes mellitus underwent a pancreas and kidney transplant approximately seven years ago and has received chronic tacrolimus. He presented with subacute dyspnea on exertion, orthopnea, and edema. His background also includes ongoing chronic kidney disease stage 3A, orthostatic hypotension, and spinal stenosis. On exam, he had abdominal and lower extremity swelling. An echocardiogram showed preserved LVEF, concentric hypertrophy, hyperrefractile myocardium, reduced longitudinal strain with apical sparing, and a tiny pericardial effusion. Hypothesis: His echocardiogram indicated an infiltrative process such as amyloidosis or tacrolimus cardiotoxicity or possibly hypertrophic cardiomyopathy. Methods: Free light chains and protein studies with mass-fixation demonstrated no monoclonal gammopathy. PYP scan was negative for transthyretin amyloidosis. A cardiac MRI showed patchy subendocardial and midmyocardial delayed gadolinium enhancement, supporting the clinical suspicion for cardiac amyloidosis. With the need to exclude tacrolimus toxicity as well, subsequent endomyocardial biopsy revealed apolipoprotein A-IV-associated cardiac amyloidosis (Figure 1). Results: Apolipoprotein A-IV-associated cardiac amyloidosis occurs in about 0.6% of patients with cardiac amyloid and has classic manifestations of LV outflow obstruction, microvascular disease, and especially renal insufficiency. When these features occur in patients with clinical and imaging findings suggesting cardiac amyloidosis despite negative testing for more common types of amyloidosis, clinicians should proceed with endomyocardial biopsy to evaluate for less common forms. Conclusions: We report a rare case of apolipoprotein A-IV-associated cardiac amyloidosis. This case highlights the need for endomyocardial biopsy when clinical suspicion for cardiac amyloidosis persists despite negative testing.

Interventional Radiology Approaches for Managing Postpancreatic Transplant Complications and Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-secreting beta cells in the pancreas, resulting in metabolic disturbances and long-term complications. While subcutaneous insulin remains the primary approach for achieving normoglycemia, pancreatic transplantation has emerged as an effective intervention for long-standing T1DM, providing insulin independence and normalized glycosylated hemoglobin levels. However, complications associated with pancreatic transplantation are frequent, necessitating thorough evaluation using diverse imaging modalities. This manuscript presents an overview of vascular complications encountered with pancreatic transplantation, including vascular complications such as arterial and venous graft thrombosis, vessel stenosis, pseudoaneurysm, arterio-enteric fistula, and arteriovenous malformations (AVM). Additionally, the manuscript discusses other associated complications such as pancreatitis, pseudocyst formation, fistulas, pseudo-thrombosis of the iliac vein, post-transplantation lymphoproliferative disorder, and fluid collections. The integration of various imaging modalities plays a crucial role in diagnosing and managing these complications, with interventional radiologists assuming a vital role in employing image-guided procedures. Moreover, the manuscript explores pancreatic islet cell transplantation as a promising cellular-based therapy for T1DM, offering stable long-term glycemic control and decreased reliance on exogenous insulin in a significant proportion of recipients. This minimally invasive procedure involves the image-guided transcatheter infusion of islet cells obtained from deceased donors into the recipient's liver. The importance of interventional radiologists in managing complications related to pancreatic transplantation is underscored, with endovascular or image-guided approaches being utilized to address the diverse spectrum of encountered complications. Furthermore, the potential of islet cell transplantation as a minimally invasive alternative to traditional pancreatic transplantation is emphasized, as it offers the prospect of alleviating many associated complications.

Role of gastric peroral endoscopic myotomy (GPOEM) in chronic gastroparesis management after pancreas transplantation.

Gastroparesis is a common complaint among patients with diabetes. Symptoms tend to improve following successful pancreas transplantation (PTx), but persist despite euglycemia in a subset of patients. We aimed to assess the benefit of gastric peroral endoscopic myotomy (G-POEM) in persistent gastroparesis following PTx. This was a single center retrospective review of all patients who underwent G-POEM for persistent gastroparesis following PTx. Patient demographics, pre and post procedure perception of symptom severity according to the patient assessment of upper gastrointestinal symptoms severity index (PAGI-SYM), gastroparesis cardinal symptom index (GCSI) score, and 36-item short form survey (SF36) score along with gastric emptying scintigraphy (GES) were analyzed. Seven PTx recipients underwent G-POEM for persistent gastroparesis symptoms. The majority were female. All reported nausea/vomiting, abdominal pain, bloating, and post prandial fullness prior to G-POEM. The post procedure survey scores improved in all patients although this was not significant. The improvement in gastric emptying on GES was statistically significant. G-POEM is a relatively new treatment option for gastroparesis. While it requires specialized proceduralist and training, we have documented improvement in the management of symptoms. With increasing experience, we anticipate more significant benefit in post PTx patients with persistent symptoms of gastroparesis undergoing G-POEM.

Midnight Cortisol is Associated with Changes in Systolic Blood Pressure and Diabetic Neuropathy in Subjects with Type1 Diabetes Undergoing Simultaneous Kidney-Pancreas Transplantation.

An increased midnight cortisol (MC) has been described in end-stage kidney disease (ESKD) and type1 diabetes (T1D). Lower circulating levels of the cytokine soluble tumor necrosis factor (TNF)-like weak inducer of apoptosis (sTWEAK) have been found in T1D and ESKD and associated with cardiovascular (CV) events in the latter. We aimed to study MC and sTWEAK in simultaneous pancreas-kidney transplant (SPKT) recipients, and the association of these markers with CV risk factors and transplant outcomes. This was a retrospective cohort study including subjects with T1D who received a first SPKT between 2008 and 2020. MC and sTWEAK at baseline were correlated with CV risk factors and evolution 1year after SPKT. We included 29 subjects (58.6% women, mean age 43.5 ± 7.5years, diabetes duration 31.9 ± 9.4years). Systolic blood pressure (SBP) increased directly with MC quartiles, despite similar hypertension prevalence (p < 0.05). At 1year, antihypertensive treatment was deintensified in those in lower MC quartiles (p < 0.05). Diabetic neuropathy prevalence decreased progressively in higher cortisol quartiles (p for trend = 0.005). Low MC was associated with delayed kidney graft function (p for trend = 0.044), and high sTWEAK with kidney graft rejection (p for trend = 0.018). In multivariate analyses, MC (standardized-β 0.505, p = 0.004) and age (standardized-β - 0.460, p = 0.040) were independently correlated with SBP, and MC was independently associated with the presence of diabetic neuropathy (OR 0.633, 95%CI 0.425-0.944, p = 0.025), adjusted for confounders. In this exploratory study, lower MC was associated with a lower baseline SBP, an improvement of antihypertensive treatment 1year after transplant, and a higher diabetic neuropathy prevalence in SPKT recipients.

Disseminated Intravascular Coagulation in the Immediate Postoperative Period After a Simultaneous Kidney Pancreas Transplant (SPK)

Disseminated Intravascular Coagulation in the Immediate Postoperative Period After a Simultaneous Kidney Pancreas Transplant (SPK)

Pretransplant HbA1C as a Predictor of Kidney and Pancreas Allograft Survival in Simultaneous Pancreas-Kidney Transplantation: A Retrospective Nationwide Study

Pretransplant HbA1C as a Predictor of Kidney and Pancreas Allograft Survival in Simultaneous Pancreas-Kidney Transplantation: A Retrospective Nationwide Study

Incidence, Risk Factors, and Outcomes of Post-Transplant Erythrocytosis Among Simultaneous Pancreas and Kidney Transplant Recipients

Incidence, Risk Factors, and Outcomes of Post-Transplant Erythrocytosis Among Simultaneous Pancreas and Kidney Transplant Recipients

ECM-based bioactive microencapsulation significantly improves islet function and graft performance.

Microencapsulation is a promising strategy to prolong the survival and function of transplanted pancreatic islets for diabetes therapy, albeit its translation has been impeded by incoherent graft performance. The use of decellularized ECM has lately gained substantial research momentum due to its innate capacity to augment the function of cells originating from the same tissue type. In the present study, the advantages of both these approaches are leveraged in a porcine pancreatic ECM (pECM)-based microencapsulation platform, thus significantly enhancing murine pancreatic islet performance. pECM-encapsulated islets sustain high insulin secretion levels in vitro, surpassing those of islets encapsulated in conventional alginate microcapsules. Moreover, pECM-encapsulated islet cells proliferate and produce an enriched intra-islet ECM framework, displaying a distinctive structural rearrangement. The beneficial effect of pECM encapsulation is further reinforced by the temporary protection against cytokine-induced cytotoxicity. In-vivo, this platform significantly improves glucose tolerance and achieves glycemic correction in 100% of immunocompetent diabetic mice without any immunosuppression, compared to only 50% mice achieved glycemic correction by alginate encapsulation. Altogether, the results presented herein reveal that pECM-based microencapsulation offers a natural pancreatic niche that can restore the function of isolated pancreatic islets and deliver them safely, avoiding the need for immunosuppression. STATEMENT OF SIGNIFICANCE: Aiming to improve pancreatic islet transplantation outcomes in diabetic patients, we developed a microencapsulation platform based on pancreatic extracellular matrix (pECM). In these microcapsules the islets are entrapped within a pECM hydrogel that mimics the natural pancreatic microenvironment. We show that pECM encapsulation supports the islets' viability and function in culture, and provides temporal protection against cytokine-induced stress. In a diabetic mouse model, pECM encapsulation significantly improved glucose tolerance and achieved glycemic correction without any immunosuppression. These results reveal the potential of pECM encapsulation as a viable treatment for diabetes, providing a solid scientific basis for more advanced preclinical studies.

Understanding Barriers and Strategies to Increase Pancreas Transplantation: A Delphi Survey of US Transplant Professionals

Understanding Barriers and Strategies to Increase Pancreas Transplantation: A Delphi Survey of US Transplant Professionals

Newest And Most Promising Type 1 Diabetes Treatment.

Dear Madam, According to the International Diabetes Federation, Pakistan has the highest diabetes prevalence in the world (1).Ttype 1 diabetes (T1DM), a chronic condition where the pancreas makes little or no insulin. Despite extensive research, cure for T1DM has not been found. Typical treatment uses insulin injections, diet modifications, and exercise to manage blood sugar. This letter concisely explains the latest treatments for T1DM. Conventionally, exogenic insulin substitution was done by testing blood sugar levels after finger pricking. However, modern treatments include automated glucose monitoring technology and insulin pumps. Since T1DM is an autoimmune disease caused by the destruction of B-cells, the replacement of B-cells using allogeneic solid organ pancreas or islet transplantation treats the disease (2). However, this treatment requires lifelong immunosuppression drugs, that could lead to severe infections or nephrotoxicity. Other approaches include targeting T-cells, B-cells, or specific single antigens of which limitations range from side effects due to cytokine storm or inability to identify the key antigen. Even though immunotherapies further refined targeted inflammatory pathways, there is a lack of evidence as to if they can restore immune tolerance. On the other hand, therapies targeting cell-intrinsic metabolism may enhance B-cell survival but may result in B-cell dysfunction (2). Given the grim situation of current T1DM treatments, the artificial pancreas is revolutionary. Specific hybrid artificial pancreas required the patient to count the carbohydrates consumed at mealtime. The modern system uses continuous glucose monitoring technology (a sensor inserted under the skin), delivering insulin via the infusion pump according to the blood glucose level. The modern MiniMed 780G artificial pancreas is the first insulin delivery system to automatically administer bolus correction insulin dosage every 5 minutes and adjust insulin doses based on glucose levels. This technology can rectify insufficient or skipped pre-meal dosages by providing extra insulin. A study of 4120 780G users reported that outcomes matched the recommended goals by the American Diabetes Association’s Standards while commending its ability to achieve low variability in glycemic controls (3). Another prospective study published in 2023 concluded that switching to the 780G improves the restoration of hypoglycemia awareness and metabolic control(4). One notable side effect of this system is localized skin infection(5). In conclusion, treatment options for T1DM are ever-growing. The artificial pancreas shows promising results with milder side effects compared to other treatments. Further advancements are integral.

Real-World Experience With CMV inSIGHT T Cell Immunity Testing in High-Risk Kidney and Pancreas Transplant Recipients.

Cytomegalovirus (CMV)-specific cell-mediated immunity is important for control of CMV after transplant. Assays exist to measure this, but their place in therapy is unclear, particularly in CMV high-risk recipients, without pretransplant exposure. The objective of this study was to evaluate predictive potential of a positive assay to determine freedom from DNAemia and describe subsequent 3-month CMV outcomes. Adult CMV high-risk kidney and/or pancreas transplant recipients were included if a CMV inSIGHT T Cell Immunity Panel (TCIP, Eurofins Viracor) was ordered and resulted between 1 August, 2019 and 30 July, 2022. Seventy-six patients were included in our study; 49 tested during prophylaxis and 27 during treatment. Most TCIP assays obtained in the prophylaxis cohort were negative (n = 46, 93.9%). Rate of post-TCIP CMV infection was 10.2%. In those tested during treatment, 33.3% were positive and rate of post-TCIP CMV recurrence was 22.2%. The positive predictive value of the assay to successfully predict immunity was 66.7% during both prophylaxis and treatment. There were 4 cases of TCIP predictive failure with progressive CMV replication. At time of replication, 2 patients had concomitant clinical confounders thought to influence immune control of viral replication. All patients had intensification of immunosuppression prior to recurrent replication, but after TCIP was collected. The data obtained from the TCIP are not static, immune control of CMV in latency can change and must be evaluated in clinical context. Timing of TCIP after transplant is significant, and patient-specific factors remain important to assess the likelihood of CMV in each unique patient-specific scenario. A CMV stewardship program can aid in application and interpretation of results.

Novel technique for arterial reconstruction in simultaneous pancreas-kidney transplantation, a randomized clinical trial

IntroductionSimultaneous pancreas kidney (SPK) transplantation is an invaluable procedure to enhance the quality of life of insulin-dependent patients with advanced renal disease. The creation of vascular anastomoses of the donor’s pancreas vessels to the recipient’s, is of utmost importance to predict the graft outcome and surgical complications. In the study we introduce a novel technique for arterial reconstruction during SPK transplantation.MethodsConventionally, during the SPK transplantation, a so-called Y-graft is anastomosed between donor’s superior mesenteric and splenic artery to the recipient’s right iliac artery. In the study we adopted a new technique by preparing an extra extension using the donor’s carotid artery, to be anastomosed to the Y-graft and the iliac artery. In this non-blinded randomized clinical trial we compared the surgical complications and early outcomes between the 2 groups of patients with the traditional and new arterial reconstruction techniques during 3 months after transplantation.ResultsThirty adult patients were included in the study. The incidence of pancreatitis, vascular thrombosis and surgical site infection was lower in the new Y-graft and extension technique, which was not statistically significant. However, the calculated Cohen’s d index showed the medium effect of new Y-graft and extension technique on complication after SPK transplantations.ConclusionThe post-operative complications tend to be lower in the novel arterial reconstruction technique, however a study on a larger patient group is encouraged to confirm our primary results.Trial registrationThe study was registered at the Iranian Registry of Clinical Trials on 12/05/2022; IRCT 20210625051701N2; (http://www.irct.ir/).

Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell–mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods

The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell–mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.

Incidental appendicectomy in pancreas transplantation: A single-center study.

Appendicitis in pancreatic transplant recipients can be challenging to diagnose and manage. Incidental appendicectomy (IA) during pancreas transplantation obviates the risk of appendicitis but potentially at the cost of increased operating time or early post-operative complications. This study reviewed the value of IA at a single center. This was a retrospective study of patients who underwent a pancreas transplant in our unit from January 1st, 2012 to December 31st, 2020, with end of follow-up on May 21st, 2023; recipients were grouped by whether or not an IA was performed during pancreas transplantation. Donor, recipient, operative, and graft outcomes were compared between the two groups. Post-transplant complications related to appendiceal pathology (or IA) were recorded and classified. Two hundred forty-three patients underwent a pancreas transplant; 227 (93%) patients had an appendix in situ at transplantation, and of these 53 (23%) underwent an IA and 174 (77%) did not. There were no statistically significant differences in operative time (p=.06) or hospital stay (p=.50) between the two groups. In the IA cohort, there were no Clavien-Dindo Grade III-V complications relating to the appendicectomy. In those that did not undergo an IA, two patients (1%) subsequently required appendicectomy due to appendicitis. Comparison of pancreatic graft survival showed no statistically significant difference between the groups (p=.44). This study suggests that IA is effective at reducing risks of post-transplant appendiceal complications without significantly prolonging inpatient stay or impairing graft survival. These data support the consideration of undertaking an IA for all patients undergoing a pancreas transplant.

Risk of cytomegalovirus infection and subsequent allograft failure after pancreas transplantation

Cytomegalovirus (CMV) is a common cause of infection after transplantation, but few studies have evaluated its epidemiology, risk factors, and outcomes among pancreas transplant recipients. We performed a retrospective cohort study of adults who underwent pancreas transplantation from January 1, 2010, through December 31, 2020, at 3 sites in Arizona, Florida, and Minnesota. The primary outcome was clinically significant CMV infection (csCMVi), defined as CMV disease or infection requiring antiviral therapy. The secondary outcome was pancreas allograft failure. Among 471 pancreas transplant recipients, 117 (24.8%) developed csCMVi after a median of 226 (interquartile range 154-289) days. CMV donor (D)+/R- patients had a significantly higher incidence of csCMVi (hazard ratio [HR] 4.01, 95% confidence interval [CI] 2.10-7.64; P < .001). In adjusted analysis, a lower absolute lymphocyte count (ALC) was associated with a greater risk of csCMVi among seropositive recipients (HR 1.39 per 50% decrease, 95% CI 1.13-1.73; P = .002) but not among D+/R- patients (HR 1.04 per 50% decrease, 95% CI 0.89-1.23; P = .595). csCMVi, lower ALC, and acute rejection (P < .001) were independently associated with pancreas allograft failure. In conclusion, CMV D+/R- was associated with csCMVi in pancreas recipients, although ALC was associated with csCMVi only among seropositive patients. The development of csCMVi in pancreas recipients was associated with poor pancreas allograft outcomes.

The Current Status of Allogenic Islet Cell Transplantation.

Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized T1D treatment and offered a glimpse at a cure for the disease. In 2022, the 20-year follow-up findings of islet cell transplantation demonstrated the long-term safety of islet cell transplantation despite chronic immunosuppression. The Edmonton Protocol, however, remains limited by two obstacles: scarce organ donor availability and risks associated with chronic immunosuppression. To overcome these challenges, the search has begun for an alternative cell source. In 2006, pluripotency genomic factors, coined "Yamanaka Factors," were discovered, which reprogram mature somatic cells back to their embryonic, pluripotent form (iPSC). iPSCs can then be differentiated into specialized cell types, including islet cells. This discovery has opened a gateway to a personalized medicine approach to treating diabetes, circumventing the issues of donor supply and immunosuppression. In this review, we present a brief history of allogenic islet cell transplantation from the early days of pancreatic remnant transplantation to present work on encapsulating stem cell-derived cells. We review data on long-term outcomes and the ongoing challenges of allogenic islet cell and stem cell-derived islet cell transplant.