Donor Pancreas Research Articles

P.170: Preliminary Results on the Development of a Perfusion Device to Study the Function of 3D Bioprinted Pancreatic Tissue In Vitro

Background: The emergent field of 3D bioprinting has the potential to overcome hypoxia and lack of immunoprotection, two major limitations of islet transplantation in encapsulation systems. When transitioning tissue engineered constructs from bench to bedside, several design parameters must be considered, including tissue geometry, islet density, and oxygen tension in different transplantation sites. To address this challenging multifactorial optimization process, we have designed an in vitro flow device that can be used to evaluate bioprinted tissue performance in vitro under different flow, oxygen and tissue geometry conditions. The aim of this work was to assess the function and viability of single 3D bioprinted core-shell fibres containing pseudo-islets or human islets in a novel perfusion device designed to accommodate bioprinted tissues. Methods: The perfusion device was designed using computer-aided design modelling. Computational fluid dynamics (CFD) was used to simulate flow and compute input parameters that would ensure laminar, uniform flow. Pseudo-islets were formed after aggregation of MIN6 cells in AggrewellTM culture plates during 48h. Pseudo-islets and human islets were 3D bioprinted in alginate using an RX1 bioprinter (AspectBiosystems, Vancouver, CA). Free or encapsulated pseudo-islets or human islets were cultured in static conditions as controls. Pseudo-islet function was determined using a glucose stimulation insulin secretion (GSIS) assay in static or perfused conditions. Viability of human islets was evaluated using Calcein AM/Ethidium Homodimer staining. Results: Based on our computational models, by setting the inlet flow speed to 1.0 cm/s, we can achieve physiological flow velocities within the device. This inlet flow speed is also expected to generate smooth, undisturbed streamlines and laminar flow. After a 24h culture in the perfusion device, we detected increased insulin secretion of pseudo-islets in fibres in response to high glucose stimulation (ratio of secreted to total insulin of 0.27% after 15 min at high glucose vs 0.13% after 15 min at low glucose). Human islets bioprinted in fibres showed higher cell viability compared to free human islets after a 48h culture (95% of viability in fibres cultured in the perfusion device compared to 80% viability for free islets). As these results were obtained from a single human pancreas donor, further studies are needed to assess the reproducibility and statistical significance of these observations. Conclusion: These promising preliminary results suggest that (1) the flow device we designed can be used to evaluate the performance of 3D bioprinted pancreatic tissue and (2) pseudo-islets and human islets can be safely bioprinted in core-shell fibres. The platform can be used to streamline the characterization and optimize the configuration in vitro of promising artificial tissues at human-scale. MITACS Accelerate in collaboration with Aspect Biosystems Ltd. Stem Cell Network. ThéCell. CMDO, réseau de recherche en santé cardiométabolique, diabète et obésité. Montreal Diabetes Research Center. Centre Québécois sur les Matériaux Fonctionnels. PROTEO. McGill Regenerative Medicine. Bioencapsulation Research Group.

Impact of insulin therapy before donation on graft outcomes in pancreas transplantation: An analysis of the OPTN/UNOS database

AimsInformation on the impact of insulin therapy before pancreas donation on pancreas outcomes is scarce. We aim to explore the influence of insulin therapy before donation on recipient and pancreas graft survival. MethodsRegistry study including 12,841 pancreas recipients from the OPTN/UNOS registry performed between 2000 and 2017. Inverse probability of treatment weighting (IPTW) was used to account for covariate imbalance between recipients from a donor with and without insulin requirements. ResultsA total of 7765 (60%) patients received a pancreas from a donor with insulin before donation (IBD). Pancreas graft survival (death-censored) was similar between recipients from IBD and non-IBD donors at 1, 5 and 10 years (89% vs 89%, 78% vs 79 and 69% vs 70%, respectively, P = 0.35). Recipients from IBD donors presented a similar 90-days pancreas graft survival. After IPTW weighting, IBD donors were neither associated with any post-transplant surgical complication (HR 1.11 [95% CI 0.98–1.24], P = 0.06), nor with risk for recipient death (HR 0.94 [95% CI 0.85–1.04], P = 0.26), nor pancreas graft failure (HR 1.06 [95% CI 0.98–1.16], P = 0.15). ConclusionsInsulin therapy before donation in accepted pancreas donors was not associated, per se, with an impaired pancreas graft and patient survival.

Association of human leukocyte antigen mismatches between donor-recipient and donor-donor in pancreas after kidney transplant recipients.

The effects of HLA mismatching on pancreas outcomes among pancreas after kidney (PAK) recipients are undefined. Outcomes might potentially differ depending on whether there is a mismatch between pancreas donor and recipient (PD-R) or pancreas donor and kidney donor(PD-KD). All primary PAK at our centre were included in this study. Patients were divided into two groups based on the degree of HLA mismatching: low (L-MM) as 0-4 and high (H-MM) as 5-6. We analysed all (N=73) PAK for PD-R mismatch and the subset of PAK for PD-KD mismatch (N=71). Comparing PD-R L-MM (n=39) and H-MM (n=34) PAKs, we observed no difference in the rate of pancreas graft failure. There was also no difference in the rate of rejection (L-MM 33% vs. H-MM 41%) or the severity of rejection. However, we observed a significantly (P<0.01) shorter time to acute pancreas rejection in the H-MM group (6.8±8.7 mo) versus the L-MM cohort (29.0±36.2 mo) (P<0.001). Similar to the PD-R mismatched cohort, we did not observe a detrimental effect of HLA mismatching on graft outcomes in the PD-KD cohort; time to rejection was again shorter in the H-MM subset. In this study, we found no impact of HLA mismatch on either pancreas graft survival or rejection rates, though rejection occurred earlier in high mismatched PAK transplants.

Pancreas Donor Risk Index and Preprocurement Pancreas Suitability Score for Prediction of Pancreas Transplant Outcomes

The Pancreas Donor Risk Index and Preprocurement Pancreas Suitability Score were designed to assist in the evaluation of pancreases for transplant. Preprocurement Pancreas Suitability Score <17 and PancreasDonor Risk Index ≤1.57 were deemed ideal.We aimed to determine the ability ofthese scores to predict pancreas transplant outcomes. The Pancreas Donor Risk Index and the Preprocurement Pancreas Suitability Score were retrospectively calculated from a prospectively maintained database of consecutive pancreas transplants performed during a 13-year period (December 2004 to November 2017). Outcomes measuredwere rejection rate, graft and patient survival, and duration of hospital stay. Of 159 pancreas transplants (108 simultaneous pancreas and kidney transplants, 33 pancreas after kidney transplants, 18 pancreas-only transplants), full data were available for 155 (97%) to calculate Pancreas Donor Risk Indexes and 129 (81%) to calculate Preprocurement Pancreas Suitability Scores. Fortyseven patients (30%) experienced at least 1 episode of acute rejection. We calculated Pancreas Donor Risk Indexes for 155 patients, and 19 (23%) and 27 (38%) were in the ≤1.57 and >1.57 groups, respectively (P = .047). We calculated Preprocurement Pancreas Suitability Scores for 129 patients, and 12 (21%) and 27 (32%) were in the <17 and ≥17 groups, respectively (P = .202). Donor age and recipientfemale sex were the main predictors forrejection (binary logistic regression, P < .05). One-year graft survival rates were 95% and 81% forthe ≤1.57 and >1.57 PancreasDonor Risk Index groups,respectively, and 95% and 80% forthe <17 and ≥17 Preprocurement Pancreas Suitability Score groups, respectively (not significant). Pancreas Donor Risk Index and Preprocurement Pancreas Suitability Score were not helpful to predict graft/patient survival in our population. A higher Pancreas Donor Risk Index was associated with higher risk of graft rejection. Further studies with larger cohorts are required.

Intraperitoneal administration of human "Neo-Islets", 3-D organoids of mesenchymal stromal and pancreatic islet cells, normalizes blood glucose levels in streptozotocin-diabetic NOD/SCID mice: Significance for clinical trials.

Globally, individuals with autoimmune Type 1 diabetes mellitus (T1DM) continue to depend for survival on insulin injections. While pancreas and intrahepatic pancreatic islet transplants can produce insulin-independence and ameliorate serious complications, both therapies depend on potentially toxic anti-rejection drugs. Furthermore, the scarcity of pancreas donors and islet transplant failures limit the general availability of such interventions. Recently, fetal and induced Pluripotent Stem Cells have been successfully differentiated to generate insulin producing β-like cells that generate euglycemia in diabetic mice. However, their clinical use still depends on anti-rejection drugs or immune-isolating encapsulation systems. We reported recently that allogeneic “Neo-Islets” (NI), 3-D organoids of Mesenchymal Stromal and Islet Cells are immune protected and permanently correct autoimmune diabetes in NOD mice by omental engraftment and endocrine cell redifferentiation. This new “endocrine pancreas” delivers islet hormones physiologically into the hepatic portal vein. Furthermore, treatment of insulin-dependent dogs with allogeneic canine NIs (ongoing FDA-approved Pilot Study) consistently improved glycemic control without the need for antirejection drugs. As there remains a critical need for curative therapies of T1DM, we engineered human NIs and tested their ability, after i.p. administration, to reestablish euglycemia in streptozotocin (STZ)-diabetic NOD/SCID mice. This diabetes model reproduces, in part, the clinical situation in which recipients of allogeneic biotherapies must take potent anti-rejection drugs that similarly create a life-long immune-compromised status. The present study demonstrates that human NI therapy (2x10e5/kg bw NIs/mouse) of STZ-diabetic NOD/SCID mice (n = 6), compared to controls (n = 6) significantly improved glycemic control, and most importantly, that a second dose given to the initial group normalized blood glucose levels long-term. Conclusion: Despite the limitations of the utilized diabetic NOD/SCID mouse model, the obtained data show that human NIs are curative, an observation that has high translational relevance and significantly supports the planned conduct of clinical trials with human NIs.

Chronic marijuana usage by human pancreas donors is associated with impaired islet function.

We investigated the effect of chronic marijuana use, defined as 4 times weekly for more than 3 years, on human pancreatic islets. Pancreata from deceased donors who chronically used marijuana were compared to those from age, sex and ethnicity matched non-users. The islets from marijuana-users displayed reduced insulin secretion as compared to islets from non-users upon stimulation with high glucose (AUC, 3.41 ± 0.62 versus 5.14 ±0.47, p<0.05) and high glucose plus KCl (AUC, 4.48 ± 0.41 versus 7.69 ± 0.58, p<0.001). When human islets from chronic marijuana-users were transplanted into diabetic mice, the mean reversal rate of diabetes was 35% versus 77% in animals receiving islets from non-users (p<0.01). Immunofluorescent staining for cannabinoid receptor type 1 (CB1R) was shown to be colocalized with insulin and enhanced significantly in beta cells from marijuana-users vs. non-users (CB1R intensity/islet area, 14.95 ± 2.71 vs. 3.23 ± 0.87, p<0.001). In contrast, CB1R expression was not co-localized with glucagon or somatostatin. Furthermore, isolated islets from chronic marijuana-users appeared hypertrophic. In conclusion, excessive marijuana use affects islet endocrine phenotype and function in vitro and in vivo. Given the increasing use of marijuana, our results underline the importance of including lifestyle when evaluating human islets for transplantation or research.

Adult Pig Islet Isolation.

Type 1 diabetes mellitus (T1DM) is caused by autoimmune destruction of pancreatic β cells, which results in little or no insulin production. Islet transplantation plays an important role in the treatment of T1DM, with the improved glycometabolic control, the reduced progression of complications, the reduction of hypoglycemic episodes when compared with traditional insulin therapy. The results of phase III clinical trial also demonstrated the safety and efficacy of islet allotransplantation in T1DM. However, the shortage of pancreas donors limits its widespread use. Animals as a source of islets such as the pig offer an alternative choice. Because the architecture of the pig pancreas is different from the islets of mice or humans, the pig islet isolation procedure is still challenging. Since the translation of alternative porcine islet sources (xenogeneic) to the clinical setting for treating T1DM through cellular transplantation is of great importance, a cost-effective, standardized, and reproducible protocol for isolating porcine islets is urgently needed. This manuscript describes a simplified and cost-effective method to isolate and purify adult porcine islets based on the previous protocols that have successfully transplanted porcine islets to non-human primates. This will be a beginners guide without the use of specialized equipment such as a COBE 2991 Cell Processor.

Basement membrane proteins improve human islet survival in hypoxia: Implications for islet inflammation

Enzymatic digestion of the pancreas during islet isolation is associated with disintegration of the islet basement membrane (IBM) that can cause reduction of functional and morphological islet integrity. Attempts to re-establish IBM by coating the surface of culture vessels with various IBM proteins (IBMP) have resulted in loss of islet phenotype and function. This study investigated the capability of Collagen-IV, Laminin-521 and Nidogen-1, utilised as single or combined media supplements, to protect human islets cultured in hypoxia.When individually supplemented to media, all IBMP significantly improved islet survival and in-vitro function, finally resulting in as much as a two-fold increase of islet overall survival. In contrast, combining IBMP enhanced the production of chemokines and reactive oxygen species diminishing all positive effects of individually added IBMP. This impact was concentration-dependent and concerned nearly all parameters of islet integrity.Predictive extrapolation of these findings to data from 116 processed human pancreases suggests that more than 90% of suboptimal pancreases could be rescued for clinical islet transplantation increasing the number of transplantable preparations from actual 25 to 40 when adding Nidogen-1 to pretransplant culture.This study suggests that media supplementation with essential IBMP protects human islets from hypoxia. Amongst those, certain IBMP may be incompatible when combined or applied at higher concentrations. Statement of significancePancreatic islet transplantation is a minimally-invasive treatment that can reverse type 1 diabetes in certain patients. It involves infusing of insulin-producing cell-clusters (islets) from donor pancreases. Unfortunately, islet extraction is associated with damage of the islet basement membrane (IBM) causing reduced islet function and cell death. Attempts to re-establish the IBM by coating the surface of culture vessels with IBM proteins (IBMP) have been unsuccessful. Instead, we dissolved the most relevant IBM components Collagen-IV, Laminin-521 and Nidogen-1 in media routinely used for clinical islet culture and transplantation. We found human islet survival and function was substantially improved by IBMP, particularly Nidogen-1, when exposed to a hypoxic environment as found in vivo. We also investigated IBMP combinations. Our present findings have important clinical implications.

In vitro Induction of Human Dental Pulp Stem Cells Toward Pancreatic Lineages.

As of 2000, the success of pancreatic islet transplantation using the Edmonton protocol to treat type I diabetes mellitus still faced some obstacles. These include the limited number of cadaveric pancreas donors and the long-term use of immunosuppressants. Mesenchymal stem cells (MSCs) have been considered to be a potential candidate as an alternative source of islet-like cell generation. Our previous reports have successfully illustrated the establishment of induction protocols for differentiating human dental pulp stem cells (hDPSCs) to insulin-producing cells (IPCs). However, the induction efficiency varied greatly. In this paper, we demonstrate the comparison of hDPSCs pancreatic induction efficiency via integrative (microenvironmental and genetic manipulation) and non-integrative (microenvironmental manipulation) induction protocols for delivering hDPSC-derived IPCs (hDPSC-IPCs). The results suggest distinct induction efficiency for both the induction approaches in terms of 3-dimensional colony structure, yield, pancreatic mRNA markers, and functional property upon multi-dosage glucose challenge. These findings will support the future establishment of a clinically applicable IPCs and pancreatic lineage production platform.

Fibroblast growth factor 7 releasing particles enhance islet engraftment and improve metabolic control following islet transplantation in mice with diabetes

Transplantation of islets in type 1 diabetes (T1D) is limited by poor islet engraftment into the liver, with two to three donor pancreases required per recipient. We aimed to condition the liver to enhance islet engraftment to improve long‐term graft function. Diabetic mice received a non‐curative islet transplant (n = 400 islets) via the hepatic portal vein (HPV) with fibroblast growth factor 7‐loaded galactosylated poly(DL‐lactide‐co‐glycolic acid) (FGF7‐GAL‐PLGA) particles; 26‐µm diameter particles specifically targeted the liver, promoting hepatocyte proliferation in short‐term experiments: in mice receiving 0.1‐mg FGF7‐GAL‐PLGA particles (60‐ng FGF7) vs vehicle, cell proliferation was induced specifically in the liver with greater efficacy and specificity than subcutaneous FGF7 (1.25 mg/kg ×2 doses; ~75‐µg FGF7). Numbers of engrafted islets and vascularization were greater in liver sections of mice receiving islets and FGF7‐GAL‐PLGA particles vs mice receiving islets alone, 72 h posttransplant. More mice (six of eight) that received islets and FGF7‐GAL‐PLGA particles normalized blood glucose concentrations by 30‐days posttransplant, versus zero of eight mice receiving islets alone with no evidence of increased proliferation of cells within the liver at this stage and normal liver function tests. This work shows that liver‐targeted FGF7‐GAL‐PLGA particles achieve selective FGF7 delivery to the liver‐promoting islet engraftment to help normalize blood glucose levels with a good safety profile.

Estado actual del trasplante de páncreas. Experiencia del Hospital Doce de Octubre

Pancreas transplantation (PT) is considered as the only treatment that can convert a diabetic patient in a euglucemic state without the use of insulin or oral antidiabetic drugs. From 1996 to the end of 2016, more than 50,000 PT were performed in USA, and in Spain were performed 1.730 PT during the last 10 years. In this review we will perform an update of PT considering the introduction of several advances in the last years, adding our accumulated experience from the beginning of our program in the year 1995. The first PT was carried out in the Hospital of the University of Minnesota, and from that date several significant improvements have been introduced along the time due to advances in surgical technique in pancreas donors and recipients, perioperative management of patients, and introduction of more potent immunosuppressors able to reduce the rejection rate under 20%. Although PT is a therapy associated with a higher morbidity (pancreas graft thrombosis, systemic and intraabdominal infections, anastomotic leakages, etc.), currently most of the PT teams have obtained a rate of 93% of patient survival at 3-years, and between 78% and 83% of graft survival at 3-years. Additionally, the normal pancreas graft function is associated with an improvement of quality of life and most of complications related to diabetes, without the necessity to treat with antidiabetics drugs or insulin.

Donor Predictors of Donor Pancreas Retrieval and Subsequent Solid Pancreas Transplantation in Australia and New Zealand from 2007 to 2016

Donor characteristics help guide donor pancreas acceptance for solid pancreas-kidney transplantation; however, these criteria vary worldwide. Such variation could result in nonuse of potentially transplantable organs. Using a registry cohort, we identified donor characteristics associated with donor pancreas retrieval and subsequent solid pancreas transplantation in Australia and New Zealand. Australia and New Zealand Organ Donor registry donor data from 2007 to 2016 were used to define cohort 1 (all donors authorized for pancreas retrieval) and cohort 2 (all retrieved donor pancreata considered for solid pancreas transplantation). Donor factors significantly associated with donor pancreas retrieval (cohort 1) and solid pancreas transplantation of retrieved donor pancreata (cohort 2) were determined via multivariable logistic regression. Nonretrieval and nonuse of solid organ donor pancreas increased throughout the study period, and nonauthorization for pancreas donation remained stable. Donor body mass index, sex, and viral serology were associated with donor pancreas retrieval but not transplantation. Donor age, cause of death, donation after brain death status, terminal serum creatinine, and donor region were associated with both donor pancreas retrieval and acceptance for solid pancreas transplantation with donation after brain death status being the strongest predictor for both outcomes. Donor age, cause of death, donation after brain death status, terminal serum creatinine, and donor region were associated with both donor pancreas retrieval and subsequent transplantation in Australia and New Zealand. Subsequent correlation of these factors with post-pancreas transplant outcomes would help guide pancreas transplant decisions and minimize nonuse of potentially usable donor pancreata.

Training Experiences of American Society of Transplant Surgeons Fellows in Deceased Donor Organ Procurement.

Training Experiences of American Society of Transplant Surgeons Fellows in Deceased Donor Organ Procurement.

Simultaneous Pancreas-kidney Transplantation for Type 2 Diabetes Mellitus.

We read with interest the “KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation” published in the April 2020 issue of Transplantation,1 and we congratulate the authors for this important work. However, we are surprised to see the omission of patients with type 2 diabetes mellitus (DM) (often identified by having a normal c-peptide) as potential candidates for simultaneous pancreas-kidney transplantation (SPK) (Recommendation 8.1.1: We suggest candidates with ESKD and type 1 DM be considered for simultaneous pancreas-kidney transplantation in regions where this procedure is available [2A]). Numerous studies in the past decade have shown that carefully chosen SPK recipients with type 2 DM have comparable outcomes including patient and graft survival, reduction in overall morbidity, and improvement in quality-of-life metrics as those with type 1 DM. An analysis of the primary deceased donor pancreas transplants in patients with type 2 DM reported to International Pancreas Transplant Registry/United Network of Organ Sharing between 1995 and 2015 showed that SPK is a safe procedure with excellent pancreas and kidney graft outcome in patients with type 2 DM.2 In addition, in the United States, the Organ Procurement and Transplantation Network policy reflecting careful review of these data does not differentiate between type 1 and type 2 DM patients for SPK candidacy and allows the treatment option for any diabetic patient on insulin.3 Certainly, careful patient selection is paramount. Furthermore, restriction of SPK solely to type 1 DM patients disadvantages African Americans. In the United States, White Americans are more likely to develop type 1 DM, but the prevalence of type 2 DM is 1.4-fold to 2.3-fold higher in African Americans compared with White Americans. African Americans bear a disproportionate burden of the morbidity associated with diabetes, including a higher rate of retinopathy, microalbuminuria, end-stage kidney disease, lower-extremity amputation, and significant mortality. The waiting time for transplant is longer for African Americans than White candidates, and living-donor kidney transplantation rate is lowest for African Americans compared with all other racial groups. SPK allows for both shorter waiting time and often better-quality kidneys as compared with receiving a deceased donor kidney transplant alone, when living-donor kidney transplantation is not an option. Although a major revision to the US pancreas allocation system in 2014 has resulted in a demonstrable increase in pancreas transplant volume, the needs of the diabetic community remain unmet.4 Largely driven by SPK, pancreas transplants in patients with type 2 DM have increased, with comparable results to type 1 DM recipients.5 The proportion of patients with type 2 DM on the waiting list increased to 14.6% in 2018 (Figure 1), with SPK candidates accounting for 74.2% of the list.5 We respectfully request that KDIGO guidelines incorporate current evidence and practice to recommend SPK to medically suitable diabetic patients on insulin regardless of type. This change would be an important step to reduce the inequities in access to transplant benefits to racial minorities with type 2 DM.FIGURE 1.: Distribution of adults waiting for pancreas transplant by diagnosis. Candidates waiting for transplant at any time in the given year. Candidates listed concurrently at multiple centers are counted once. Active and inactive candidates are included.5

Local islet remodelling associated with duct lesion-islet complex in adult human pancreas.

Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)-islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN-islet complex. Cadaveric donor pancreases (26-65years old, n = 10) were fixed and sectioned (350μm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment. In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion-islet complexes detected; size: 3.18 ± 1.34mm). Important features of the lesion-islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct-islet cell contacts, forming a cluster. The duct-islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication. We identify local islet remodelling associated with PanIN-islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN-islet complex is derived from tissue repair after a local injury.

The impact of donor pancreas extraction time on graft survival and postoperative complications in pancreas transplant recipients

BackgroundSimultaneous pancreas kidney transplantation (SPK) is the best therapeutic option for patients with diabetes mellitus type 1 and end-stage renal disease. Recently, donor organ extraction time has been shown to affect kidney and liver graft survival. This study aimed to assess the effect of pancreas donor extraction time on graft survival and postoperative complications. MethodsWe retrospectively analyzed all pancreas transplants performed in two Eurotransplant centers. The association of pancreas extraction time with pancreas graft survival was analyzed by a Cox proportional hazards regression analysis after 3 months, 1 and 5 year. Besides, the effect of pancreas extraction time on the incidence of severe postoperative complications was analyzed. ResultsA total of 317 pancreas transplants were included in this study. Death-censored pancreas graft survival was 85.7% after one year and 76.7% after five years. Median pancreas donor extraction time was 64 min [IQR: 52–79 min]. After adjustment for potential confounders, death censored graft survival after 30 days (HR 1.01, 95% CI 0.9–1.03 (p = 0.23), 1 year (HR 1.01, 95% CI 0.99–1.03 (p = 0.22) and 5 years (HR 1.00, 95% CI 0.99–1.02 (p = 0.57) was not associated with pancreas donor extraction time. However, extraction time was significantly associated with a higher incidence of Clavien-Dindo ≥3 complications compared to Clavien-Dindo 1 + 2 complications: OR 1.012, 95% CI 1.00–1.02 (p = 0.039). ConclusionsOur findings suggest that although no effect on graft survival was found, limiting pancreas extraction time can have a significant impact on lowering postoperative complications.

Lower beta cell yield from donor pancreases after controlled circulatory death prevented by shortening acirculatory warm ischemia time and by using IGL-1 cold preservation solution.

Organs from donors after controlled circulatory death (DCD III) exhibit a higher risk for graft dysfunction due to an initial period of warm ischemia. This procurement condition can also affect the yield of beta cells in islet isolates from donor pancreases, and hence their use for transplantation. The present study uses data collected and generated by our Beta Cell Bank to compare the number of beta cells in isolates from DCD III (n = 141) with that from donors after brain death (DBD, n = 609), before and after culture, and examines the influence of donor and procurement variables. Beta cell number per DCD III-organ was significantly lower (58 x 106 versus 84 x 106 beta cells per DBD-organ; p < 0.001) but their purity (24% insulin positive cells) and insulin content (17 μg / 106 beta cells in DCD III-organs versus 19 μg / 106 beta cells in DBD-organs) were similar. Beta cell number correlated negatively with duration of acirculatory warm ischemia time above 10 min; for shorter acirculatory warm ischemia time, DCD III-organs did not exhibit a lower beta cell yield (74 x 106 beta cells). Use of Institut Georges Lopez-1 cold preservation solution instead of University of Wisconsin solution or histidine-tryptophan-ketoglutarate also protected against the loss in beta cell yield from DCD III-organs (86 x 106 for IGL-1 versus 54 x 106 and 65 x 106 beta cells respectively, p = 0.042). Multivariate analysis indicates that both limitation of acirculatory warm ischemia time and use of IGL-1 prevent the reduced beta cell yield in islet cell isolates from DCD III-organs.

Results from an International Survey of Donor and Recipient Eligibility for Solid Organ Pancreas Transplantation.

BackgroundCurrent solid organ pancreas transplantation protocols have differing donor criteria for donor pancreas acceptance and recipient eligibility criteria for transplant workup. We quantified this variation and compared current Australia and New Zealand (ANZ) solid pancreas transplant eligibility criteria with current international practice.Material/MethodsA survey of donor and recipient eligibility criteria for solid pancreas transplantation was disseminated to 85 transplant units in 23 countries. Responses were grouped by regions (ANZ, North America, Eurotransplant, Europe, United Kingdom) and analyzed for significant differences between regions and for ANZ compared to all other regions.ResultsResponding UK pancreas transplant units reported the highest mean donor upper age limit (61 years old) and the highest mean donation after cardiac death donor (DCD) age limit (55 years old). All responding UK and USA units utilized DCD pancreas donors and accepted suitable type 2 diabetes (T2DM) recipients for pancreas transplantation; however, this was less common among responding European or Eurotransplant units. ANZ mean standard and DCD pancreas donor upper age limits (47 and 35 years old, respectively) were lower compared to all other regions (54 years old and 48 years old, respectively).ConclusionsPancreas donor age limits, DCD pancreas donor utilization, and transplanting T2DM recipients differ between responding pancreas transplant units. ANZ units have more conservative donor upper age limits compared to other responding units. Increased utilization of DCD pancreas donors and T2DM recipients while standardizing pancreas donor age limits might increase donor numbers and improve access to solid pancreas transplantation both locally and abroad.

Lessons from Human Islet Transplantation Inform Stem Cell-Based Approaches in the Treatment of Diabetes

Diabetes mellitus is characterized by the body’s inability to control blood glucose levels within a physiological range due to loss and/or dysfunction of insulin producing beta cells. Progressive beta cell loss leads to hyperglycemia and if untreated can lead to severe complications and/or death. Treatments at this time are limited to pharmacologic therapies, including exogenous insulin or oral/injectable agents that improve insulin sensitivity or augment endogenous insulin secretion. Cell transplantation can restore physiologic endogenous insulin production and minimize hyper- and hypoglycemic excursions. Islet isolation procedures and management of transplant recipients have advanced over the last several decades; both tight glycemic control and insulin independence are achievable. Research has been conducted in isolating islets, monitoring islet function, and mitigating the immune response. However, this procedure is still only performed in a small minority of patients. One major barrier is the scarcity of human pancreatic islet donors, variation in donor pancreas quality, and variability in islet isolation success. Advances have been made in generation of glucose responsive human stem cell derived beta cells (sBCs) and islets from human pluripotent stem cells using directed differentiation. This is an emerging promising treatment for patients with diabetes because they could potentially serve as an unlimited source of functional, glucose-responsive beta cells. Challenges exist in their generation including long term survival of grafts, safety of transplantation, and protection from the immune response. This review focuses on the progress made in islet allo- and auto transplantation and how these advances may be extrapolated to the sBC context.

Risk indices predicting graft use, graft and patient survival in solid pancreas transplantation: a systematic review

BackgroundRisk indices such as the pancreas donor risk index (PDRI) and pre-procurement pancreas allocation suitability score (P-PASS) are utilised in solid pancreas transplantation however no review has compared all derived and validated indices in this field. We systematically reviewed all risk indices in solid pancreas transplantation to compare their predictive ability for transplant outcomes.MethodsMedline Plus, Embase and the Cochrane Library were searched for studies deriving and externally validating risk indices in solid pancreas transplantation for the outcomes of pancreas and patient survival and donor pancreas acceptance for transplantation. Results were analysed descriptively due to limited reporting of discrimination and calibration metrics required to assess model performance.ResultsFrom 25 included studies, discrimination and calibration metrics were only reported in 88% and 38% of derivation studies (n = 8) and in 25% and 25% of external validation studies (n = 12) respectively. 21 risk indices were derived with mild to moderate ability to predict risk (C-statistics 0.52–0.78). Donor age, donor body mass index (BMI) and donor gender were the commonest covariates within derived risk indices. Only PDRI and P-PASS were subsequently externally validated, with variable association with post-transplant outcomes. P-PASS was not associated with pancreas graft survival.ConclusionMost of the risk indices derived for use in solid pancreas transplantation were not externally validated (90%). PDRI and P-PASS are the only risk indices externally validated for solid pancreas transplantation, and when validated without reclassification measures, are associated with 1-year pancreas graft survival and donor pancreas acceptance respectively. Future risk indices incorporating recipient and other covariates alongside donor risk factors may have improved predictive ability for solid pancreas transplant outcomes.