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OBJECTIVE - To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS -

Embryonic stem (ES) cells possess the potential to develop into multiple cell lineages in vitro, the differentiated progeny of which might be used for cell-based transplantation therapies. We have previously demonstrated that mouse ES cells can be induced to express several pancreas-restricted genes, including insulin (INS), glucagon (GLUC), somatostatin (SOM), pancreatic polypeptide (PP), islet amyloid polypeptide (IAPP), and PDX 1, the pancreaticoduodenal homeobox transcription factor essential for pancreas development. This study seeks to characterize the nature of the pancreatic endocrine precursor cells present in ES cell progeny. Murine D3 ES cells were allowed to spontaneously differentiate into embryoid bodies (EBs) in suspension cultures in 10% fetal calf serum and 5% [CO.sub.2] without specific growth factors or additives and then plated on adhesive plastic for up to 3 weeks. Cultures were studied using confocal double label immunofluorescence microscopy. Clusters of cells in 2 and 3 week cultures coexpressed both [Beta] cell hormones, INS and IAPP, in intracytoplasmic granules, IAPP-expressing cells did not coexpress SSEA-3, a visceral yolk sac endoderm marker or NCAM, a neural marker. Cells expressing GLUC, SOM, and PP were also present but were not coexpressed with IAPP or INS. GLUC-expressing cells did not express SOM; but many GLUC-expressing cells in 2 week cultures also expressed peptide YY. Conclusions: Mouse ES cells can be induced to express a pancreatic islet-like phenotype. This study demonstrates the ability of pluripotent murine ES cells to differentiate into endodermally-derived pancreatic islet precursors.

Objective: To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.Research Design and Methods: A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999-2002), mid (2003-2006), or recent (2007-2010) transplant era based on annual follow-up to 5 years.Results: Insulin independence at 3 years after transplant improved from 27% in the early era (1999-2002, n = 214) to 37% in the mid (2003-2006, n = 255) and to 44% in the most recent era (2007-2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA(1c) and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007-2010 vs. 60-65% in 1999-2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).Conclusions: The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007-2010 compared with those in 1999-2006, with fewer islet infusions and adverse events per recipient. [ABSTRACT FROM AUTHOR]

Purpose: Evaluate cytomegalovirus (CMV) post-prophylaxis surveillance in high-risk (D+/R-) kidney and liver transplant recipients., Methods: Adult D+/R- patients were included if transplanted between 6/1/15 and 11/30/22 and divided into a pre-CMV-stewardship-era (6/1/15-5/31/18), CMV-stewardship-era (6/1/18-6/30/20), and a surveillance-era (7/1/2020-11/30/2022) then followed through 12 months. The primary objective was to evaluate CMV-related outcomes. The secondary objective was to assess graft and patient survival by era., Results: There were 328 patients in the study period; 133 in the pre-stewardship-era, 103 in the stewardship-era, and 92 in the surveillance-era. Replication rates in the surveillance-era were significantly higher, as anticipated due to increased sampling (pre 38.4%, stewardship 33.0%, surveillance 52.2%, p = 0.02). Time from transplant to first replication was similar (pre 214.0 ± 79.0 days, stewardship 231.1 ± 65.5, surveillance 234.9 ± 61.4, p = 0.29). CMV viral load (VL) at first detection, maximum-VL, and incidence of VL > 100 000 IU/mL were numerically lower in the surveillance era, although not statistically significant. CMV end-organ disease (p < 0.0001) and ganciclovir-resistance (p = 0.002) were significantly lower in the surveillance era than in both previous eras. Rejection was not different between eras (p = 0.4). Graft (p = 0.0007) and patient survival (p = 0.008) were significantly improved in the surveillance era., Conclusions: Post-prophylaxis surveillance significantly reduced CMV end-organ disease and resistance. Despite observing increased replication rates in the surveillance era, rejection was not significantly different and there was no graft loss or patient mortality at 12 months., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: 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., Objective: 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., Methods: 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., Results: 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., Conclusion and Relevance: 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., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mouse models are extensively used in metabolic studies. However, inherent differences between the species, notably their blood glucose levels, hampered data translation into clinical settings. In this study, we confirmed GLUT1 to be the predominantly expressed glucose transporter in both adult and fetal human β-cells. In comparison, GLUT2 is detected in a small yet significant subpopulation of adult β-cells and is expressed to a greater extent in fetal β-cells. Notably, GLUT1/2 expression in INS+ cells from human stem cell-derived islet-like clusters (SC-islets) exhibited a closer resemblance to that observed in fetal islets. Transplantation of primary human islets or SC-islets, but not murine islets, lowered murine blood glucose to the human glycemic range, emphasizing the critical role of β-cells in establishing species-specific glycemia. We further demonstrate the functional requirements of GLUT1 and GLUT2 in glucose uptake and insulin secretion through chemically inhibiting GLUT1 in primary islets and SC-islets and genetically disrupting GLUT2 in SC-islets. Finally, we developed a mathematical model to predict changes in glucose uptake and insulin secretion as a function of GLUT1/2 expression. Collectively, our findings illustrate the crucial roles of GLUTs in human β-cells, and identify them as key components in establishing species-specific glycemic set points., (© 2024 by the American Diabetes Association.)

Background: Cytomegalovirus (CMV) infections are common opportunistic infections in solid organ transplants (SOT) with increased health care resource USE and costs. Costs are further increased with ganciclovir-resistance (GR). This study aimed to evaluate the real-world impact of conversion to oral step-down therapy on duration of foscarnet and hospital length of stay (LOS) for treatment of GR-CMV infections in SOT., Methods: This study included adult recipients of kidney or lung transplants who received foscarnet for genotypically documented GR-CMV while admitted at the University of Wisconsin Hospital from October 1, 2015, to January 31, 2022. Patients in the oral step-down group were converted from standard of care (SOC; foscarnet) to maribavir or letermovir; patients in the historical control group were treated with SOC., Results: Twenty-six patients met the inclusion criteria: 5 in the intervention group and 21 in the SOC group. The median viral load at foscarnet initiation was 11,435 IU/mL. Patients who received oral step-down conversion had shorter mean foscarnet duration than those who received SOC (7 ± 4 vs 37 ± 25 days, P = .017). Mean hospital LOS in the oral step-down group (16 ± 3 days) was shorter than the SOC group (33 ± 21 days; P < .001). In the SOC group, 9 patients lost their graft, and 9 patients died; 2 deaths were attributed to CMV. There were 2 deaths in the oral step-down group, neither of which was attributed to CMV., Conclusion and Relevance: In this real-world case series of patients receiving treatment for GR-CMV infection, oral step-down conversion decreased foscarnet therapy duration and hospital LOS. Future studies are needed to evaluate better the effect of oral step-down in treating GR-CMV infection on treatment duration and cost-savings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is considerable interest in therapeutically engaging human γδ T cells. However, due to the unique TCRs of human γδ T cells, studies from animal models have provided limited directly applicable insights, and human γδ T cells from key immunological tissues remain poorly characterized. In this study, we investigated γδ T cells from human spleen tissue. Compared to blood, where Vδ2+Vγ9+ T cells are the dominant subset, splenic γδ T cells included a variety of TCR types, with Vδ1+ T cells typically being the most frequent. Intracellular cytokine staining revealed that IFN-γ was produced by a substantial fraction of splenic γδ T cells, IL-17A by a small fraction, and IL-4 was minimal. Primary splenic γδ T cells frequently expressed NKG2D (NK group 2 member D) and CD16, whereas expression of DNAM-1 (DNAX accessory molecule 1), CD28, PD-1, TIGIT, and CD94 varied according to subset, and there was generally little expression of natural cytotoxicity receptors, TIM-3, LAG-3, or killer Ig-like receptors. In vitro expansion was associated with marked changes in expression of these activating and inhibitory receptors. Analysis of functional responses of spleen-derived Vδ2+Vγ9+, Vδ1+Vγ9+, and Vδ1+Vγ9- T cell lines to recombinant butyrophilin BTN2A1 and BTN3A1 demonstrated that both Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells were capable of responding to the extracellular domain of BTN2A1, whereas the addition of BTN3A1 only markedly enhanced the responses of Vδ2+Vγ9+ T cells. Conversely, Vδ1+Vγ9+ T cells appeared more responsive than Vδ2+Vγ9+ T cells to TCR-independent NKG2D stimulation. Thus, despite shared recognition of BTN2A1, differential effects of BTN3A1 and coreceptors may segregate target cell responses of Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Purpose: Valganciclovir (VGC) is the gold-standard for cytomegalovirus (CMV) prophylaxis (PPX) after solid organ transplant (SOT). Letermovir (LTV) was recently approved in high-risk kidney transplant and has reduced myelosuppressive toxicity. Conversion from VGC to LTV may be pursued in the setting of leukopenia. It is unknown if this strategy is effective., Methods: Adult patients receiving abdominal SOT were included if converted from VGC to LTV between January 1, 2018 and January 31, 2023. Primary objective was to describe the impact of LTV conversion as measured by WBC recovery, mycophenolate modification, and use of GCSF, and prophylaxis efficacy assessed by course completion and breakthrough DNAemia. Secondary objective was to evaluate rates of post-prophylaxis CMV., Results: Seventy five SOT recipients met inclusion criteria. Mean change in WBC in response to LTV conversion by day 14 was +2.02 ± 2.52 k/uL. 75%(56/75) of the population did not require mycophenolate adjustment or had their dose increased after conversion. GCSF was required in 38.7%(29/75) prior to conversion; only 21.3%(16/75) of patients required GCSF after conversion. Early termination was uncommon, 14.7%(11/75) stopped due to lack of ongoing insurance approval, only one patient stopped due to adverse effects (1.3%). One patient had clinically significant breakthrough (1.3%) that was successfully managed with VGC. Incidence of post prophylaxis CMV was 40%., Conclusion: Withholding of VGC with LTV conversion may improve leukopenia without need for additional supportive measures. Most importantly, this strategy avoided additional mycophenolate modifications. In our study, LTV was associated with low rates of breakthrough. Post-prophylaxis CMV was similar to VGC prophylaxis., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To review the efficacy and safety of maribavir for management of cytomegalovirus (CMV) in solid organ transplant recipients., Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (1960 to early July 2022) was performed using the following search terms: maribavir, 1263W94 , and cytomegalovirus ., Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered, with a focus on phase 3 trials., Data Synthesis: Maribavir, an orally available benzimidazole riboside with minimal adverse effects, was originally studied for universal prophylaxis in phase 3 trials but failed to demonstrate noninferiority over placebo and oral ganciclovir. It was effective for preemptive treatment in a dose-finding Phase 2 study. Maribavir is FDA approved for treatment of refractory/resistant CMV infection based on improved response rate at 8 weeks compared with investigator-assigned therapy (IAT) when initiated at median viral loads less than approximately 10 000 IU/mL (55.7% vs 23.9%, P < 0.001). Recurrence after 8-week treatment for refractory/resistant CMV was high (maribavir 50% vs IAT 39%). Significant drug interactions exist and must be managed by a pharmacotherapy expert to prevent harm., Relevance to Patient Care and Clinical Practice: The addition of maribavir to the antiviral armamentarium should improve the management of refractory/resistant CMV, allowing early transition from toxic, high-cost, intravenous agents such as foscarnet and outpatient management. Optimal timing of initiation, duration, and potential alternative uses are unclear., Conclusion: Future studies are needed to fully elucidate the role of maribavir in the management of CMV after transplant.

Pancreas transplantation offers patients with diabetes an opportunity for glucose homeostasis. Current blood tests to surveil for rejection have poor sensitivity and specificity for identifying rejection, and pancreas biopsies are challenging and associated with morbidity and graft loss. Donor-derived cell-free DNA (dd-cfDNA) is shed from transplanted organs and detectable in peripheral blood. Thus, a potential dd-cfDNA blood test assessing rejection would be clinically advantageous., Methods: One hundred eighty-one dd-cfDNA samples (n) were collected from 77 patients (N) up to 132 mo posttransplant., Results: The median dd-cfDNA level among all subjects was 0.28% (0.13%, 0.71%). In simultaneous pancreas-kidney (SPK) transplant recipients, the median dd-cfDNA level was 0.29% (0.13%, 0.71%), and it was 0.23% (0.08%, 0.71%) in pancreas transplant alone (PTA) recipients. When isolating for when without infection or rejection, the median dd-cfDNA level was 0.28% (0.13%, 0.64%) for SPK and 0.20% (0.00%, 0.32%) for PTA. Both transplant types approached 1.0% ≤1 mo posttransplant followed by a decrease in median dd-cfDNA. During episodes of rejection or infection, median dd-cfDNA levels were greater among all transplant types., Conclusions: The mean dd-cfDNA level for all pancreas transplant recipients is <1.0%, consistent with the published kidney transplant rejection threshold (>1.0%), regardless of SPK or PTA. Early posttransplant dd-cfDNA levels are transiently higher than later measurements. Dd-cfDNA elevation also correlates with rejection and infection and thus is a promising biomarker for surveilling pancreas transplant dysfunction., Competing Interests: A.Y. received grant funding from the ASTS for this study. J.S.B. receives clinical trial grant funding from CareDx and Natera. J.S.O. receives clinical trial support from CareDx, Natera, Vertex, and Veloxis. M.C. receives clinical trial support from CareDx and Natera. The funders had no role in study design, data collection and analyses, decision to publish, or preparation of this manuscript. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

The identification of genes associated with human pancreatic beta cell maturation could stimulate a better understanding of normal human islet development and function, be informative for improving stem cell-derived islet (SC-islet) differentiation, and facilitate the sorting of more mature beta cells from a pool of differentiated cells. While several candidate factors to mark beta cell maturation have been identified, much of the data supporting these markers come from animal models or differentiated SC-islets. One such marker is Urocortin-3 (UCN3). In this study, we provide evidence that UCN3 is expressed in human fetal islets well before the acquisition of functional maturation. When SC-islets expressing significant levels of UCN3 were generated, the cells did not exhibit glucose-stimulated insulin secretion, indicating that UCN3 expression is not correlated with functional maturation in these cells. We utilized our tissue bank and SC-islet resources to test an array of other candidate maturation-associated genes, and identified CHGB, G6PC2, FAM159B, GLUT1, IAPP and ENTPD3 as markers with expression patterns that correlate developmentally with the onset of functional maturation in human beta cells. We also find that human beta cell expression of ERO1LB, HDAC9, KLF9, and ZNT8 does not change between fetal and adult stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tremmel, Mikat, Gupta, Mitchell, Curran, Menadue, Odorico and Sackett.)

Objectives: This study aimed to find the association between immediate postoperative increases in pancreatic enzymes and posttransplant complications among pancreas transplant recipients (PTRs)., Methods: We analyzed all PTRs transplanted at the University of Wisconsin between June 2009 and September 2018. Enzyme levels were presented as a ratio of absolute numbers to the upper limit of normal value, with value >1 considered as abnormal. We specifically evaluated bleeding, fluid collections, and thrombosis complications based on the amylase or lipase ratios on day 1 (Amylase1, Lipase1) and maximum ratios within 5 days of transplant (Amylasemax, Lipasemax). For early complications, we focused on technical complications that occurred within 90 days of transplant. For long-term outcomes, we assessed patient and graft survival, and rejections., Results: There were a total of 443 PTRs, 287 were simultaneous pancreas and kidney recipients, and 156 were solitary pancreas recipients. Higher Amylase1, Liplase1, Amylasemax, and Lipasemax were associated with an increase in early complications, mainly need for pancreatectomy, fluid collections, bleeding complications, or graft thrombosis, particularly in the solitary pancreas group., Conclusions: Our finding suggests that cases of early perioperative enzyme increase merit consideration for early imaging investigation to mitigate detrimental outcomes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Antimicrobial stewardship programs (ASPs) are essential entities that promote the appropriate use of antimicrobials, leading to improved patient outcomes and reduced resistance. Application to the immunocompromised host is a natural progression for expansion. Cytomegalovirus (CMV) infection is a common complication following solid organ transplant with significant implications on graft survival, making it an attractive ASP target. The aim of this piece is to review our center-specific experience with the development, implementation, and maintenance of a CMV stewardship initiative at a large transplant center., Methods: Our CMV stewardship initiative began in 2018. Herein, we review 3 years' experience and quality-related improvement that occurred from initiation to present state and share our stewardship algorithms. Special attention is paid to the impact of the program as well as our increased understanding of the complex interplay between prevention, treatment, and host development of CMV-specific cell-mediated immunity (CMI)., Results: We found our stewardship initiative not only reduced the incidence of ganciclovir resistance but also streamlined care via a centralized and structured approach. This objective, protocolized program has resulted in a significant shift away from a reactive to a proactive state and in turn, reduced CMV treatment rates (26% at initiation to 12% in the current state, p = .012)., Conclusion: A dedicated multidisciplinary team focused on CMV stewardship is imperative in providing a patient-centered approach focused on development of CMV-specific CMI, and as a result prevention of CMV disease. We believe these programs will be the new gold standard for CMV management., (© 2022 Wiley Periodicals LLC.)

Pancreas transplantation in patients with type 2 diabetes (T2D) remains relatively uncommon compared with pancreas transplantation in patients with type 1 diabetes (T1D); however, several studies have suggested similar outcomes between T2D and T1D, and the practice has become increasingly common. Despite this growing interest in pancreas transplantation in T2D, no study has systematically summarized the data to date. We systematically reviewed the literature on pancreas transplantation in T2D patients including patient and graft survival, glycemic control outcomes, and comparisons with outcomes in T2D kidney transplant alone and T1D pancreas transplant recipients. We searched biomedical databases from January 1, 2000, to January 14, 2021, and screened 3314 records, of which 22 full texts and 17 published abstracts met inclusion criteria. Full-text studies were predominantly single center (73%), whereas the remaining most often studied the Organ Procurement and Transplantation Network database. Methodological quality was mixed with frequent concern for selection bias and concern for inconsistent definitions of both T2D and pancreas graft survival across studies. Overall, studies generally reported favorable patient survival, graft survival, and glycemic control outcomes for pancreas transplantation in T2D and expressed a need to better characterize the T2D patients who would benefit most from pancreas transplantation. We suggest guidance for future studies, with the aim of supporting the safe and evidence-based treatment of end-stage T2D and judicious use of scarce resources., Competing Interests: The authors declare no conflict of interests., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The long-term outcomes of both pancreas and islet allotransplantation have been compromised by difficulties in the detection of early graft dysfunction at a time when a clinical intervention can prevent further deterioration and preserve allograft function. The lack of standardized strategies for monitoring pancreas and islet allograft function prompted an international survey established by an International Pancreas and Islet Transplant Association/European Pancreas and Islet Transplant Association working group., Methods: A global survey was administered to 24 pancreas and 18 islet programs using Redcap. The survey addressed protocolized and for-cause immunologic and metabolic monitoring strategies following pancreas and islet allotransplantation. All invited programs completed the survey., Results: The survey identified that in both pancreas and islet allograft programs, protocolized clinical monitoring practices included assessing body weight, fasting glucose/C-peptide, hemoglobin A1c, and donor-specific antibody. Protocolized monitoring in islet transplant programs relied on the addition of mixed meal tolerance test, continuous glucose monitoring, and autoantibody titers. In the setting of either suspicion for rejection or serially increasing hemoglobin A1c/fasting glucose levels postpancreas transplant, Doppler ultrasound, computed tomography, autoantibody titers, and pancreas graft biopsy were identified as adjunctive strategies to protocolized monitoring studies. No additional assays were identified in the setting of serially increasing hemoglobin A1c levels postislet transplantation., Conclusions: This international survey identifies common immunologic and metabolic monitoring strategies utilized for protocol and for cause following pancreas and islet transplantation. In the absence of any formal studies to assess the efficacy of immunologic and metabolic testing to detect early allograft dysfunction, it can serve as a guidance document for developing monitoring algorithms following beta-cell replacement., Competing Interests: J.S.O. is an investigator in multicenter trials supported by CareDx, Natera, and Vertex. He is a principal investigator of a single-center trial supported by Veloxis. The other authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Enteric drainage in pancreas transplantation is complicated by an enteric leak in 5%-8%, frequently necessitating pancreatectomy. Pancreatic salvage outcomes are not well studied. Risk factors for enteric leak were examined and outcomes of attempted graft salvage were compared to immediate pancreatectomy. Pancreas transplants performed between 1995 and 2018 were reviewed. Donor, recipient, and organ variables including demographics, donor type, ischemic time, kidney donor profile index, and pancreas donor risk index were analyzed. Among 1153 patients, 33 experienced enteric leaks (2.9%). Donors of allografts that developed leak were older (37.9y vs. 29.0y, p = .001), had higher KDPI (37% vs. 24%, p < .001), higher pancreas donor risk index (1.83 vs. 1.32, p < .001), and longer cold ischemic time (16.5 vs. 14.8 h, p = .03). Intra-abdominal abscess and higher blood loss decreased the chance of successful salvage. Enteric leak increased 6-month graft loss risk (HR 13.9[CI 8.5-22.9], p < .001). However, 50% (n = 12) of allografts undergoing attempted salvage survived long-term. After 6 months of pancreas graft survival, salvage and non-leak groups had similar 5-year graft survival (82.5% vs. 81.5%) and mortality (90.9% vs. 93.5%). Enteric leaks remain a challenging complication. Pancreatic allograft salvage can be attempted in suitable patients and accomplished in 50% of cases without significantly increased graft failure or mortality risk., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

The pancreas and liver arise from a common pool of progenitors. However, the underlying mechanisms that drive their lineage diversification from the foregut endoderm are not fully understood. To tackle this question, we undertook a multifactorial approach that integrated human pluripotent-stem-cell-guided differentiation, genome-scale CRISPR-Cas9 screening, single-cell analysis, genomics and proteomics. We discovered that HHEX, a transcription factor (TF) widely recognized as a key regulator of liver development, acts as a gatekeeper of pancreatic lineage specification. HHEX deletion impaired pancreatic commitment and unleashed an unexpected degree of cellular plasticity towards the liver and duodenum fates. Mechanistically, HHEX cooperates with the pioneer TFs FOXA1, FOXA2 and GATA4, shared by both pancreas and liver differentiation programmes, to promote pancreas commitment, and this cooperation restrains the shared TFs from activating alternative lineages. These findings provide a generalizable model for how gatekeeper TFs like HHEX orchestrate lineage commitment and plasticity restriction in broad developmental contexts., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Extracellular matrix (ECM) plays a multitude of roles, including supporting cells through structural and biochemical interactions. ECM is damaged in the process of isolating human islets for clinical transplantation and basic research. A platform in which islets can be cultured in contact with natural pancreatic ECM is desirable to better understand and support islet health, and to recapitulate the native islet environment. Our study demonstrates the derivation of a practical and durable hydrogel from decellularized human pancreas that supports human islet survival and function. Islets embedded in this hydrogel show increased glucose- and KCl-stimulated insulin secretion, and improved mitochondrial function compared to islets cultured without pancreatic matrix. In extended culture, hydrogel co-culture significantly reduced levels of apoptosis compared to suspension culture and preserved controlled glucose-responsive function. Isolated islets displayed altered endocrine and non-endocrine cell arrangement compared to in situ islets; hydrogel preserved an islet architecture more similar to that observed in situ. RNA sequencing confirmed that gene expression differences between islets cultured in suspension and hydrogel largely fell within gene ontology terms related to extracellular signaling and adhesion. Natural pancreatic ECM improves the survival and physiology of isolated human islets., (© 2022. The Author(s).)

Purpose: To evaluate the association of conversion from valganciclovir to letermovir on cytomegalovirus-specific cellular immunity., Methods: Adult patients were included if they received a kidney or liver transplant between 8/1/2018-12/31/20, developed symptomatic, high-level CMV viremia and were converted to letermovir 480 mg daily as monotherapy after treatment with ganciclovir-derivatives for a minimum of 4 weeks and had subsequent CMV cell-mediated immunity (CMI) testing via ICS assay by flow cytometry (Viracor Eurofins T Cell Immunity Panel)., Results: Seven patients met inclusion criteria; 87.5% were male and recipients of a kidney transplant. All patients were CMV high risk (D+/R-). Mean time from transplant to CMV disease was 200 ± 91 days. Peak viral load (VL) during CMV treatment was 540,341 ± 391,211 IU/mL. Patients received a mean of 30 ± 24 weeks (range: 4-78 weeks) of therapy with ganciclovir-derivatives at induction doses prior to letermovir introduction. The median absolute lymphocyte count (ALC) at letermovir initiation was 400/μL (IQR 575) and the median VL was 51.6 (range: ND-490) IU/mL. Most patients (n = 5/7, 71.4%) experienced an increase in VL 1 and/or 2 weeks after conversion to letermovir. All patients had positive CMI per ICS assay after conversion. Patients received a mean of 10.3 ± 6.9 weeks of letermovir prior to having a positive result. Median ALC at positivity was 900/μL. Immunosuppression was not further reduced from initiation of letermovir to demonstration of CMV CMI. No patient had progressive replication or breakthrough disease while maintained on letermovir and three patients (42.9%) underwent antiviral withdrawal without recurrence at the last follow-up., Conclusion: In this case series of abdominal transplant recipients with severe or persistent CMV infection, patients developed CMV-specific CMI after conversion to letermovir monotherapy. These data suggest that using letermovir in place of valganciclovir for secondary prophylaxis may address the lack of efficacy previously seen with this approach, as well as the issues that plague antiviral withdrawal with systematic monitoring. Future prospective studies are needed to evaluate this effect in a more controlled research environment with serial CMI testing to elucidate the optimal duration of letermovir when used in this way., (© 2021 Wiley Periodicals LLC.)

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., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

The pancreas is a vital organ with digestive and endocrine roles, and diseases of the pancreas affect millions of people yearly. A better understanding of the pancreas proteome and its dynamic post-translational modifications (PTMs) is necessary to engineer higher fidelity tissue analogues for use in transplantation. The extracellular matrix (ECM) has major roles in binding and signaling essential to the viability of insulin-producing islets of Langerhans. To characterize PTMs in the pancreas, native and decellularized tissues from four donors were analyzed. N -Glycosylated and phosphorylated peptides were simultaneously enriched via electrostatic repulsion-hydrophilic interaction chromatography and analyzed with mass spectrometry, maximizing PTM information from one workflow. A modified surfactant and chaotropic agent assisted sequential extraction/on-pellet digestion was used to maximize solubility of the ECM. The analysis resulted in the confident identification of 3650 proteins, including 517 N -glycoproteins and 148 phosphoproteins. We identified 214 ECM proteins, of which 99 were N -glycosylated, 18 were phosphorylated, and 9 were found to have both modifications. Collagens, a major component of the ECM, were the most highly glycosylated of the ECM proteins and several were also heavily phosphorylated, raising the possibility of structural and thus functional changes resulting from these modifications. To our knowledge, this work represents the first characterization of PTMs in pancreatic ECM proteins. This work provides a basal profile of PTMs in the healthy human pancreatic ECM, laying the foundation for future investigations to determine disease-specific changes such as in diabetes and pancreatic cancer, and potentially helping to guide the development of tissue replacement constructs. Data are available via ProteomeXchange with identifier PXD025048.

Problem: Mathematical modeling suggests aggressive ganciclovir dosing in the first week of cytomegalovirus disease (CMV) treatment may improve response. This has not been evaluated clinically., Methods: Adult kidney and/or pancreas transplant recipients admitted with CMV (4/29/19-7/15/20) received IV ganciclovir(10 mg/kg Q12 h × 7 days) with step-down to standard-of-care (SOC) dosing thereafter (5 mg/kg Q12). A SOC cohort admitted before implementation of the dosing strategy (10/20/16-3/2/19) served as a comparator., Primary Objective: rate of viral clearance (delta log CMV) at therapy day 7., Secondary Objective: safety/short term efficacy., Results: Fifty-four patients met inclusion criteria; 22 high-dose, 32 SOC. Demographics were similar with the exception of more women (45.4% vs. 15.6%,P = .03) and higher presenting viral-load in the high-dose group (log 6.0±.7 vs. log 5.2±1.2, P = .02). High-dose resulted in significantly greater response to therapy at day 7 (log -.92±.51 vs. log -.56±.79, P = .04). Change in WBC at day 7 was not different (-.49±1.92 vs. -.45±5.1, P = .97). Short-term clinical outcomes were similar between groups including mean hospital length-of-stay (P = .52), readmission rates (30 d: P = .38; 90 d: P = .5) and achievement of CMV viral-load less-than-lower-limit-of-quantification by day 90 (73% vs. 84%, P = .06). Rejection after CMV as well as graft/patient survival were similar between groups (P = .56, P > .99, P > .99)., Conclusion: A high-dose IV ganciclovir strategy results in improved viral clearance kinetics without safety concerns and similar short term clinical outcomes., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246., (© 2021 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: The vast majority of cases of diabetes mellitus (DM) in the United States are classified as type 2 DM (T2DM). Restrictive listing criteria and uncertainty regarding outcomes have historically limited access to pancreas transplantation for individuals with T2DM, although it has been used with success in patients with type 1 DM (T1DM). This review summarizes several recent studies that have sought to clarify the indications, appropriate patient selection, and outcomes of pancreas transplantation in the setting of T2DM., Recent Findings: Pancreas transplants have increased over the last few years, largely due to an increase in listings for simultaneous pancreas-kidney transplant (SPK) in patients with T2DM. Retrospective data demonstrate similar patient and allograft survival in patients with T1DM and T2DM undergoing SPK, and improved outcomes in patients with T2DM after SPK compared to those receiving a kidney transplant alone, although these studies are often confounded by selection biases. Patient selection for pancreas transplant has traditionally focused on body mass index, pretransplant insulin requirements, and fasting C-peptide, and the categorization of patients to T1DM or T2DM. Emerging data suggests this practice is inadvertently and unnecessarily restrictive., Summary: There is a growing body of evidence to support increasing consideration of pancreas transplantation in patients with T2DM, with support for equivalent patient and graft survival and glycemic control. Future prospective studies are indicated to better evaluate the role of preoperative patient factors in selection for pancreas transplantation and to explore long-term outcomes in patients with T2DM., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV., Methods: Adult patients receiving a kidney or kidney-pancreas transplant were included if they developed CMV viremia and initiated letermovir 480 mg daily as part of a dual therapy regimen with valganciclovir 900 mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log 10  < 3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels., Results: Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73-355) IU/ml and did not clear or change significantly after 2, 4 and 12 weeks of adjunctive letermovir (132.5 [range: 34.5-513] IU/ml vs. 68.7 [range: 34.5-574] IU/ml vs. 78.3 [range: 34.5-347] IU/ml, p > 0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir-tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6 ng/ml vs 8.0 ± 4.6 ng/ml)., Conclusion: In kidney and kidney-pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed., (© 2021 Wiley Periodicals LLC.)

Studies have found similar outcomes of Simultaneous Pancreas-Kidney transplantation (SPKT) in patients with Type 2 (T2D) and Type 1 diabetes (T1D). However, there are scarce data evaluating the association of recipient factors such as age, BMI, or pretransplant insulin requirements with outcomes, thus the criteria for the optimal recipient selection remains unclear. In this study, 284 T1D and 39 T2D patients, who underwent SPKT between 2006 and 2017 with 1 year of follow-up at minimum, were assessed for potential relationship of pretransplant BMI and insulin requirements with posttransplant diabetes and pancreatic graft failure. Kaplan-Meier analysis showed similar rates of freedom from posttransplant diabetes (94.7% T2D vs. 92.3% T1D at 1 yr, and 88.1% T2D vs. 81.1% T1D at 5 yrs) and graft survival (89.7% T2D vs. 90.4% T1D at 1 yr, and 89.7% T2D vs. 81.2% T1D at 5 yrs). There was no significant association between BMI or pretransplant insulin requirements with posttransplant diabetes occurrence in either T1D (p = .10, .43, respectively) or T2D (p = .12, .63) patients in the cohort; or with graft failure (T1D: p = .40, .09; T2D: p = .71, .28). These observations suggest a less restricted approach to selective use of SPKT in patients with T2D., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Problem: Incidence and impact of CMV infection in pancreas-transplant recipients (PTRs) in the valganciclovir prophylaxis era has not been completely elucidated., Methods: Adult D+/R- PTRs were divided into a current era (1/1/2011-12/31/17; 6-month PPX) and a historic era (1/1/2003-12/31/09; 3-month PPX)., Primary Objective: effect of prophylaxis extension on the incidence of CMV infection., Secondary Objective: impact of extension on valganciclovir-related toxicity (leukopenia) and transplant outcomes., Results: There were 177 D+/R- PTRs in the study period (historic:98, current:79). Prophylaxis extension resulted in significant reduction of CMV infection from 25.4% to 10.9% at 6 months, (57% reduction, p = .021). However, 1-year rates of CMV infection (historic:31% vs current:36%) and end-organ disease (historic:7.7% vs current:6.9%) were not different (p = .93). Prophylaxis extension significantly increased leukopenia (white blood cell count<3 K/uL) at 6 months (historic:9.5% vs current:28.6%, p = .018). On multivariable analysis prophylaxis extension was not associated with reduced rates of CMV infection (p = .99) or CMV end-organ disease (p = .3). Additionally, there was no significant difference in rejection (p = .2), graft survival (p = .08), death-censored graft survival(p = .07) or patient survival (p = .6)., Conclusions: Prophylaxis extension in D+/R- PTRs appears to delay time to first CMV but not reduce overall incidence. These findings suggest a hybrid approach, incorporating antiviral withdrawal and protocolized monitoring, may be needed to improve CMV-related outcomes., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Backgrounds: Cytomegalovirus (CMV) negatively affects transplant outcomes. The current geographic distribution of CMV risk within the US has not been described., Methods: CMV serostatus of donors and recipients in each US state were collected from the Scientific Registry of Transplant Recipients between April 1, 2015, and March 31, 2019. The objective was to describe rates of CMV recipient seropositivity (R+) and high-risk serostatus (D+/R-) across the US in kidney transplant recipient (KTR) and pancreas transplant recipient (PTR) and explore geographic disparities., Results: A total of 79 276 KTRs and 4023 PTRs were included. The average KTR R+ rate across states was 59.5% (range 39%-76%); PTR R+ rate was 49.5% but with a broader range (0%-100%). The average KTR D+/R- rate across the US was 19% (range 8.7%-25%); PTR D+/R- rate was notably higher (26.9%, range 0%-50%). KTR seropositivity varied geographically with more R+ recipients in the southern states, Alaska, and Hawaii. D+/R- KTRs also varied by region, with higher rates in the Rocky Mountain Region as well as the Midwest and the northern-most states of the Northeast. Trends found in KTR persisted in PTR., Conclusions: The distribution of CMV serostatus in the US varies by state and allograft type. These data may be useful in further discussion of national CMV donor-matching strategies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Objectives: Despite advances in surgical techniques and organ preservation, transplant ureteric strictures remain a common complication in kidney transplantation. A variety of endourological and surgical techniques have been utilized; however, there is a lack of consensus on the optimal modality in dealing with these complex cases., Materials and Methods: We present challenging ureteral reconstruction cases after failed attempts at ureteral dilatation, failed conventional open repairs, and/or with bladder dysfunction., Results: All renal allografts were salvaged by successful use of bladder Boari flap and intestinal segment interpositions/diversions., Conclusions: Operative repair remains the most durable and successful approach, and minimally invasive options should be reserved for nonsurgical candidates, with consideration of a single attempt in patients with early, distal, short (<2 cm), nonischemic strictures.

Purpose of Review: The aim of the present review is to gather recent reports on the use of pancreas and islet transplantation and conventional insulin therapy for treating patients experiencing diabetes and its related complications. The present review directs attention to the current status, challenges and perspectives of these therapies and sheds light on potential future cellular therapies., Recent Findings: The risks and benefits of diabetes treatment modalities continue to evolve, altering the risk versus benefit calculation for patients. As continuous subcutaneous insulin infusion and monitoring technologies demonstrate increasing effectiveness in achieving better diabetes control and reducing hypoglycemia frequency, so are pancreas and islet transplantation improving and becoming more effective and safer. Both beta-cell replacement therapies, however, are limited by a dependence on immunosuppression and a shortage of cadaver donors, restricting more widespread and safer deployment. Based on the effectiveness of clinical beta-cell replacement for lengthening lifespan and improving quality of life, scientists are aggressively investigating alternative cell sources, transplant platforms, and means of preventing immunological damage of transplanted cells to overcome these principle limitations., Summary: Essential goals of diabetes therapy are euglycemia, avoidance of hypoglycemia, and prevention or stabilization of end-organ damage. With these goals in mind, all therapeutic options should be considered., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The extracellular matrix (ECM) is unique to each tissue and capable of guiding cell differentiation, migration, morphology, and function. The ECM proteome of different developmental stages has not been systematically studied in the human pancreas. In this study, we apply mass spectrometry-based quantitative proteomics strategies using N,N-dimethyl leucine isobaric tags to delineate proteome-wide and ECM-specific alterations in four age groups: fetal (18-20 weeks gestation), juvenile (5-16 years old), young adults (21-29 years old) and older adults (50-61 years old). We identify 3,523 proteins including 185 ECM proteins and quantify 117 of them. We detect previously unknown proteome and matrisome features during pancreas development and maturation. We also visualize specific ECM proteins of interest using immunofluorescent staining and investigate changes in ECM localization within islet or acinar compartments. This comprehensive proteomics analysis contributes to an improved understanding of the critical roles that ECM plays throughout human pancreas development and maturation.

Despite good organ quality, pancreata from extremely small pediatric donors (<30 kg) are generally avoided by many centers because of concerns of reduced islet cell mass and early technical failure. Therefore, we sought to compare the outcomes of small pancreas grafts (<30 kg) to those from higher weight donors from transplants performed between 1994 and 2015 (n = 1183). A total of 33 pancreata were from donors' ≤30 kg (3%), with a mean weight of 23.8 kg and mean age of 7.8 years. Patient survival was similar at 1, 5, and 10 years between recipients of ≤30 and >30 kg donors (≤30 kg: 96.8%, 86.8%, and 78.1% vs. >30 kg: 96.8%, 89.5%, and 79.1%, P = 0.5). Pancreas graft survival at 1, 5, and 10 years was also similar, ≤30 kg: 93.9%, 73.2%, and 61.0% vs. >30 kg: 87%, 73.3%, and 58.3% (P = 0.7). This graft survival pattern was also seen when comparing pancreata from ≤20 kg donors to those from >20 to 30 kg. Cause of graft loss, and metabolic and physiologic outcomes did not differ between the groups. After assessing the impact of donor weight as a continuous variable and calculating recipient-to-donor weight ratio (RDWR), we observed no effect of donor weight on patient and graft outcomes., (© 2020 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Delayed graft function (DGF) is a common complication associated with significant untoward effects in kidney-alone transplantation. The incidence and outcomes following kidney delayed graft function (K-DGF) among patients undergoing simultaneous pancreas-kidney (SPK) transplantation are less certain. We analyzed SPK recipients transplanted at our center between January 1994 and December 2017. A total of 632 recipients fulfilled the selection criteria, including 69 (11%) with K-DGF and 563 without. The incidence of K-DGF was significantly higher in recipients of organs from older donors and donation after circulatory death (DCD). The presence of K-DGF was significantly associated with an increased risk of pancreas graft failure during the first 90 days (n = 9, incidence rate [IR] 2.45/100 person-months), but not with late pancreas failure (n = 32, IR 0.84/100 person-months), kidney graft failure, or patient death. Although DCD was associated with K-DGF, it was not associated with either pancreas (hazard ratio [HR] 0.91, 95% CI 0.58-1.44, P = .69) or kidney (HR 1.09, 95% CI 0.66-1.82, P = .74) graft failure after adjustment for potential confounders. We found K-DGF to be a significant risk factor for pancreas graft failure but not kidney graft failure, with the major risk period being early (<90 days) posttransplant, and the major donor risk factor being older donor age., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: Despite significant improvement in pancreas allograft survival, rejection continues to be a major clinical problem. This review will focus on emerging literature related to the impact of pretransplant and de-novo DSA (dnDSA) in pancreas transplant recipients, and the diagnosis and treatment of T-cell-medicated rejection (TCMR) and antibody-mediated rejection (ABMR) in this complex group of patients., Recent Findings: Recent data suggest that pretransplant DSA and the emergence of dnDSA in pancreas transplant recipients are both associated with increased risk of ABMR. The pancreas allograft biopsy is essential for the specific diagnosis of TCMR and/or ABMR, distinguish rejection from other causes of graft dysfunction, and to guide-targeted therapy. This distinction is important especially in the setting of solitary pancreas transplants but also in simultaneous pancreas-kidney transplants where solid evidence has now emerged demonstrating discordant biopsy findings. Treatment of rejection in a functioning pancreas can prolong allograft survival., Summary: The accurate and timely diagnosis of active alloimmune destruction in pancreas transplant recipients is paramount to preserving graft function in the long term. This review will discuss new, rapidly evolving information that is valuable for the physician caring for these patients to achieve optimal immunological outcomes.

Pancreatic steatosis is thought to be a negative risk factor for pancreas transplant outcomes. Despite considering donor body mass index (BMI) and the visualization of intercalated fat as indicators of donor pancreas lipid content, transplant surgeons do not use a quantitative method to directly measure steatosis when deciding to transplant a pancreas. In this study, we used nondiabetic human pancreata donated for research to measure the pancreatic and islet-specific lipid content to determine which clinical markers correlate best with lipid content. Interestingly, we found that BMI and age correlate with increased pancreatic lipid content (Panc-LC) in men, but not women. Our findings further suggest that total Panc-LC correlates with an increase in islet lipid content for both men and women. We noted that pancreata donated from individuals with a history of hypertension have increased Panc-LC independent of donor BMI or sex. Moreover, we identify hypertension as a risk factor for reduced islet function after islet isolation. Together, our findings emphasize differences in pancreas graft quality related to pancreatic and islet lipid content, which may not be predicted by assessing BMI alone but may be influenced by a donor history of hypertension., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Lymphocyte-depleting induction with alemtuzumab (ALEM) or rabbit antithymocyte-globulin (rATG) is commonly used at retransplantation. It is unknown which agent is preferable, particularly when ALEM was used at primary transplant., Objective: Evaluate outcomes after ALEM at retransplant following primary transplant with ALEM induction (ALEM-ALEM) as compared to retransplant with rATG (ALEM-rATG)., Materials and Methods: Single-center, observational cohort study of adult patients receiving kidney or pancreas transplant between January 1, 2001 and December 12, 2016., Results: 45 patients (16 ALEM-ALEM and 29 ALEM-rATG) met inclusion criteria. The ALEM-ALEM group had fewer days between transplants (621.0 ± 821.8 vs. 2,024.4 ± 1,285.8, p = 0.049), lower panel-reactive-antibodies (PRA) prior to transplant 2 (15.7 ± 31.5 vs. 53.2 ± 37.8; p = 0.0003), and more pancreas secondary transplants, although this was not statistically significant (ALEM-ALEM 37.5% vs. ALEM-rATG 10.3%, p = 0.05). The ALEM-ALEM group experienced a significantly higher rate of fungal infection (ALEM-ALEM 46.8% vs. ALEM-rATG 11.3%, p = 0.02). When adjusted in a multivariate model, this trend persisted (HR 3.97, CI 0.95 - 16.5, p = 0.05). A subgroup analysis of patients receiving a kidney for both transplant 1 and 2 to remove the possible confounding effect of pancreas allografts also found incidence of fungal infection at 1 year to be significantly higher in the ALEM-ALEM group (ALEM-ALEM 25% vs. ALEM-rATG 9.3%, p = 0.025). Rejection rates were not different between groups at 1 year (ALEM-ALEM 25% vs. ALEM-rATG 24.2%). Rates of cytomegalovirus (CMV) infection, BK polyomavirus infection, patient and graft survival were also similar., Conclusion: Patients with repeat courses of ALEM induction across multiple transplants may have a higher incidence of fungal infection. Future studies are needed to explore this risk, particularly in light of current drug manufacturer allocation practices and potential increased utilization by transplant centers.

Transplant centers may decline an import pancreas offer based on demographics and laboratory test results, without information on actual gland quality. The relationship between position on the match run, indicative of the number of centers that chose not to use a pancreas, and patient and death-censored graft survival, is not known. We studied all 199 isolated pancreas grafts transplanted at the University of Wisconsin since July 2000 and compared overall patient and death-censored graft survival based on import vs local status. Of the 199 isolated pancreas transplants, 184 (92.5%) were imported from another donor service area with a median match rank of 49 (interquartile range 14-129). Median cold ischemia time was longer for imported pancreata (16.6 vs 13.4 hours, P = .02). In multivariate Cox modeling, there was no association with position on the rank list and patient (P = .44) or death-censored graft survival (P = .99). There was an overall rate of 6.5% of graft failure within 30 days; however, there was no association with position on the rank list and graft failure at 30 days (P = .33). Although the logistics may be challenging, sound judgment to accept offers independent of prior centers' decisions can result in quality utilization of imported pancreata., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose of Review: Stem cell-derived islets are likely to be useful as a future treatment for diabetes. However, the field has been limited in the ability to generate β-like cells with both phenotypic maturation and functional glucose-stimulated insulin secretion that is similar to primary human islets. The field must also establish a reliable method of delivering the cells to patients while promoting rapid in-vivo engraftment and function. Overcoming these barriers to β cell differentiation and transplantation will be key to bring this therapy to the clinic., Recent Findings: The ability to generate stem cell-derived β-like cells capable of dynamic glucose-responsive insulin secretion, as well as β-like cells expressing key maturation genes has recently been demonstrated by several groups. Other groups have explored the potential of vascularized subcutaneous transplant sites, as well as endothelial cell co-transplant to support β cell survival and function following transplantation., Summary: The generation of stem cell-derived islets with dynamic glucose-responsive insulin secretion has brought the field closer to clinical translation, but there is still need for improving insulin content and secretory capacity, as well as understanding the factors affecting variable consistency and heterogeneity of the islet-like clusters. Other questions remain regarding how to address safety, immunogenicity and transplantation site moving forward.

In the early experience of pancreas transplantation, bladder drainage was favored, but it often caused urologic, metabolic, and infectious complications that necessitated conversion to enteric drainage. Long-term graft survival after enteric conversion and the impact of time interval from transplantation to enteric conversion on graft survival is poorly understood. We studied all bladder-drained first-time pancreas transplantations performed at the University of Wisconsin from 1985 to 2000. Time to conversion was estimated with the Kaplan-Meier technique, whereas risk factors associated with conversion were estimated via a time-varying Cox proportional hazards model. Of 386 bladder-drained pancreata, 162 (41.9%) eventually required enteric conversion, 29 (17.9%) within the first year. Median time to conversion varied by indication: 0.68 years for surgical, 3.1 years for urologic, and 2.7 years for metabolic disorders. In a time-varying Cox model adjusting for donor and recipient factors, enteric conversion did not affect the risk of pancreas graft loss (hazard ratio [HR] 0.86, P = .26). Kidney survival was not associated with enteric conversion. When necessary due to symptoms or complications, enteric conversion of bladder-drained pancreata is safe and does not affect overall graft survival. This relationship appears to be true no matter when the conversion is performed., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Extracellular matrix (ECM) is an important component of the pancreatic microenvironment which regulates β cell proliferation, differentiation, and insulin secretion. Protocols have recently been developed for the decellularization of the human pancreas to generate functional scaffolds and hydrogels. In this work, we characterized human pancreatic ECM composition before and after decellularization using isobaric dimethylated leucine (DiLeu) labeling for relative quantification of ECM proteins. A novel correction factor was employed in the study to eliminate the bias introduced during sample preparation. In comparison to the commonly employed sample preparation methods (urea and FASP) for proteomic analysis, a recently developed surfactant and chaotropic agent assisted sequential extraction/on pellet digestion (SCAD) protocol has provided an improved strategy for ECM protein extraction of human pancreatic ECM matrix. The quantitative proteomic results revealed the preservation of matrisome proteins while most of the cellular proteins were removed. This method was compared with a well-established label-free quantification (LFQ) approach which rendered similar expressions of different categories of proteins (collagens, ECM glycoproteins, proteoglycans, etc.). The distinct expression of ECM proteins was quantified comparing adult and fetal pancreas ECM, shedding light on the correlation between matrix composition and postnatal β cell maturation. Despite the distinct profiles of different subcategories in the native pancreas, the distribution of matrisome proteins exhibited similar trends after the decellularization process. Our method generated a large data set of matrisome proteins from a single tissue type. These results provide valuable insight into the possibilities of constructing a bioengineered pancreas. It may also facilitate better understanding of the potential roles that matrisome proteins play in postnatal β cell maturation.

The OPTN Pancreas Transplantation Committee performed a multicenter retrospective study to determine if undetectable serum C-peptide levels correspond to center-reported pancreas graft failures. C-peptide data from seven participating centers (n = 415 graft failures for transplants performed from 2002 to 2012) were analyzed pretransplant, at graft failure, and at return to insulin. One hundred forty-nine C-peptide values were submitted at pretransplant, 94 at return to insulin, and 233 at graft failure. There were 77 transplants with two available values (at pretransplant and at graft failure). For recipients in the study with pretransplant C-peptide <0.75 ng/mL who had a posttransplant C-peptide value available (n = 61), graft failure was declared at varying levels of C-peptide. High C-peptide values at graft failure were not explained by nonfasting testing or by individual center bias. Transplant centers declare pancreas graft failure at varying levels of C-peptide and do not consistently report C-peptide data. Until February 28, 2018, OPTN did not require reporting of posttransplant C-peptide levels and it appears that C-peptide levels are not consistently used for evaluating graft function. C-peptide levels should not be used as the sole criterion for the definition of pancreas graft failure., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In 2017, 1492 patients were added to the pancreas transplant waiting list, 964 listed as active, a slight increase from 2016. This is significant because for the first time in the past decade, the steady downward trend in additions to the waiting list has been reversed. Proportions of pancreas donors with cerebrovascular accident as cause of death decreased, with a concomitant increase in proportions with anoxia and head trauma. This is partly a result of the national opioid crisis, and it reflects increasing use of younger donors for pancreas transplant. The 2017 outcome report remains compromised by previous variation in reporting graft failure. Although the OPTN Pancreas Transplantation Committee has approved more precise definitions of pancreas graft failure, implementation of these definitions took place recently, and the data are not reflected in this report., (.)

β-cell replacement therapy, available currently as pancreas or islet transplantation, has developed without a clear definition of graft functional and clinical outcomes. The International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplantation Association held a workshop to develop consensus for an International Pancreas and Islet Transplant Association and European Pancreas and Islet Transplant Association Statement on the definition of function and failure of current and future forms of β-cell replacement therapy. There was consensus that β-cell replacement therapy could be considered as a treatment for β-cell failure, regardless of etiology and without requiring undetectable C-peptide, accompanied by glycemic instability with either problematic hypoglycemia or hyperglycemia. Glycemic control should be assessed at a minimum by glycated hemoglobin (HbA1c) and the occurrence of severe hypoglycemia. Optimal β-cell graft function is defined by near-normal glycemic control (HbA1c ≤6.5% [48 mmol/mol]) without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Good β-cell graft function requires HbA1c less than 7.0% (53 mmol/mol) without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production. Marginal β-cell graft function is defined by failure to achieve HbA1c less than 7.0% (53 mmol/mol), the occurrence of any severe hypoglycemia, or less than 50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. A failed β-cell graft is defined by the absence of any evidence for clinically significant C-peptide production. Optimal and good function are considered successful clinical outcomes.

Purpose of Review: The volume of pancreas transplants performed annually in the United States (US) has steadily declined for more than a decade. In the face of this negative trend, efforts at several centers are underway to expand their pancreas transplant volumes through alterations in the structure and function of their pancreas transplant programs. We highlight these programmatic changes and emphasize the culture and characteristics of these high volume centers to serve as models for other centers to emulate. As the results of modern-day pancreas transplantation are excellent and continue to improve, pancreas transplant remains an outstanding option for selected patients suffering from diabetes mellitus and end stage renal disease (ESRD) or symptomatic hypoglycemic events (SHEs). Through strong leadership commitment and programmatic restructuring, the transformation of low-volume pancreas transplant centers into high-volume programs is achievable without the need for cost-prohibitive investment., Recent Findings: Multiple examples may be cited of transplant centers reinvigorating their pancreas transplant programs, increasing their pancreas transplant evaluations and transplant rates, through personnel reorganization and operational restructuring. As a means of providing a roadmap to encourage other transplant centers to re-energize their pancreas transplant programs, we will outline strategies that can be readily instituted to transform a pancreas transplant program, and delineate the basic steps that any transplant center can take to achieve high-volume success., Summary: The negative trends in access to pancreas transplantation in the US may ultimately be addressed by low-volume pancreas transplant programs re-committing themselves through easily achievable institutional changes without substantial added capital investment, thereby maximizing access to pancreas transplantation for their diabetic patients and maintaining excellent outcomes.