Early Pancreas Research Articles

Abstract C056: Characterization of chromatin accessibility patterns in the human pancreas and early pancreatic neoplastic lesions using snATAC-seq

Abstract Study of early pancreas neoplasia in humans had previously been limited by lack of available tissue. Recent work by our group on deceased donor pancreata identified pancreatic intraepithelial neoplasia (PanIN) lesions in non-diseased organs and defined a transcriptomic signature for the microenvironment of these pre-cancerous lesions. Prevalence of PanINs in healthy human tissue was higher than expected and established a novel model to expand understanding of the complex biology of these precursor lesions. Epigenetic changes in chromatin structure and the subsequent effects on gene expression are essential processes in neoplasia that have yet to be described at the single cell level in the human pancreas. We hypothesized that previously defined gene signatures could identify acinar, ductal, and PanIN cells in donor pancreata based on chromatin accessibility profiling by single nuclear transposase-accessible chromatin preparation followed by high-throughput sequencing (snATAC-seq). Comparison between the accessibility patterns, transcription factor motifs, and differences in accessibility versus expression profiles can then be used to expand prior knowledge of early pancreatic neoplasia and identify novel targets for further study and therapy selection. To test this hypothesis, single nuclei from seventeen donor pancreata (twenty total samples) were isolated for snATAC-seq using the 10x Genomics platform. Data analysis was conducted using CellRanger, Seurat, Signac, AUCell, and other programs to identify and label chromatin peaks in individual nuclei corresponding to acinar, ductal, and PanIN origin according to gene signatures identified by scRNA-seq and special transcriptomics on matched donor pancreata. Using this method, cells corresponding to these gene signatures, including PanIN- like cells, were indeed identifiable with differentially accessible regions of the genome then analyzed for transcription factor motif enrichment between these cell types. Motifs enriched in cells identified as PanINs compared to either ductal or acinar cells included several transcription factors implicated in tumorigenesis. These results are similar to previously demonstrated essential factors in pancreatic neoplasia, suggesting this strategy is a relevant method for data analysis and discovery of novel factors implicated in tumorigenesis. Ongoing studies include validation of these findings in vitro using human pancreatic normal epithelial cells, human tumor cell lines, and organoid models derived from human normal and tumor samples. Together, this study demonstrates that PanINs can be identified in human pancreas tissue by snATAC-seq and that differentially expressed motifs can be identified, providing opportunity for further integration with transcriptomic information to elucidate detailed understanding of early neoplasia in the pancreas for future drug development and targeted therapeutics studies. Citation Format: Jamie N Mills, Aaron Dendekker, Joyce K Thompson, Hannah Watkoske, Simone Benitz, Padma Kadiyala, Ahmed Elhossiny, Howard Crawford, Eileen Carpenter, Marina Pasca di Magliano, Filip Bednar. Characterization of chromatin accessibility patterns in the human pancreas and early pancreatic neoplastic lesions using snATAC-seq [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C056.

The role of donor hypertension and angiotensin II in the occurrence of early pancreas allograft thrombosis.

About 10-20% of pancreas allografts are still lost in the early postoperative period despite the identification of numerous detrimental risk factors that correlate with graft thrombosis. We conducted a multicenter study including 899 pancreas transplant recipients between 2000 and 2018. Early pancreas failure due to complete thrombosis, long-term pancreas, kidney and patient survivals were analyzed and adjusted to donor, recipient and perioperative variables using a multivariate cause-specific Cox model stratified to transplant centers. Pancreas from donors with history of hypertension (6.7%), as well as with high body mass index (BMI), were independently associated with an increased risk of pancreas failure within the first 30 post-operative days (respectively, HR= 2.57, 95% CI from 1.35 to 4.89 and HR= 1.11, 95% CI from 1.04 to 1.19). Interaction term between hypertension and BMI was negative. Donor hypertension also impacted long-term pancreas survival (HR= 1.88, 95% CI from 1.13 to 3.12). However, when pancreas survival was calculated after the postoperative day 30, donor hypertension was no longer a significant risk factor (HR= 1.22, 95% CI from 0.47 to 3.15). A lower pancreas survival was observed in patients receiving a pancreas from a hypertensive donor without RAAS (Renin Angiotensin Aldosterone System) blockers compared to others (50% vs 14%, p < 0.001). Pancreas survival was similar among non-hypertensive donors and hypertensive ones under RAAS blockers. Donor hypertension was a significant and independent risk factor of pancreas failure. The well-known pathogenic role of renin-angiotensin-aldosterone system seems to be involved in the genesis of this immediate graft failure.

Abstract B113: Characterization of the epigenomic landscape of the human pancreas and early pancreatic neoplastic lesions

Abstract Study of early pancreas neoplasia in humans had previously been limited by lack of available tissue. Recent work by our group on deceased donor pancreata identified pancreatic intraepithelial neoplasia (PanIN) lesions in non-diseased organs and defined a transcriptomic signature for the microenvironment of these pre-cancerous lesions. Prevalence of PanINs in healthy human tissue was higher than expected and established a novel model to expand understanding of the complex biology of these precursor lesions. Epigenetic changes in chromatin structure and the subsequent effects on gene expression are essential processes in neoplasia that have yet to be described at the single cell level in the human pancreas. We hypothesized that characterization of the epigenomic landscape in donor pancreata would identify differences in chromatin structure and gene expression between healthy human tissue and PanINs, thereby expanding prior knowledge and identifying novel targets of study in the biology of early neoplasia in the pancreas. Single nuclei from five donor pancreata (six total samples including one replicate sample from a single donor pancreas) were isolated for transposase-accessible chromatin preparation followed by high-throughput sequencing (ATAC-seq) using the 10x Genomics platform. Data analysis was conducted using CellRanger, Seurat, Signac, and AUCell to identify and label chromatin peaks in individual nuclei corresponding to acinar, ductal, and PanIN origin according to gene signatures identified by scRNA on matched pancreata (Carpenter et al 2023, Cancer Discovery). Using this method, cells corresponding to these gene signatures, including PanIN-like cells, were indeed identified in preliminary analysis. Differentially accessible regions of the genome were then analyzed for motif enrichment between these cell types. Motifs enriched in cells identified as PanINs compared to either ductal or acinar cells included several transcription factors implicated in tumorigenesis, including members of the AP-1/Fos/Jun family and multiple zinc-finger protein family members, such as the KLF. These results are similar to previously demonstrated essential factors in pancreatic neoplasia. Differentially expressed motifs between ductal and acinar cells included factors associated with differentiation, including Myod1, Ptf1a, and the TCF family of transcription factors. Together, this study demonstrates that PanINs can be identified in human pancreas tissue by ATAC-seq and that differentially expressed motifs can be identified this model, providing opportunity for further integration with transcriptomic information to elucidate detailed understanding of early neoplasia in the pancreas. Citation Format: Jamie N. Mills, Joyce Thompson, Jacqueline Morales, Padma Kadiyala, Ahmed M. Elhossiny, Howard Crawford, Eileen Carpenter, Marina Pasca di Magliano, Filip Bednar, Simone Benitz. Characterization of the epigenomic landscape of the human pancreas and early pancreatic neoplastic lesions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B113.

Primate-specific ZNF808 is essential for pancreatic development in humans

Identifying genes linked to extreme phenotypes in humans has the potential to highlight biological processes not shared with all other mammals. Here, we report the identification of homozygous loss-of-function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein family, a large and rapidly evolving group of epigenetic silencers which target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of regulatory potential contained in the primate-specific transposable elements it represses during early pancreas development. This leads to inappropriate specification of cell fate with induction of genes associated with liver identity. Our results highlight the essential role of ZNF808 in pancreatic development in humans and the contribution of primate-specific regions of the human genome to congenital developmental disease.

Deciphering early human pancreas development at the single-cell level

Understanding pancreas development can provide clues for better treatments of pancreatic diseases. However, the molecular heterogeneity and developmental trajectory of the early human pancreas are poorly explored. Here, we performed large-scale single-cell RNA sequencing and single-cell assay for transposase accessible chromatin sequencing of human embryonic pancreas tissue obtained from first-trimester embryos. We unraveled the molecular heterogeneity, developmental trajectories and regulatory networks of the major cell types. The results reveal that dorsal pancreatic multipotent cells in humans exhibit different gene expression patterns than ventral multipotent cells. Pancreato-biliary progenitors that generate ventral multipotent cells in humans were identified. Notch and MAPK signals from mesenchymal cells regulate the differentiation of multipotent cells into trunk and duct cells. Notably, we identified endocrine progenitor subclusters with different differentiation potentials. Although the developmental trajectories are largely conserved between humans and mice, some distinct gene expression patterns have also been identified. Overall, we provide a comprehensive landscape of early human pancreas development to understand its lineage transitions and molecular complexity.

85-OR: Swi/Snf Controls Transcriptional Programs Required for ß-Cell Development and Postnatal Islet Function

A key feature of diabetes is insufficient functional β-cell mass. Strategies to augment functional β-cell mass include directed differentiation of stem cells towards a β-cell fate, which requires extensive knowledge of transcriptional programs governing differentiation in vivo. Pdx1, an essential transcription factor involved in β-cell differentiation, dynamically recruits coregulators to drive different gene expression programs. A recent study identified the ATP-dependent Swi/Snf chromatin remodeling complex as an important Pdx1-interacting partner. In the developing pancreas, conditional removal of the Brg Swi/Snf ATPase subunit compromised final pancreas mass, and loss of both ATPase subunits, Brg1 and Brm, led to glucose dyshomeostasis. While Swi/Snf is essential during early pancreas development and mature β-cell function, the role of Swi/Snf during endocrine cell development has yet to be explored. Here, we generated a conditional knockout of either Brg1 (Brg1ΔendoBrm+/-), Brm (Brg1Δendo/+Brm-/-), or both subunits (DKOΔendo) during endocrine development using Neurogenin 3 Cre. Four-week-old Brg1ΔendoBrm+/- mice are glucose intolerant, hyperglycemic, and hypoinsulinemic, with no phenotype observed in Brg1Δendo/+Brm-/-mice. Impaired glucose homeostasis of Brg1ΔendoBrm+/- mice was due in part to reduced islet number, impaired insulin secretion, and altered gene expression programs. DKOΔendo mice have not been found at weaning; however, postnatal day 6 DKOΔendo mice are severely hyperglycemic with reduced plasma insulin levels. Single-cell RNA-Seq of embryonic day 15.5 lineage-labeled cells revealed reduced insulin and glucagon transcript in the β-cell and α-cell clusters, respectively, in both Brg1ΔendoBrm+/- and DKOΔendo mice and reduced Neurogenin 3­ transcript in DKOΔendo endocrine progenitor clusters. These data suggest Swi/Snf plays a critical role in governing gene-expression programs essential for endocrine cell development. Disclosure R.K.Davidson: Employee; Eli Lilly and Company. S.Kanojia: None. M.E.Osmulski: None. J.Spaeth: None. Funding National Institutes of Health (R01DK129287, R03DK127129)

Does dialysis modality or duration influence outcomes in simultaneous pancreas-kidney transplant recipients? Single center experience and review of the literature.

The influence of dialysis modality and duration on outcomes following simultaneous pancreas-kidney transplantation (SPKT) remains uncertain. We performed a single-center retrospective review in 255 SPKT recipients according to dialysis modality (55 preemptive/no dialysis-ND, 70 peritoneal dialysis-PD, 130 hemodialysis-HD) and duration (55 none, 137<2 years, 41 2-4 years, 22>4 years). Mean follow-up was 9.4 years (median 9.2 years). Early (3-month) relaparotomy rate (20% ND vs. 36% PD/HD, p=.03) was lower in ND patients. There were no differences in early graft loss, patient survival, overall or death-censored kidney or pancreas graft survival rates (GSR) at 1 or 10 years follow-up. When analyzing dialysis duration, there were no differences in rates of pancreas thrombosis or early pancreas graft loss. Kidney delayed graft function (DGF) was lower in the ND/short dialysis groups combined (1.0%), compared to the intermediate/long dialysis groups combined (9.5%, p=.003). Early relaparotomy rates were higher with longer duration of dialysis (p=.045 between ND and >4 years of dialysis). Patient survival in the long dialysis group was 50% compared to 69.5% in the other three groups combined (p=.09). However, both overall and death-censored kidney and pancreas GSR were comparable. Preemptively transplanted patients had a lower incidence of kidney DGF and relaparotomy whereas patient survival was slightly lower with longer dialysis vintage prior to SPKT. Dialysis modality and duration did not influence either overall or death-censored pancreas or kidney GSR in patients with short waiting times, low KDPI donor organs, and dialysis duration up to 4 years.

PD31-08 HEPARIN THROMBOPROPHYLAXIS IN SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF OBSERVATIONAL STUDIES

You have accessJournal of UrologyCME1 Apr 2023PD31-08 HEPARIN THROMBOPROPHYLAXIS IN SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF OBSERVATIONAL STUDIES Erica Ai-Li, Kaveh Farrohki, Max Zhang, Juliano Offerni, Patrick Luke, and Alp Sener Erica Ai-LiErica Ai-Li More articles by this author , Kaveh FarrohkiKaveh Farrohki More articles by this author , Max ZhangMax Zhang More articles by this author , Juliano OfferniJuliano Offerni More articles by this author , Patrick LukePatrick Luke More articles by this author , and Alp SenerAlp Sener More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003324.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Thrombosis is a leading causes of pancreas graft loss after simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA). There remains no standardized thromboprophylaxis protocol. The aim of this systematic review and meta-analysis is to evaluate the impact of heparin thromboprophylaxis on the incidence of pancreas thrombosis, pancreas graft loss, bleeding, and secondary outcomes in SPK, PAK, and PTA. METHODS: Following PRISMA guidelines, we systematically searched BIOSIS®, PubMed®, Cochrane Library®, EMBASE®, MEDLINE®, and Web of Science® on April 21, 2021. Primary peer-reviewed studies that met inclusion criteria were included. Two methods of quantitative synthesis were performed to account for comparative and non-comparative studies. RESULTS: We included 11 studies, comprising of 1122 patients in the heparin group and 236 patients in the no-heparin group. When compared to the no-heparin control, prophylactic heparinization significantly decreased the risk of early pancreas thrombosis and pancreas loss for SPK, PAK and PTA without increasing the incidence of bleeding or acute return to the operating room. CONCLUSIONS: This study is the first to highlight that heparin thromboprophylaxis yields an approximate two-fold reduction in both pancreas thrombosis and pancreas loss for SPK, PAK and PTA. We report the dosage, frequency, and duration of heparin administration to consolidate the available evidence. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e903 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Erica Ai-Li More articles by this author Kaveh Farrohki More articles by this author Max Zhang More articles by this author Juliano Offerni More articles by this author Patrick Luke More articles by this author Alp Sener More articles by this author Expand All Advertisement PDF downloadLoading ...

Heparin Thromboprophylaxis in Simultaneous Pancreas-Kidney Transplantation: A Systematic Review and Meta-Analysis of Observational Studies.

Thrombosis is a leading causes of pancreas graft loss after simultaneous pancreas kidney (SPK), pancreas after kidney (PAK), and pancreas transplant alone (PTA). There remains no standardized thromboprophylaxis protocol. The aim of this systematic review and meta-analysis is to evaluate the impact of heparin thromboprophylaxis on the incidence of pancreas thrombosis, pancreas graft loss, bleeding, and secondary outcomes in SPK, PAK, and PTA. Following PRISMA guidelines, we systematically searched BIOSIS®, PubMed®, Cochrane Library®, EMBASE®, MEDLINE®, and Web of Science® on April 21, 2021. Primary peer-reviewed studies that met inclusion criteria were included. Two methods of quantitative synthesis were performed to account for comparative and non-comparative studies. We included 11 studies, comprising of 1,122 patients in the heparin group and 236 patients in the no-heparin group. When compared to the no-heparin control, prophylactic heparinization significantly decreased the risk of early pancreas thrombosis and pancreas loss for SPK, PAK and PTA without increasing the incidence of bleeding or acute return to the operating room. Heparin thromboprophylaxis yields an approximate two-fold reduction in both pancreas thrombosis and pancreas loss for SPK, PAK and PTA. We report the dosage, frequency, and duration of heparin administration to consolidate the available evidence.

Influence of donor and recipient sex on outcomes following simultaneous pancreas-kidney transplantation in the new millennium: Single-center experience and review of the literature.

The influence of sex on outcomes following simultaneous pancreas-kidney transplantation (SPKT) in the modern era is uncertain. We retrospectively studied 255 patients undergoing SPKT from 11/2001 to 8/2020. Cases were stratified according to donor (D) sex, recipient (R) sex, 4 D/R sex categories, and D/R sex-matched versus mismatched. D-male was associated with slightly higher patient (p=.08) and kidney (p=.002) but not pancreas (p=.23) graft survival rates (GSR) compared to D-female. There were no differences in recipient outcomes other than slightly higher pancreas thrombosis (8% R-female vs. 4.2% R-male, p=.28) and early relaparotomy rates in female recipients (38% R-female vs. 29% R-male, p=.14). When analyzing the 4 D/R sex categories, the two D-male groups had higher kidney GSRs compared to the two D-female groups (p=.01) whereas early relaparotomy and pancreas thrombosis rates were numerically higher in the D-female/R-female group compared to the other three groups. Finally, there were no significant differences in outcomes between sex-matched and sex-mismatched groups although overall survival outcomes were lower with female donors irrespective of recipient sex. The influence of D/R sex following SPKT is subject to multiple confounding issues but survival rates appear to be higher in D-male/R-male and lower in D-female/R-male categories.

Survival After Simultaneous Pancreas-Kidney Transplantation in Type 1 Diabetes: The Critical Role of Early Pancreas Allograft Function.

Simultaneous pancreas-kidney transplantation (SPK) carries about a 7%–22% risk of technical failure, but the impact of early pancreas allograft loss on subsequent kidney graft and patient survival is not well-defined. We examined national transplant registry data for type 1 diabetic patients who received SPK between 2000 and 2021. Associations of transplant type (i.e., SPK, deceased‐donor kidney transplant [DDKA], living‐donor kidney transplant [LDKA]) with kidney graft failure and patient survival were estimated by multivariable inverse probability of treatment-weighted accelerated failure-time models. Compared to SPK recipients with a functioning pancreas graft 3 months posttransplant (SPK,P+), LDKA had 18% (Time Ratio [TR] 0.82, 95%CI: 0.70–0.95) less graft survival time and 18% (TR 0.82, 95%CI: 0.68–0.97) less patient survival time, DDKA had 23% (TR 0.77, 95%CI: 0.68–0.87) less graft survival time and 29% (TR 0.71, 95%CI: 0.62–0.81) less patient survival time, and SPK with early pancreas graft loss had 34% (TR 0.66, 95%CI: 0.56–0.78) less graft survival time and 34% (TR 0.66, 95%CI: 0.55–0.79) less patient survival time. In conclusion, SPK,P+ recipients have better kidney allograft and patient survival compared with LDKA and DDKA. Early pancreas graft failure results in inferior kidney and patient survival time compared to kidney transplant alone.

343.1: Donor Hypertension Is Associated With an Increased Risk of Early Pancreas Allograft Failure

343.1: Donor Hypertension Is Associated With an Increased Risk of Early Pancreas Allograft Failure

234.4: Survival After Simultaneous Pancreas-Kidney Transplantation in Type 1 Diabetes: The Critical Role of Early Pancreas Allograft Function

Objective: Simultaneous pancreas-kidney transplantation (SPK) is a well-established treatment option for patients with diabetes mellitus and end-stage kidney disease, but SPK carries a 7-22% rate of technical failure. The impact of early pancreas graft function on subsequent kidney graft and patient survival in type 1 diabetic recipients of SPK is not well-defined. Methods: We examined national U.S. transplant registry data for type 1 diabetic patients who received SPK between 2000 and 2021 and survived the first 3 months with a functioning kidney. Transplant patients were categorized as: deceased-donor kidney transplant alone (DDKA), living-donor kidney transplant alone (LDKA), SPK recipients with a functioning pancreas graft 3 months posttransplant (SPK,P+), or SPK recipients with pancreas graft failure within 3 months posttransplant (SPK,P-). Associations of transplant type with kidney graft failure and patient survival through September 2021 were estimated by multivariable inverse probability of treatment weighted (IPTW) accelerated failure-time (AFT) models, with weights estimated using generalized boosted regression. Results: Compared to SPK,P+ recipients, LDKA had 18% less graft survival time (TR: 0.730.820.92) and 18% less patient survival time (TR: 0.720.820.93), DDKA had 23% less graft survival time (TR: 0.710.770.85) and 29% less patient survival time (TR: 0.640.710.79), and SPK,P- had 34% less graft survival time (TR: 0.590.660.75) and 34% less patient survival time (TR: 0.580.660.75). Compared to LDKA, SPK,P- had 19% less graft survival time (TR: 0.700.810.94) and 19% less graft survival time (TR: 0.690.810.95). Compared to DDKA recipients, SPK,P- had 14% less graft survival time (TR: 0.760.860.97). No difference was found for patient survival time between SPK,P- and DDKA. Conclusions: SPK recipients with functioning pancreas grafts within 3-month posttransplant have better kidney allograft and patient survival compared with LDKA and DDKA. Early pancreas graft failure results in inferior kidney and patient survival time compared to kidney transplant alone. This study was supported by grant 4746 from the Foundation for Barnes-Jewish Hospital.

Pancreas transplantation from donors after cardiac death – The US experience

IntroductionSince the beginning of pancreas transplantation, the rate of donation after cardiac (or circulatory) death (DCD) accounts for only 3% of all transplants in the US. This is the result of perceived higher complication rates and overall worse outcome with DCD donors. Such misconceptions and an increased demand for deceased donor (DD) organs warrant a systematic review of the use of DCD compared with donation after brain death (DBD) pancreata to objectively assess DCD outcome after pancreas transplantation in the US. MethodsAll 22,160 DD pancreas transplants performed in diabetic patients between 1/1/2001 and 12/31/2020 were included in this analysis. To assess changes in outcomes, patient and graft survival was computed using the Kaplan-Meier method in 5-year intervals. Comprehensive univariate and multivariable comparisons of posttransplant complications and patient and pancreas and kidney graft survival between DCD and DBD pancreas transplants were performed to assess the donor impact. ResultsIn the US over the past 20 years most DCD donors were used for simultaneous pancreas and kidney (SPK) transplants and less often for solitary pancreas transplants. DCD transplants never accounted for more than 4% per year of all pancreas transplants. A comparison of the pancreas donor risk index (pDRI) between DCD and DBD pancreata showed that the only distinguishing factor was DCD donation. SPK patient, pancreas, and kidney graft survival for DCD donors did not change significantly over time. One- and 3 -year DCD patient survival reached 96% and 93%, pancreas graft survival 90% and 84%, and kidney graft survival 96% and 91%, respectively. For the last decade, no differences in patient and graft survival between DCD and DBD donors were detected (P > 0.67). The relative risk for the use of a DCD donor was not increased (P > 0.6). Influential risk factors were older donor and recipient age as well as longer preservation times. Larger transplant center accepted DCD donors more frequently and showed better outcome. While the rate of early pancreas complications was the same for DCD vs. DBD transplants, delayed kidney graft function was significantly higher in DCD kidneys secondary to more long-distance shipping across the country. The multivariable analysis showed a 4-times higher rate in delayed graft function. Longer cold preservation time and older donor age further increased the risk of graft failure. The use of machine perfusion of the kidney graft reduced the relative risk of delayed graft function by 50%. SummaryThe use of DCD donor organs in pancreas transplantation is not associated with higher failure or complication rates in the US. A pancreas offer from a DCD donor should not be the sole reason to decline the organ for transplantation. Careful selection of specific donor and recipient factors, as well as advanced preservation techniques are essential for good outcome.

Donor-derived Cell-free DNA Shows High Sensitivity for the Diagnosis of Pancreas Graft Rejection in Simultaneous Pancreas-kidney Transplantation.

Background.Pancreas graft status in simultaneous pancreas-kidney transplant (SPKTx) is currently assessed by nonspecific biochemical markers, typically amylase or lipase. Identifying a noninvasive biomarker with good sensitivity in detecting early pancreas graft rejection could improve SPKTx management.Methods.Here, we developed a pilot study to explore donor-derived cell-free DNA (dd-cfDNA) performance in predicting biopsy-proven acute rejection (P-BPAR) of the pancreas graft in a cohort of 36 SPKTx recipients with biopsy-matched plasma samples. dd-cfDNA was measured using the Prospera test (Natera, Inc.) and reported both as a fraction of the total cfDNA (fraction; %) and as concentration in the recipient’s plasma (quantity; copies/mL).Results.In the absence of P-BPAR, dd-cfDNA was significantly higher in samples collected within the first 45 d after SPKTx compared with those measured afterward (median, 1.00% versus 0.30%; median, 128.2 versus 35.3 cp/mL, respectively with both; P = 0.001). In samples obtained beyond day 45, P-BPAR samples presented a significantly higher dd-cfDNA fraction (0.83 versus 0.30%; P = 0.006) and quantity (81.3 versus 35.3 cp/mL; P = 0.001) than stable samples. Incorporating dd-cfDNA quantity along with dd-cfDNA fraction outperformed dd-cfDNA fraction alone to detect active rejection. Notably, when using a quantity cutoff of 70 cp/mL, dd-cfDNA detected P-BPAR with a sensitivity of 85.7% and a specificity of 93.7%, which was more accurate than current biomarkers (area under curve of 0.89 for dd-cfDNA (cp/ml) compared with 0.74 of lipase and 0.46 for amylase).Conclusions.dd-cfDNA measurement through a simple noninvasive blood test could be incorporated into clinical practice to help inform graft management in SPKTx patients.

Organ-wide human PanIN and microadenoma analyses: bidirectional exocrine-endocrine relationship in early pancreas remodeling

Organ-wide human PanIN and microadenoma analyses: bidirectional exocrine-endocrine relationship in early pancreas remodeling

Organ-wide human PanIN and microadenoma analyses: bidirectional exocrine-endocrine relationship in early pancreas remodeling

Organ-wide human PanIN and microadenoma analyses: bidirectional exocrine-endocrine relationship in early pancreas remodeling

Impact of Simultaneous Pancreas-kidney Transplantation on Cardiovascular Risk in Patients With Diabetes.

Cardiovascular disease is the major cause of death in patients with type 1 diabetes. Of the available risk predictors for this population, the Steno Type 1 Risk Engine (STENO T1) is the only one that includes kidney function as a risk factor, which is a well-described independent risk factor for cardiovascular disease. We explore how simultaneous pancreas-kidney transplantation (SPKT) modifies the predicted cardiovascular risk by the STENO T1 through a retrospective study including recipients of a first SPKT between 2000 and 2016. Two hundred sixty-eight SPKT recipients with a mean age of 40 y old and a median follow-up of 10 y were included. Before transplantation, the expected incidence of cardiovascular events (CVEs) at 5 and 10 y according to STENO T1 would have been 31% and 50%, respectively, contrasting with an actual incidence of 9.3% and 16% for the same timepoints, respectively (P < 0.05). These differences were attenuated when STENO T1 was recalculated assuming 12th-mo glomerular filtration rate (at 5 and 10 y predicted CVE incidence was 10.5% and 19.4%, respectively). Early pancreas graft failure (hazard ratio [HR] 3.00, 95% confidence interval [CI], 1.14-7.88; P = 0.02) was an independent risk factor for post-SPKT CVE, alongside kidney graft failure (HR 2.90, 95% CI, 1.53-5.48; P = 0.001), and diabetes duration (HR 1.04, 95% CI, 1.00-1.09, P = 0.04). SPKT decreases in more than two-thirds of the predicted cardiovascular risk by the STENO T1. A functioning pancreas graft further reduces CVE risk, independently of kidney graft function.

306.7: Do Pretransplant C-peptide Levels Influence Outcomes in Simultaneous Pancreas-Kidney Transplantation? A Matched Case-Control Study

Introduction: Experiences with simultaneous pancreas-kidney transplantation (SPKT) in uremic patients with detectable pretransplant C-peptide (Cp) levels with a “type 2” diabetes mellitus (DM) phenotype have demonstrated survival outcomes equivalent to those with type 1 (Cp negative) DM. However, few studies have analyzed these outcomes in a case-control fashion. The study purpose was to evaluate outcomes in SPKT recipients according to presence or absence of pretransplant Cp. Methods: Selection criteria for Cp positive (Cp+, ≥2.0 ng/ml) were similar to Cp negative (Cp-) patients. We retrospectively analyzed 215 SPKTs performed at our center between 8/02 - 5/19 and identified 41 patients who were Cp+ pretransplant (mean level 5.4 ng/ml) and compared to 41 Cp- (level undetectable) case controls matched for recipient age, gender, race, and date of transplant. All SPKTs were performed as intent to treat with portal-enteric drainage; all patients received depleting antibody induction with FK/MMF ± steroids. Pancreas graft failure (GF) was defined as return to daily insulin therapy. Results: The two groups were well-matched for numerous donor, preservation, recipient, and immunological characteristics. Mean donor (26 Cp+ vs 23 years Cp-) and recipient (both 44 years) ages were similar. Both groups had 21 males/20 females and 19 Caucasian (C)/20 African American (AA) patients. There was one early death secondary to infection in each group. There were no other early (<6 month) kidney GFs in either group. There were 5 other early pancreas GFs, 3 in Cp+ and 2 in Cp- patients. With a mean follow-up of 7.3 years in both groups, 5-year patient survival (PS, 93% vs 95%), kidney graft survival (GS, 73% vs 85%), and pancreas GS (68% vs 85%, p=0.11) rates were slightly lower in Cp+ vs Cp- patients, respectively. Death-censored kidney (69% vs 73%) and pancreas GS (59% vs 81%, p=0.07) rates were also slightly lower in Cp+ vs Cp- patients, respectively. The Cp+ group had fewer deaths with functioning grafts (9.8% vs 19.5% Cp) but more pancreas GFs (9.8% vs 0 Cp-, p=0.12) due to either insulin resistance (in patients with normal C-p levels and excessive weight gain) or rejection (19.5% vs 12% Cp-, p=NS). There were no differences in outcomes according to gender or race. Post-transplant weight gain >3 kg occurred in 76% of Cp+ vs 32% of Cp- patients (p=.0001). Mean post-transplant weight gain was 15 kg in Cp+ vs 6.5 kg in Cp- patients (p<.001). In patients with functioning grafts, mean post-transplant Cp (4.9 vs 2.6 ng/ml), HbA1c (5.5 vs 5.2%) and serum creatinine (1.4 vs 1.2 mg/dl) levels were slightly higher in Cp+ patients whereas mean eGFR levels (61 vs 66 ml/min/1.73 m2) were slightly lower compared to Cp- patients. Conclusions: In this matched case-control study, survival and functional outcomes in Cp+ patients are slightly inferior following SPKT, with post-transplant weight gain and GF due to insulin resistance or rejection accounting for differences in outcomes.

P.133: Systemic Venous Versus Portal Venous Drainage in Simultaneous Pancreas-Kidney Transplantation: A Matched-pair Analysis

Purpose: Portal venous drainage of pancreatic transplant appears more physiologic compared to systemic venous drainage. However, present data does not support the superiority of one technique over the other. The study purpose was to evaluate outcomes in vascularized pancreas transplantation (PTx) with enteric exocrine drainage based on technique of venous delivery. Methods: We retrospectively analyzed 231 simultaneous pancreas-kidney transplants (SPKTs) performed at our center between 7/2003 – 7/2019 and identified 27 that were performed with systemic venous (iliac vein) and enteric exocrine (systemic-enteric [S-E]) drainage. These 27 patients were compared to 27 case controls with portal venous and enteric exocrine drainage matched for recipient age, gender, race, and date of transplant. Results: The 2 groups were well-matched.Indications for S-E drainage were central obesity/thickened mesentery (10), unfavorable vascular anatomy (11), or surgeon preference (6). The S-E drainage group was characterized byslightly more patients ≥ 80 kg (44% S-E versus 26% P-E), with C-peptide positive diabetes (30% S-E versus 18% P-E), and with diabetes onset at >20 years of age (41% S-E versus 26% P-E, all p=NS), suggesting a Type 2 diabetes phenotype. Although the incidence of early pancreas thrombosis (3.7% S-E versus 0% P-E), early relaparotomy (30% S-E versus 22% P-E), and mean initial length of hospital stay (11 days S-E versus 8 days P-E) were numerically higher in S-E versus P-E SPKTs, none of these differences were significant. With a mean follow-up of 5 years in both groups, respective one and 3-year patient survival (100% and 96% S-E vs 100% and 100% P-E), kidney graft survival (100% and 96% S-E vs 100% and 89% P-E), and pancreas graft survival (96% and 96% S-E vs 100% and 100% P-E) rates were comparable. Conclusions: The method of venous delivery of insulin following PTx does not appear to influence medium-term outcomes in SPKT with enteric exocrine drainage. K. Gurung2, R. Stratta2, A. Farney2, G. Orlando2, C. Jay2, A. Reeves-Daniel3, A. Mena-Gutierrez3, N. Sakhovskaya3, W. Doares4, S. Kaczmorski4, M. Magid4, J. Rogers2 .