When pancreata fly: Outcomes and lessons learned from the development of a Pancreas Transplant Import Program.

BACKGROUND: To address long waitlist times and increase pancreas transplantation, our center has implemented a protocol for long-distance importation of pancreata. METHODS: We conducted a retrospective review of pancreas transplantation at our institution from January 1, 2014, the start of our importation program, through September 30, 2021. Outcomes were compared between locally procured grafts and imported grafts, defined as grafts procured greater than 250 nautical miles (NM) from our center. RESULTS: Eighty-one patients underwent pancreas transplantation during the study time period; 19 (23.5%) received imported grafts. There were no significant differences in recipient demographics or type of transplant received. Mean distance of import was 644.2 ± 234.0 NM. Imported grafts were more likely to be from pediatric donors <18 years old (p = .02) and a significantly higher proportion of imported grafts came from donors weighing <30 kg (26.3 vs. 3.2%, p = .007). Cold ischemic time was longer for imported grafts than for local grafts (13.4 ± 2.3 h vs. 9.8 ± 2.2 h, p < .01). There was no significant difference in deaths or graft losses within 90 days or at 1 year between groups. CONCLUSION: Centers should consider expanding criteria for acceptance of imported pancreata to increase the number of transplants and combat organ nonutilization.

The best insulin delivery is a human pancreas.

PURPOSE: We wanted to compare glycemic control post pancreas transplantation with newer therapeutic options. METHODS: We conducted a retrospective analysis of pancreas transplantation at our institution from January 1, 2008, through September 30, 2021. All patients who underwent pancreatic transplantation were 18 years and older. We compared pre-transplant glycemic control of those patients, whether self-monitoring or continuous glucose monitor to their post-transplant glycemic control. Outcomes were assessed by HgbA1C level at evaluation (eval), pretransplant (pre), within the first 5 months posttransplant (post) and 1 year post transplant (1 year). RESULTS: One hundred and thirty-four patients underwent pancreas transplantation during the 14-year study period. Overall, 1-year patient and graft survival were 95% and 88%. The mean HgbA1C (%) for eval and pre were 8.5(SD ± 1.7) and 8.3(SD ± 1.7), which was significantly higher than post, and 1 year at 5.1(SD ± .6, p < .01) and 5.2(SD ± .6, p < .01). Of those, 38 patients presented with continuous glucose monitors (CGM) +/- pump. Their mean HgbA1C(%) was 8.2(SD ± 1.5) at eval 8.1(SD ± 1.3). These were also significantly higher than post 5.0(SD ± .6, p < .01), and 1 year 5.1(SD ± .5, p < .01). CONCLUSION: Pancreas transplant provides superior glycemic control to continuous glucose monitoring and remains the optimal therapy for appropriately selected patients with diabetes.

Internal Hernia With Incarceration of the Cecum: A Case Report After Simultaneous Kidney-Pancreas Transplant.

Simultaneous pancreas and kidney (SPK) transplant is the most effective form of managing difficult-to-treat diabetes; however, this does not come without risk. The surgical complications after SPK transplant can be seen in up to 30% of recipients but do not always correlate with a decrease in patient or graft survival. One of the known complications is an internal hernia. Herein, we describe the first case of cecal incarceration in an internal hernia through the defect created by the transplanted ureter and the retroperitoneum in a SPK transplant recipient. Our management entailed the reduction of large bowel and revision of the ureteroneocystostomy to eliminate the potential space that could enable reherniation. Prompt identification of this rare complication with rapid surgical intervention allowed us to avoid serious morbidity or mortality.

Pharmacological conversion of gut epithelial cells into insulin-producing cells lowers glycemia in diabetic animals.

As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic ß cells in diabetes. Gut enterochromaffin cells can be converted to insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate ß-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-ß that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.

Number of Donor Renal Arteries and Early Outcomes after Deceased Donor Kidney Transplantation.

Background: Anatomic abnormalities increase the risk of deceased donor kidney discard, but their effect on transplant outcomes is understudied. We sought to determine the effect of multiple donor renal arteries on early outcomes after deceased donor kidney transplantation. Methods: For this retrospective cohort study, we identified 1443 kidneys from 832 deceased donors with ≥1 kidney transplanted at our center (2006-2016). We compared the odds of delayed graft function and 90-day graft failure using logistic regression. To reduce potential selection bias, we then repeated the analysis using a paired-kidney cohort, including kidney pairs from 162 donors with one single-artery kidney and one multiartery kidney. Results: Of 1443 kidneys included, 319 (22%) had multiple arteries. Multiartery kidneys experienced longer cold ischemia time, but other characteristics were similar between groups. Delayed graft function (50% multiartery versus 45% one artery, P=0.07) and 90-day graft failure (3% versus 3%, P=0.83) were similar between groups before and after adjusting for donor and recipient characteristics. In the paired kidney analysis, cold ischemia time was significantly longer for multiartery kidneys compared with single-artery kidneys from the same donor (33.5 versus 26.1 hours, P<0.001), but delayed graft function and 90-day graft failure were again similar between groups. Conclusions: Compared with single-artery deceased donor kidneys, those with multiple renal arteries are harder to place, but experience similar delayed graft function and early graft failure.

COVID-19 in pancreas transplant recipients.

Coronavirus disease 2019 (COVID-19) has become a pandemic since first being described in January 2020. Clinical manifestations in non-transplant patients range from asymptomatic infection to severe pneumonia with acute respiratory distress syndrome, multiorgan system failure, and death. Limited reports in kidney transplant recipients suggest similar characteristics in that population. We report here the first case series of COVID-19 infection occurring in pancreas transplant recipients.

Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes.

Ischemia-reperfusion injury increases allograft immunogenicity and enhances myeloid dendritic cell maturation and trafficking to recipient's secondary lymphoid tissue. Here, we used postreperfusion biopsies from patients who received kidney allografts from deceased donors between 2006 and 2009 to assess the impact of ischemia-reperfusion damage and myeloid dendritic cell density on subsequent allograft rejection episodes. Histologic changes of severe ischemia-reperfusion damage in postreperfusion biopsies were found to be associated with subsequent rejection episodes and suboptimal allograft survival. Using BDCA-1 as a marker of myeloid dendritic cells, postreperfusion biopsies from deceased donors had lower dendritic cell density compared to postreperfusion biopsies from living donors or normal controls. This suggests a rapid emigration of donor dendritic cells out of the allograft. In our cohort, low dendritic cell density was associated with a subsequent increase in rejection episodes. However, it appears that the donor's cause of death also influenced dendritic cell density. Therefore, we assessed the additive impact of severe ischemia-reperfusion changes and low dendritic cell density on subsequent rejection. The aforementioned combination was a powerful and independent predictor of allograft rejection. Thus, our data highlight the prognostic value of histopathologic changes associated with ischemia-reperfusion in postreperfusion biopsies and suggest a rapid posttransplant emigration of myeloid dendritic cells out of the allograft to enhance alloimmunity. These findings may provide a rationale for minimizing ischemia-reperfusion injury and therapeutic targeting of donor-derived dendritic cells to promote rejection-free allograft survival.

Nature, timing, and severity of complications from ultrasound-guided percutaneous renal transplant biopsy.

We sought to review our kidney transplant biopsy experience to assess the incidence, type, presenting symptoms, and timing of renal transplant biopsy complications, as well as determine any modifiable risk factors for postbiopsy complications. This is an observational analysis of patients at the University of Wisconsin between January 1, 2000, and December 31, 2009. Patients with an INR ≥1.5 or platelet counts less than 50 000 were not biopsied. An 18-gauge needle was used for biopsy. Over the study period, 3738 biopsies were performed with 66 complications (1.8%). No deaths occurred. A total of 0.7% were mild complications, 0.7% were moderate complications, 0.21% were severe complications, and 0.19% were life-threatening. Most complications occurred within the 4-h postbiopsy period, although serious complications were often delayed: 67% of complications requiring surgical intervention presented greater than 4 h after biopsy. Biopsy within 1 week of transplant had a 311% increased risk of a complication. Postbiopsy reduction in hematocrit and hemoglobin at 4 h was associated with a complication. In conclusion, life-threatening complications after renal allograft biopsy occurred in 0.19% of patients. Most complications occurred within 4 h postprocedure; however, many serious complications occurred with a time delay after initially uneventful monitoring. The only clinically significant laboratory predictor of a complication was a fall in the hematocrit or hemoglobin within 4 h. Patients biopsied within a week of transplant were at the highest risk for a complication and should therefore be most closely monitored.

Loss of ERα and FOXA1 expression in a progression model of luminal type breast cancer: insights from PyMT transgenic mouse model.

The classification of breast cancer into multiple molecular subtypes has necessitated the need for biomarkers that can assess tumor progression and the effects of chemopreventive agents on specific breast cancer subtypes. The goal of this study was to identify biomarkers whose expression are altered along with estrogen receptor α (ERα) in the polyoma middle-T antigen (PyMT) transgenic model of breast cancer and to investigate the chemopreventive activity of phenethyl isothiocyanate (PEITC). The diet of PyMT female mice was fortified with PEITC (8 mmol/kg) and the mammary streak and/or gross tumors and metastases in lungs were subjected to immunohistochemical analyses for ERα, FOXA1, and GATA-3. FOXA1 is associated with luminal type A cancers, while GATA-3 is a marker of luminal progenitor cell differentiation. In both control and PEITC-treated groups, there was a progressive loss of ERα and FOXA1 but persistence of GATA-3 expression indicating that the tumors retain luminal phenotype. Overall, the PyMT induced tumors exhibited the entire gamut of phenotypes from ERα+/FOXA1+/GATA-3+ tumors in the early stage to ERα±/FOXA1-/GATA-3+ in the late stage. Thus, PyMT model serves as an excellent model for studying progression of luminal subtype tumors. PEITC treated animals had multiple small tumors, indicating delay in tumor progression. Although these tumors were histologically similar to those in controls, there was a lower expression of these biomarkers in normal luminal cells indicating delay in tumor initiation. In in vitro studies, PEITC depleted AldeFluor-positive putative stem/progenitor cells, which may partly be responsible for the delay in tumor initiation.

Prognosis of hormone-dependent breast cancers: implications of the presence of dysfunctional transcriptional networks activated by insulin via the immune transcription factor T-bet.

Estrogen receptor alpha (ERalpha)-positive breast cancers that co-express transcription factors GATA-3 and FOXA1 have a favorable prognosis. These transcription factors form an autoregulatory hormonal network that influences estrogen responsiveness and sensitivity to hormonal therapy. Disruption of this network may be a mechanism whereby ERalpha-positive breast cancers become resistant to therapy. The transcription factor T-bet is a negative regulator of GATA-3 in the immune system. In this study, we report that insulin increases the expression of T-bet in breast cancer cells, which correlates with reduced expression of GATA-3, FOXA1, and the ERalpha:FOXA1:GATA-3 target gene GREB-1. The effects of insulin on GATA-3 and FOXA1 could be recapitulated through overexpression of T-bet in MCF-7 cells (MCF-7-T-bet). Chromatin immunoprecipitation assays revealed reduced ERalpha binding to GREB-1 enhancer regions in MCF-7-T-bet cells and in insulin-treated MCF-7 cells. MCF-7-T-bet cells were resistant to tamoxifen in the presence of insulin and displayed prolonged extracellular signal-regulated kinase and AKT activation in response to epidermal growth factor treatment. ERalpha-positive cells with intrinsic tamoxifen resistance as well as MCF-7 cells with acquired tamoxifen and fulvestrant resistance expressed elevated levels of T-bet and/or reduced levels of FOXA1 and GATA-3. Analysis of publicly available databases revealed ERalpha-positive/T-bet-positive breast cancers expressing lower levels of FOXA1 (P = 0.0137) and GATA-3 (P = 0.0063) compared with ERalpha-positive/T-bet-negative breast cancers. Thus, T-bet expression in primary tumors and circulating insulin levels may serve as surrogate biomarkers to identify ERalpha-positive breast cancers with a dysfunctional hormonal network, enhanced growth factor signaling, and resistance to hormonal therapy.