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Nonhuman primates (NHPs) represent one of the most important models for preclinical studies of novel biomedical interventions. In contrast with small animal models, however, widespread utilization of NHPs is restricted by cost, logistics, and availability. Therefore, we sought to develop a translational primatized mouse model, akin to a humanized mouse, to allow for high-throughput in vivo experimentation leveraged to inform large animal immunology-based studies. We found that adult rhesus macaque mobilized blood (AMb) CD34+-enriched hematopoietic stem and progenitor cells (HSPCs) engrafted at low but persistent levels in immune-deficient mice harboring transgenes for human (NHP cross-reactive) GM-CSF and IL3, but did not in mice with wild-type murine cytokines lacking NHP cross-reactivity. To enhance engraftment, fetal liver-derived HSPCs were selected as the infusion product based on an increased CD34hi fraction compared with AMb and bone marrow. Coupled with cotransplantation of rhesus fetal thymic fragments beneath the mouse kidney capsule, fetal liver-derived HSPC infusion in cytokine-transgenic mice yielded robust multilineage lymphohematopoietic engraftment. The emergent immune system recapitulated that of the fetal monkey, with similar relative frequencies of lymphocyte, granulocyte, and monocyte subsets within the thymic, secondary lymphoid, and peripheral compartments. Importantly, while exhibiting a predominantly naïve phenotype, in vitro functional assays demonstrated robust cellular activation in response to nonspecific and allogenic stimuli. This primatized mouse represents a viable and translatable model for the study of hematopoietic stem cell physiology, immune development, and functional immunology in NHPs. Summary Sentence : Engraftment of rhesus macaque hematopoietic tissues in immune-deficient mice yields a robust BLT/NeoThy-type primatized mouse model for studying nonhuman primate hematopoiesis and immune function in vivo.

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

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.

Introduction Peritoneal dialysis (PD) has been used increasingly in past decade. Many of these patients undergo transplantation and may require dialysis for delayed graft function (DGF). The outcomes of DGF based on the post-transplantation dialysis modality are not well known. Methods We retrospectively reviewed all adult kidney transplant recipients (KTRs) from the University of Wisconsin School of Medicine and Public Health who developed DGF between November 2015 and April 2019. Patients were divided into those who received hemodialysis (HD) or PD during the DGF period. Immediate graft explant, DGF among living donor KTRs, or those requiring just a single dialysis treatment were excluded. Results Of 224 KTRs with DGF during the study period, 167 fulfilled our selection criteria. There were 16 patients in the PD and 151 in the HD group. Baseline characteristics were similar between the two groups, except diabetes was more prevalent in the HD group. Five of 16 PD patients had to be transitioned to HD. There was no difference in DGF duration, hospital length of stay, infectious or surgical complications, rejection at various time periods, graft function at last follow-up, or graft failure. In multivariate analysis, only rejection within the first year of transplantation (hazard ratio [HR]: 4.26; 95% confidence interval [CI]: 1.20–15.08; P = 0.02) and post-surgical complications (HR: 3.79; 95% CI: 1.03– 13.91; P = 0.04) were associated with death-censored graft failure (DCGF). The use of PD for treatment of DGF was not associated with DCGF. Conclusions In carefully selected patients, PD can be continued safely for DGF without any effect on short-term or long-term transplant outcomes., Graphical abstract

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.

Allogeneic islet transplant offers a minimally invasive option for β cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P

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.

Third-party vascular allografts (VAs) are an invaluable resource in kidney and pancreas transplantation when vascular reconstruction is needed and additional vessels from the organ donor are not available. We report the largest single-center experience to date on VA use, at a high-volume U.S. transplant center. Over a 7-year period, VAs were used for vascular reconstruction of 65 kidneys and 5 pancreases, in 69 recipients. The renal vein required reconstruction more often with right kidney transplantation (72.5% vs 27.5%, P < .001), and the renal artery required reconstruction more often with left kidney transplantation (67.6% vs 32.4%, P = .003). Eleven patients (15.9%) developed anti-VA de novo HLA donor-specific antibodies (dnDSAs) at a median time after transplantation of 19.0 months. Higher number of HLA mismatches between the VA donor and the recipient, and development of anti-organ allograft dnDSAs were significant predictors of anti-VA dnDSA development. Those with anti-VA dnDSAs had a higher rate of organ allograft rejection (45.4% vs 13.8%, P = .03) compared to those without, but there was no significant difference in incidence of vascular complications or graft outcomes. VAs can help circumvent challenging surgical situations. Anti-VA dnDSAs do not adversely affect organ allograft outcomes; however, they can contribute to HLA sensitization in the recipients.

BACKGROUND: Optimal induction for patients without pretransplant donor-specific antibodies (DSAs) is poorly defined. The goal of this study was to compare the incidence of de novo DSA (dnDSA) and graft outcomes between induction therapies in patients with a negative virtual crossmatch (VXM). METHODS: A retrospective chart review was performed, identifying 782 patients with a negative VXM who underwent kidney transplantation at a single, high-volume institution between January 2013 and May 2017. Kaplan–Meier analysis was used to assess the incidence of dnDSA and allograft survival between induction therapies in this group. dnDSA is defined as the development of new post-transplant DSA, at any MFI level. RESULTS: Induction therapy included alemtuzumab (N=87, 11%), basiliximab (N=522, 67%), and anti-thymocyte globulin (ATG; N=173, 22%). One-year graft survival was similar between groups (alemtuzumab, 100%; basiliximab, 98%; ATG, 99%). Incidence of acute rejection at 1 year was

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 (

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.

Among kidney transplant recipients, the duration of pretransplant dialysis is significantly associated with worse post-transplant outcomes. However, data on the outcomes of preemptive simultaneous pancreas and kidney (SPK) are limited. We analyzed primary SPK recipients transplanted between January 2000 and December 2017. Patients were divided into two groups based on pretransplant dialysis history of preemptive versus non-preemptive. Patient and survival of grafts were outcomes of interest. Of the 644 recipients, 174 (27%) were preemptive and 470 (73%) were not. Most of the baseline characteristics were similar between the groups. In the univariable analysis, the non-preemptive transplant was associated with 54% increased risk for kidney death-censored graft failure (DCGF; HR: 1.54; 95% CI: 1.01-2.35; P = 0.05). There was a 29% increased risk after adjustment for confounding factors (HR: 1.29; 95% CI: 0.83-2.02; P = 0.26), although this association was not statistically significant. Similarly, there was a 16% increased risk of pancreas DCGF in univariable analysis and 1% after adjustment, which was also not statistically significant. When outcomes were based on the duration of pretransplant dialysis, the duration was not associated with either patient survival or survival of either graft in K-M analysis. In SPK recipients, with pretransplant dialysis history, there was a tendency toward inferior graft survival, mainly for the kidney more than the pancreas.

Background The first simultaneous pancreas and kidney (SPK) transplant was performed in 1966. Early procedures were associated with significant morbidity and mortality and were performed in very low numbers in select patients. Methods This study includes all recipients of an SPK at the University of Wisconsin-Madison between 1986 and 1993, who were actively followed and had a functional pancreas allograft for >25 years as of October 31, 2018. Results A total of 291 SPK were performed during the study period; of these, 39 patients still had a functional graft at last follow up and 9 (18.8%) pancreas grafts were lost due to patient death or graft failure after >25 years. At last follow up, all 39 patients with functional pancreas graft had at least one comorbidity, such as hypertension, hyperlipidemia, or coronary artery disease. Twenty-seven required enteric conversion; 11 patients experienced renal allograft failure (10 underwent a repeat kidney transplant); and 6 required amputation of part of the lower extremity. In the Cox regression analysis, bladder drained pancreas was associated with lower probability of prolonged pancreas graft survival (hazard ratio: 0.52; confidence interval: 0.32-0.85; P = 0.01). Conclusions With careful and detailed follow-up and attention to complications, some recipients of pancreas grafts have outstanding outcomes. As the number of pancreas recipients with prolonged graft survival may be rising, healthcare providers should be aware of the management of complications associated with this unique group of patients.

OBJECTIVE To determine the prevalence and prognostic significance of unrecognized myocardial infarction (MI) by delayed-enhancement MRI (DE-MRI) in asymptomatic patients with diabetes. RESEARCH DESIGN AND METHODS In this prospective, two-center study of asymptomatic patients without known cardiac disease (n = 120), two prespecified cohorts underwent a research MRI: 1) a high-risk group with type 1 diabetes and chronic renal insufficiency (n = 50) and 2) an average-risk group with type 2 diabetes (n = 70). The primary end point was a composite of all-cause mortality and clinical MI. RESULTS Overall, the prevalence of unrecognized MI was 19% by DE-MRI (28% high-risk group and 13% average-risk group) and 5% by electrocardiography. During up to 5 years of follow-up with a total of 460 patient-years of follow-up, the rate of death/MI was markedly higher in patients with diabetes with (vs. without) unrecognized MI (all 44% vs. 7%, high-risk group 43% vs. 6%, and average-risk group 44% vs. 8%; all P < 0.01). After adjustment for Framingham risk score, left ventricular ejection fraction, and diabetes type, the presence of unrecognized MI by DE-MRI conferred an eightfold increase in risk of death/MI (95% CI 3.0–21.1, P < 0.0001). Addition of unrecognized MI to clinical indices significantly improved model discrimination for adverse events (integrated discrimination improvement = 0.156, P = 0.001). CONCLUSIONS Unrecognized MI is prevalent in asymptomatic patients with diabetes without a history of cardiac disease and confers a markedly increased risk of death and clinical MI.

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 (

Funder: Fondazione Pisa, Pisa, Italy; Id: http://dx.doi.org/10.13039/100007368, Funder: Tuscany Region, Italy; Id: http://dx.doi.org/10.13039/501100009888, Funder: Pisa University Hospital, Pisa, Italy, Funder: University of Pisa, Pisa, Italy; Id: http://dx.doi.org/10.13039/501100007514, 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.

Development of a new methodology to induce immunological chimerism after allogeneic hematopoietic cell (HC) transplantation in a rhesus macaque model is described. The chimeric state was achieved using a non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TomoTLI) conditioning regimen followed by donor HC infusions between 1-haplotype matched donor/recipient pairs. The technique was tested as a feasibility study in an experimental group of seven rhesus macaques that received the novel TomoTLI tolerance protocol and HC allo-transplants. Two tomotherapy protocols were compared: TomoTLI (n = 5) and TomoTLI/total-body irradiation (TBI) (n = 2). Five of seven animals developed mixed chimerism. Three of five animals given the TomoTLI protocol generated transient mixed chimerism with no graft-versus-host disease (GVHD) with survival of 33, 152 and >180 days. However, the inclusion of belatacept in addition to a single fraction of TBI resulted in total chimerism and fatal GVHD in both animals, indicating an unacceptable conditioning regimen.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.

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 and30 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 from20 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.

Background Weight change, primarily weight gain, is a common problem among solid organ transplant recipients. The incidence of weight gain or loss after successful pancreas transplant alone (PTA) and the effect on graft survival is unknown. Methods This was a single-center observational study among PTA recipients, transplanted at our center between January 1, 2005, and July 31, 2017, who had a functional pancreas graft for at least 1 year and documented weight change at the 1-year clinic visit. Results In this cohort study of 105 PTA recipients, 28 had significant weight gain, 27 had significant weight loss, and the remaining 50 did not have significant weight change at 1-year posttransplant. When comparing the weight gain and no weight change groups, the weight gain cohort started to gain weight at 3 months posttransplant to 5 years or last follow up. Similarly, the weight loss group lost weight at 3 months posttransplant up to last follow up. Clinically significant weight gain or weight loss were not associated with uncensored or death censored graft failure in univariate regression and Kaplan-Meier survival analysis. Also, there were no significant differences between the groups in the glycated hemoglobin at last follow up. Conclusions Approximately 50% of PTA recipients had a significant weight change at 1-year posttransplant, of which 25% gained significant weight and 25% loss. There was no significant difference in graft survival due to the significant weight changes. Further research is needed in this field.

Pancreas transplantation is the only durable cure for insulin-dependent diabetes mellitus. While results have significantly improved, listing for and transplantation of pancreatic allografts appears to be decreasing. Data on pancreas outcomes suggest that even “nonideal” allografts can be safely used to expand the donor supply. The chapter reviews the outcomes with ideal and nonideal allografts such as those from donors who are older, had high body mass index, or donated after cardiac death. Pancreas outcome can be effectively and accurately predicted when using the Pancreas Donor Risk Index (P-DRI) which is based on preoperative variables including donor gender, age, race, BMI, height, cause of death, preservation time, DCD status, and serum creatinine. Although the P-DRI scoring system is highly reliable, the final assessment of the safety of transplant must be made by direct examination of the allograft after recovery by an experienced pancreas transplant surgeon.

We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long-term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long-term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P < .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long-term graft survival (P = .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P = .001). However, graft survival was not statistically different in patients managed initially with open surgery (P = .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long-term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long-term graft survival.

Background Cardiovascular disease is a cause of morbidity and mortality in organ transplant recipients. Cardiac surgery after organ transplantation is not uncommon in this population. We evaluated 30-day outcomes and long-term survival of abdominal transplant recipients undergoing cardiac surgery at our institution. Methods In all, 138 patients with previous kidney, kidney-pancreas, and liver transplants underwent cardiac surgery from 2000 to 2016. Propensity score (ratio 1:3) matched 115 abdominal transplant with 345 patients undergoing cardiac surgery without a history of abdominal transplant. They were matched for type and year of cardiac surgery, age, sex, body mass index, history of diabetes mellitus, and creatinine level before cardiac surgery. Results Median time from abdominal transplant to cardiac surgery was 7 years (interquartile range, 3 to 12 years). Perioperative variables, including surgery and cardiopulmonary bypass time, aortic cross-clamp and intubation time, and intensive care unit stay did not differ between the groups. Hospital length of stay and rate of 30-day hospital readmissions did not differ between the groups. Patients with abdominal transplants had more strokes (4% versus 0.6%; p = 0.005) within 30 days after surgery. There were no differences in renal failure, bleeding, site infections, atrial fibrillation, and pneumonia between the groups. Five patients (4%) died within 30 days after surgery in the abdominal transplant group (4 kidneys, 1 liver, 0 kidney-pancreas), and 7 patients (2%) died in the nontransplanted group ( p = 0.24). Conclusions Previous history of abdominal transplant is associated with an increased 30-day incidence of stroke after cardiac surgery. Abdominal transplant does not affect 30-day mortality after cardiac surgery, whereas long-term survival is significantly reduced. Regular patient follow-up and prevention and early treatment of postoperative complications are key to patient survival.

Islet transplantation offers a minimally-invasive approach for beta cell replacement in diabetic patients with hypoglycemic unawareness. Attempts at insulin independence may require multiple islet re-infusions from distinct donors, thus increasing the risk for allogeneic sensitization. Currently, solid organ pancreas transplant is the only remaining surgical option following failed islet transplantation in the US. However, the immunologic impact of repeated exposure to donor antigens on subsequent pancreas transplantation is unclear. Here we describe a case series of seven patients undergoing solid organ pancreas transplant following islet graft failure, with long-term follow-up of pancreatic graft survival and renal function. Despite highly variable panel-reactive antibody (PRA) levels prior to pancreas transplant (mean 27±35%), all seven patients achieved stable and durable insulin independence with a mean follow-up of 6.7 years. Mean hemoglobin A1c (HgbA1c) values improved significantly from post-islet, pre-pancreas levels (mean 8.1±1.5%) to post-pancreas levels (mean 5.3±0.1%; p=0.0022). Three patients experienced acute rejection episodes successfully managed with thymoglobulin and methylprednisolone, and none of these pre-uremic type 1 diabetic recipients developed Stage 4 or 5 chronic kidney disease postoperatively. These results support pancreas-after-islet (PAI) transplantation with aggressive immunosuppression and protocol biopsies as a viable strategy to restore insulin independence after islet graft failure. This article is protected by copyright. All rights reserved.

T helper 17 (Th17)-dependent autoimmune responses can develop after heart or lung transplantation and are associated with fibro-obliterative forms of chronic rejection; however, the specific self-antigens involved are typically different from those associated with autoimmune disease. To investigate the basis of these responses, we investigated whether removal of regulatory T cells or blockade of function reveals a similar autoantigen bias. We found that Th17 cells specific for collagen type V (Col V), kα1-tubulin, and vimentin were present in healthy adult peripheral blood mononuclear cells, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1[V]), we compared Th17 cells from healthy donors with Th17 cells from Col V-reactive heart and lung patients. Although the latter responded well to α1(V) fragments and peptides in an HLA-DR-restricted fashion, Th17 cells from healthy persons responded in an HLA-DR-restricted fashion to fragments but not to peptides. Col V, kα1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, preexisting Th17 response that is MHC class II restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis.

For donation after circulatory death (DCD), many centers allow 1 h after treatment withdrawal to donor death for kidneys. Our center has consistently allowed 2 h. We hypothesized that waiting longer would be associated with worse outcome. A single-center, retrospective analysis of DCD kidneys transplanted between 2008 and 2013 as well as a nationwide survey of organ procurement organization DCD practices were conducted. We identified 296 DCD kidneys, of which 247 (83.4%) were transplanted and 49 (16.6%) were discarded. Of the 247 recipients, 225 (group 1; 91.1%) received kidneys with a time to death (TTD) of 0-1 h; 22 (group 2; 8.9%) received grafts with a TTD of 1-2 h. Five-year patient survival was 88.8% for group 1, and 83.9% for group 2 (p = 0.667); Graft survival was also similar, with 5-year survival of 74.1% for group 1, and 83.9% for group 2 (p = 0.507). The delayed graft function rate was the same in both groups (50.2% vs. 50.0%, p = 0.984). TTD was not predictive of graft failure. Nationally, the average maximum wait-time for DCD kidneys was 77.2 min. By waiting 2 h for DCD kidneys, we performed 9.8% more transplants without worse outcomes. Nationally, this practice would allow for hundreds of additional kidney transplants, annually.

To determine the prevalence and prognostic significance of unrecognized myocardial infarction (MI) by delayed-enhancement MRI (DE-MRI) in asymptomatic patients with diabetes.In this prospective, two-center study of asymptomatic patients without known cardiac disease (Overall, the prevalence of unrecognized MI was 19% by DE-MRI (28% high-risk group and 13% average-risk group) and 5% by electrocardiography. During up to 5 years of follow-up with a total of 460 patient-years of follow-up, the rate of death/MI was markedly higher in patients with diabetes with (vs. without) unrecognized MI (all 44% vs. 7%, high-risk group 43% vs. 6%, and average-risk group 44% vs. 8%; allUnrecognized MI is prevalent in asymptomatic patients with diabetes without a history of cardiac disease and confers a markedly increased risk of death and clinical MI.

Simultaneous pancreas and kidney (SPK) and pancreas after kidney (PAK) transplant are both potential options for diabetic ESRD patients. Historically, PAK pancreas graft outcomes were felt to be inferior to SPK pancreas graft outcomes. Little is known about outcomes in the modern era of transplantation. We analyzed our SPK and PAK recipients transplanted between 01/2000 and 12/2016. There were a total of 635 pancreas and kidney transplant recipients during the study period, 611 SPK and 24 PAK. Twelve of the PAK patients received a living donor kidney. There were no significant differences between the two groups in kidney or pancreas graft rejection at 1 year. Similarly, 1-year graft survival for both organs was not different. At last follow-up, uncensored and death-censored graft survival was not statistically different for kidney or pancreas grafts. In addition, in Cox regression analysis SPK and PAK were associated with similar graft survival. Although the majority of pancreas transplants are in the form of SPK, PAK is an acceptable alternative. Simultaneous pancreas and kidney avoids donor risks associated with live donation, so may be preferable in regions with short wait times, but PAK with a living donor kidney may be the best alternative in regions with long SPK wait times.

Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept-based CNIA/ESW regimens with a tacrolimus-based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti-thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease-calculated eGFR of

Background. Simultaneous pancreas-kidney (SPK) transplant is usually the best option for the diabetic end-stage renal disease patient. There is limited information about kidney graft outcomes in SPK recipients with isolated pancreas graft failure who do versus do not undergo pancreas retransplantation. Methods. Patients were divided into 2 groups based on whether they underwent pancreas retransplant (ReTx+) or not (ReTx−). Kidney graft function and survival were the primary endpoints. Results. One hundred and nine patients satisfied our selection criteria, 25 in ReTx+ and 84 in ReTx−. Mean interval from SPK to pancreas failure was significantly shorter in the ReTx+ compared with the ReTx− group, 19.3 ± 36.7 versus 45.7 ± 47.0 months (P = 0.01), respectively. There was no significant difference in kidney graft follow-up post SPK between 2 groups (P = 0.48). At last follow-up, 15 of the 25 (60%) of the repeat pancreas graft had failed, with a mean graft survival among these failed pancreas graft of 2.6 ± 2.7 years, ranging from 0 to 8.1 years. Uncensored kidney graft failure was significantly lower in the ReTx+ group compared with the ReTx− group, 44% versus 67% (P = 0.04). Death-censored kidney graft failure was also lower in the ReTx+ group, 24% versus 48% (P = 0.04). The difference in patient survival did not reach statistical significance. In adjusted Cox regression analysis, rejection as a cause of pancreas failure was associated with increased risk of death-censored kidney graft failure, and pancreas retransplantation was associated with decreased risk of kidney graft failure. A similar pattern was seen after 1:1 matching for the interval between SPK and pancreas graft failure. Conclusions. Even though ReTx+ patients accept the risks associated with repeat pancreas surgery, providers should consider this option in suitable otherwise healthy patients.

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.