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Objective: Nutcracker syndrome is a rare condition that involves mechanical compression of the left renal vein, leading to chronic and debilitating left flank pain. The etiology of the pain is misdiagnosed frequently, and patients usually require long-term opioid use to manage their pain. Multiple therapeutic options for nutcracker syndrome have been described in the literature but the reports are limited by small numbers of patients, and the lack of convincing data demonstrating consistently improved outcomes. Here we report the largest series to date of patients undergoing renal autotransplantation for the treatment of nutcracker syndrome., Methods: We performed a multicenter retrospective cohort review of patients 105 patients with nutcracker syndrome who underwent renal autotransplantation as a primary or salvage therapy., Results: During the overall study period, 93.1% of patients treated with autotransplantation had durable, complete flank pain relief at 12 months with both open and robotic surgical approach. After autotransplantation, a statistically significant decrease in the percentage of patients using opioids from 48.6% to 17.0% was demonstrated at 12 months. In those patients using opioids before autotransplantation, a statistically significant decrease in morphine milligram equivalents was demonstrated from an alarming 68.9 ± 15.0 per day to 25.0 ± 11.02 morphine milligram equivalents per day., Conclusions: Our findings suggest that renal autotransplantation, as a primary treatment or a salvage treatment, in patients with nutcracker syndrome provides durable pain relief and a marked decrease in chronic opioid use regardless of surgical approach., Competing Interests: Disclosures None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Kidney transplant outcomes have dramatically improved since the first successful transplant in 1954. In its early years, kidney transplantation was viewed more skeptically. Today it is considered the treatment of choice among patients with end-stage kidney disease., Methods: Our program performed its first kidney transplant in 1966 and recently performed our 12 000th kidney transplant. Here, we review and describe our experience with these 12 000 transplants. Transplant recipients were analyzed by decade of date of transplant: 1966-1975, 1976-1985, 1986-1995, 1996-2005, 2006-2015, and 2016-2022. Death-censored graft failure and mortality were outcomes of interest., Results: Of 12 000 kidneys, 247 were transplanted from 1966 to 1975, 1147 from 1976 to 1985, 2194 from 1986 to 1995, 3147 from 1996 to 2005, 3046 from 2006 to 2015, and 2219 from 2016 to 2022 compared with 1966-1975, there were statistically significant and progressively lower risks of death-censored graft failure at 1 y, 5 y, and at last follow-up in all subsequent eras. Although mortality at 1 y was lower in all subsequent eras after 1986-1995, there was no difference in mortality at 5 y or the last follow-up between eras., Conclusions: In this large cohort of 12 000 kidneys from a single center, we observed significant improvement in outcomes over time. Kidney transplantation remains a robust and ever-growing and improving field., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Here we test the hypothesis that, like CD81-associated "latent" IL35, the transforming growth factor (TGF)β:latency-associated peptide (LAP)/glycoprotein A repetitions predominant (GARP) complex was also tethered to small extracellular vesicles (sEVs), aka exosomes, produced by lymphocytes from allo-tolerized mice. Once these sEVs are taken up by conventional T cells, we also test whether TGFβ could be activated suppressing the local immune response., Methods: C57BL/6 mice were tolerized by i.p. injection of CBA/J splenocytes followed by anti-CD40L/CD154 antibody treatment on days 0, 2, and 4. On day 35, spleen and lymph nodes were extracted and isolated lymphocytes were restimulated with sonicates of CBA splenocytes overnight. sEVs were extracted from culture supernatants by ultracentrifugation (100 000 g ) and assayed for (a) the presence of TGFβ:LAP associated with tetraspanins CD81,CD63, and CD9 by enzyme-linked immunosorbent assay; (b) GARP, critical to membrane association of TGFβ:LAP and to activation from its latent form, as well as various TGFβ receptors; and (c) TGFβ-dependent function in 1° and 2° immunosuppression of tetanus toxoid-immunized B6 splenocytes using trans-vivo delayed-type hypersensitivity assay., Results: After tolerization, CBA-restimulated lymphocytes secreted GARP/TGFβ:LAP-coated extracellular vesicles. Like IL35 subunits, but unlike IL10, which was absent from ultracentrifuge pellets, GARP/TGFβ:LAP was mainly associated with CD81 + exosomes. sEV-bound GARP/TGFβ:LAP became active in both 1° and 2° immunosuppression, the latter requiring sEV uptake by "bystander" T cells and reexpression on the cell surface., Conclusions: Like other immune-suppressive components of the Treg exosome, which are produced in a latent form, exosomal GARP/TGFβ:LAP produced by allo-specific regulatory T cells undergoes either immediate activation (1° suppression) or internalization by naive T cells, followed by surface reexpression and subsequent activation (2°), to become suppressive. Our results imply a membrane-associated form of TGFβ:LAP that, like exosomal IL35, can target "bystander" lymphocytes. This new finding implicates exosomal TGFβ:LAP along with Treg-derived GARP as part of the infectious tolerance network., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Our research showed that patients with alcohol-associated liver disease (ALD) had more severe liver disease than those without a diagnosis of ALD yet were less likely to be selected for transplant listing due to their increased psychosocial vulnerability. This study aims to answer whether this vulnerability translates to worse short-term outcomes after transplant listing., Methods: A total of 187 patients were approved for liver transplant listing and are included in the present retrospective study. We collected dates of transplantation, retransplantation, death, and pathologic data for evidence of rejection, and reviewed alcohol biomarkers and documentation for evidence of alcohol use., Results: The ALD cohort had higher Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) scores (39.4 vs. 22.5, p <0.001) and Model for End-Stage Liver Disease (MELD)-Na scores (25.0 vs. 18.5, p <0.001) compared with the non-ALD cohort. Forty-nine (59.7%) subjects with ALD and 60 (57.1%, p =0.71) subjects without ALD subsequently received a liver transplant. Overall mortality was similar between the 2 groups (20.7% ALD vs. 21.0% non-ALD, p =0.97). Neither the SIPAT score (HR: 0.98, 95% CI: 0.96-1.00, p =0.11) nor MELD-Na score (HR 0.99, 95% CI 0.95-1.02, p =0.40) were associated with mortality. Patients with ALD were more likely to have alcohol biomarkers tested both before (84.1% vs. 24.8% non-ALD, p <0.001) and after liver transplantation (74.0% vs. 16.7% non-ALD, p <0.001). SIPAT score was associated with alcohol use after listing (OR: 1.03, 95% CI: 1.0-1.07, p =0.04), although a return to alcohol use was not associated with mortality (HR: 1.60, 95% CI: 0.63-4.10, p =0.33)., Conclusion: Patients with ALD had higher psychosocial risk compared with patients without a diagnosis of ALD who were placed on the waitlist, but had similar short-term outcomes including mortality, transplantation, and rejection. Although a high SIPAT score was predictive of alcohol use, in the short-term, alcohol use after transplant listing was not associated with mortality., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes., Methods: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR., Results: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06)., Conclusions: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077)., (Copyright © 2022 by the American Society of Nephrology.)

Exposure to non-inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo-antigens. In adult mice, the production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross-decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD-L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord blood. The average percentage of NIMA-XD among total DCs was 2.6% for myeloid and 4.5% for Plasmacytoid DC. These cells showed higher PD-L1 expression than their non-XD counterparts (mDC: p = .0016; pDC: p = .024). We detected CD9 + EVs bearing NIMA and PD-L1 in cord blood. To determine if this immune regulatory mechanism persists beyond the pregnancy, we analyzed NIMA-expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft-infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD-L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: When the metacarpal bones sustain severe osseous injury requiring reconstruction, functional recovery relies on the precise distribution of tension throughout full range of motion. While the small scale of hand structures compounds the effects of altering normal anatomy, literature lacks consensus recommendations for the acceptable degree of length alteration and/or appropriate methods of length estimation in reconstructive procedures. Length asymmetry has been reported in human metacarpal bones; however, studies assessing this phenomenon in living subjects with attention to functional implications or length prediction are lacking., Methods: Hand X-rays were obtained for 34 patients aged 25-80 without history of metacarpal trauma, joint degeneration, or pathologic bone metabolism. A scaled bivariate model predicted metacarpal length using an ipsilateral paired metacarpal and matching contralateral ratio: Estimate&#95;Dx&#95;R = Median&#95;Dy&#95;R * (Median&#95;Dx&#95;L/Median&#95;Dy&#95;L). A second set of predictions used the contralateral metacarpal as a control. Pearson correlation coefficients, paired t -tests, and chi-square tests evaluated the symmetry between bilateral metacarpal lengths and paired metacarpal ratios as well as the accuracy of each predictive method., Results: The contralateral control and target metacarpal differed significantly in digits 1, 2, 3, and 5. No significant difference in matched metacarpal ratios of the right and left hands was found. For all digits except 5D, bivariate model predictions generated were more strongly correlated with actual target length. Chi-square tests did not detect a significant difference in predictive value of the two models., Conclusion: The scaled bivariate model we describe may be useful and economic in generating accurate length estimates of metacarpals for reconstructive procedures., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

There are no prior studies assessing the risk factors and outcomes for kidney delayed graft function (K-DGF) in simultaneous heart and kidney (SHK) transplant recipients. Using the OPTN/UNOS database, we sought to identify risk factors associated with the development of K-DGF in this unique population, as well as outcomes associated with K-DGF. A total of 1161 SHK transplanted between 1998 and 2018 were included in the analysis, of which 311 (27%) were in the K-DGF (+) group and 850 in the K-DGF (-) group. In the multivariable analysis, history of pretransplant dialysis (OR: 3.95; 95% CI: 2.94 to 5.29; p < .001) was significantly associated with the development of K-DGF, as was donor death from cerebrovascular accident and longer cold ischemia time of either organ. SHK recipients with K-DGF had increased mortality (HR: 1.99; 95% CI: 1.52 to 2.60; p < .001) and death censored kidney graft failure (HR: 3.51; 95% CI: 2.29 to 5.36; p < .001) in the multivariable analysis. Similar outcomes were obtained when limiting our study to 2008-2018. Similar to kidney-only recipients, K-DGF in SHK recipients is associated with worse outcomes. Careful matching of recipients and donors, as well as peri-operative management, may help reduce the risk of K-DGF and the associated detrimental effects., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Despite an increasing demand for liver transplantation in older patients, our understanding of posttransplant outcomes in older recipients is limited to basic recipient and graft survival. Using National Surgical Quality Improvement Program Transplant, we tracked early outcomes after liver transplantation for patients >65., Methods: We conducted a retrospective analysis of patients in National Surgical Quality Improvement Program Transplant between March 1, 2017 and March 31, 2019. Recipients were followed for 1 y after transplant with follow-up at 30, 90, and 365 d. Data were prospectively gathered using standard definitions across all sites., Results: One thousand seven hundred thirty-one adult liver transplants were enrolled; 387 (22.4%) were >65 y old. The majority of older recipients were transplanted for hepatocellular carcinoma. The older cohort had a lower lab Model for End-Stage Liver Disease and was less likely to be hospitalized at time of transplant. Overall, older recipients had higher rates of pneumonia but no difference in intensive care unit length of stay (LOS), total LOS, surgical site infection, or 30-d readmission. Subgroup analysis of patients with poor functional status revealed a significant difference in intensive care unit and total LOS. Pneumonia was even more common in older patients and had a significant impact on overall survival., Conclusions: By targeting patients with hepatocellular carcinoma and lower Model for End-Stage Liver Diseases, transplant centers can achieve nearly equivalent outcomes in older recipients. However, older recipients with poor functional status require greater resources and are more likely to develop pneumonia. Pneumonia was strongly associated with posttransplant survival and represents an opportunity for improvement. By truly understanding the outcomes of elderly and frail recipients, transplant centers can improve outcomes for these higher-risk recipients., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage-specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer-specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST-sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Aims: End-stage heart failure patients often present with severe kidney failure and have limited treatment options. We compared the clinical characteristics and outcomes among end-stage heart and kidney failure patients who underwent combined heart and kidney transplant (HKTx) with those who underwent kidney transplant after heart transplant (KAH)., Methods and Results: All patients from 2007-2016 who underwent combined HKTx (n = 715) and those who underwent KAH (n = 130) using the United Network for Organ Sharing database were included. Kaplan-Meier curves and Cox models compared survivals and identified predictors of death. Number of combined HKTx performed annually in United States increased from 59 in 2007 to 146 in 2016 whereas KAH decreased from 34 in 2007 to 6 in 2016. Among KAH patients, average wait time for kidney transplant was 3.0 years, time to dialysis or to kidney transplant after heart transplant did not differ with varying severity of kidney disease at baseline (P for both >0.05). Upon follow-up (mean 3.5 ± 2.7 years), 151 patients died. In multivariable models, patients who underwent combined HKTx had 4.7-fold greater risk of death [95% confidence interval (CI) 2.4-9.4) than KAH patients upon follow up. A secondary analysis using calculation of survival only after kidney transplant for KAH patients still conferred higher risk for combined HKTx patients [hazard ratio (HR) 2.6 95% CI 1.33-5.15]. In subgroup analyses after excluding patients on dialysis (HR 3.99 95% CI 1.98-8.04) and analysis after propensity matching for age, gender, and glomerular filtration rate (HR 3.01 95% CI 1.40-6.43) showed similar and significantly higher risk for combined HKTx patients compared with KAH patients. Lastly, these results also remained unchanged after excluding transplant centres who performed only one type of procedure preferentially, i.e. HKTx or KAH (HR 4.70 95% CI 2.35-9.42)., Conclusions: National registry data show continual increase in combined HKTx performed annually in the United States but inferior survival compared with KAH patients. Differences in patient characteristics or level of kidney dysfunction at baseline do not explain these poor outcomes among HKTx patients compared with KAH patients. Consensus guidelines are greatly needed to identify patients who may benefit more from dual organ transplants., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

The National Surgical Quality Program (NSQIP) Transplant was designed by transplant surgeons from the ground up to track posttransplant outcomes beyond basic recipient and graft survival. After an initial pilot phase, the program has expanded to 29 participating sites and enrolled more than 4300 recipient-donor pairs into the database, including 2876 complete kidney transplant cases. In this analysis, surgical site infection (SSI), urinary tract infection (UTI), and reoperation/intervention were evaluated for kidney transplant recipients. We observed impressive variation in the crude incidence between sites for SSI (0%-17%), UTI (0%-14%), and reoperation/intervention (0%-25%). After adjustment for donor and recipient factors, 2 sites were outliers with respect to their incidence of UTI. For the first time, the field of transplantation has data that demonstrate variation in kidney recipient surgical outcomes between sites. More importantly, NSQIP Transplant provides a powerful platform to improve care beyond basic patient and graft survival., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Multiple reports have demonstrated that liver transplantation following donation after circulatory death (DCD) is associated with poorer outcomes when compared with liver transplantation from donation after brain death (DBD) donors. We hypothesized that carefully selected, underutilized DCD livers recovered from younger donors have excellent outcomes. We performed a retrospective study of the United Network for Organ Sharing database to determine graft survivals for patients who received liver transplants from DBD donors of age ≥ 60 years, DBD donors < 60 years, and DCD donors < 50 years of age. Between January 2002 and December 2014, 52,271 liver transplants were performed in the United States. Of these, 41,181 (78.8%) underwent transplantation with livers from DBD donors of age < 60 years, 8905 (17.0%) from DBD donors ≥ 60 years old, and 2195 (4.2%) livers from DCD donors < 50 years of age. DCD livers of age < 50 years with < 6 hours of cold ischemia time (CIT) had superior graft survival when compared with DBD livers ≥ age 60 years (P < 0.001). In 2014, there were 133 discarded DCD livers; of these, 111 (83.4%) were from donors < age 50 years old. Young DCD donor livers (age < 50 years old) with short CITs yield results better than that seen with DBD livers > 60 years old. Careful donor organ and recipient selection can lead to excellent results, despite previous reports suggesting otherwise. Increased acceptance of these DCD livers would lead to shorter wait list times and increased national liver transplant rates. Liver Transplantation 22 1197-1204 2016 AASLD., (© 2016 by the American Association for the Study of Liver Diseases.)

Hepatic ischemia/reperfusion injury (IRI) is an unavoidable consequence of liver transplantation that can lead to postoperative hepatic dysfunction. Myeloid cells that include Kupffer cells, monocytes, and neutrophils contribute to the inflammatory response and cellular injury observed during hepatic IRI. We hypothesize that overactivation of the nuclear erythroid 2 p45-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in myeloid cells leads to decreased cellular damage after hepatic IRI. We constructed transgenic mice with constitutively active nuclear erythroid 2 p45-related factor 2 (caNrf2) that over activates the Nrf2-ARE pathway in myeloid cells (lysozyme M cre recombinase [LysMcre]+/caNrf2+, n = 9), and their littermate controls lacking transgene expression (LysMcre+/caNrf2-, n = 11). The mice underwent either sham or partial hepatic ischemia surgery, with 60 minutes of ischemia followed by 6 hours of reperfusion. After IRI, LysMcre+/caNrf2+ mice demonstrated significantly decreased serum alanine aminotransferase and decreased areas of necrosis. Immunohistochemistry and immunoblot of caspase 3 showed a significantly decreased cleaved to full-length caspase 3 ratio in LysMcre+/caNrf2+ animals. Lymphocyte antigen 6 complex locus G and CD68 staining demonstrated reduced inflammatory cell infiltration. LysMcre+/caNrf2+ animals also had significantly decreased gene expression of proinflammatory cytokines, including interleukin (IL) 1β, IL6, tumor necrosis factor α, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 10, and significantly decreased levels of 8-isoprostanes. In our model, Nrf2 overactivation in myeloid cells leads to decreased hepatocellular damage, necrosis, apoptosis, inflammation, and oxidative stress. Pharmacologic targeting of the Nrf2-ARE pathway in myeloid cells may be a novel strategy to mitigate hepatic IRI. Liver Transplantation 22 1115-1128 2016 AASLD., (© 2016 American Association for the Study of Liver Diseases.)

Hepatic ischemia/reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element pathway in warm hepatic IRI. Nrf2 knockout (KO) and wild-type (WT) animals and novel transgenic mice expressing a constitutively active nuclear factor (erythroid-derived 2)-like 2 (caNrf2) mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were killed 6 hours after reperfusion, and their serum and tissue were collected for analysis. As compared to WT animals after ischemia/reperfusion (IR), Nrf2 KO mice had increased hepatocellular injury with increased serum alanine aminotransferase and aspartate aminotransferase, Suzuki score, apoptosis, an increased inflammatory infiltrate, and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte-specific Nrf2 overactivation providing protection against warm hepatic IRI., (© 2015 American Association for the Study of Liver Diseases.)

As the mean Model for End-Stage Liver Disease (MELD) score at time of liver transplantation continues to increase, it is crucial to implement preemptive strategies to reduce wait-list mortality. We review the most common complications that arise in patients with a high MELD score in an effort to highlight strategies that can maximize survival and successful transplantation., (© 2015 American Association for the Study of Liver Diseases.)

Objectives: This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (≥75 years of age)., Background: In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients., Methods: We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 ± 3 years of age) or (n = 82) nonelderly (NE) (≥45 to <65 years of age; mean: 56 ± 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference <15%., Results: Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 ± 14%) than clopidogrel (63 ± 14%; p < 0.001) in VE but higher than prasugrel 10 mg in NE (46 ± 12%; p < 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg., Conclusions: In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.

Background and Objectives: Expanded-criteria donor (ECD) kidneys are used to expand the number of deceased-donor kidney transplants, often for elderly recipients. This study sought to determine whether older recipients had significantly worse outcomes from receiving ECD kidneys and whether outcomes of ECD versus standard-criteria donor (SCD) kidneys differed in younger recipients., Design, Setting, Participants, & Measurements: This is a single-center, retrospective review of all primary deceased-donor kidney transplantations performed between 2000 and 2005. Group 1 consisted of patients ≥60 years of age (n=189) who received an ECD (n=96) or an SCD (n=93) kidney. Group 2 consisted of patients 40-59 years of age (n=370) who received an ECD (n=105) or an SCD (n=265) kidney., Results: Older recipients (group 1) who received ECD kidneys demonstrated significantly shortened 5-year actuarial patient and graft survival rates compared with older recipients of SCD allografts. Group 1 ECD recipients also had significantly worse outcomes than younger (group 2) ECD recipients. In multivariate analysis, ECD kidneys remained an independent predictor of poorer outcome in group 1., Conclusions: Morbidity and mortality were increased in elderly recipients of ECD kidneys. These findings may have implications in kidney allocation policy developments that encourage placement of ECD kidneys for older recipients.

Between 1 January 2002 and 31 December 2007, our center performed 1687 adult renal transplants. A retrospective analysis was performed to compare outcomes between patients receiving alemtuzumab (n = 632) and those receiving either basiliximab (n = 690) or thymoglobulin (n = 125). Patients receiving alemtuzumab were younger (49 vs. 51 years, P = 0.02), had fewer HLA matches (1.7 vs. 2.0, P < 0.0001), were more likely to have a cytomegalovirus (CMV) donor(+)/recipient(-) transplant (22% vs. 17%, P = 0.03) and were less likely to receive a living donor allograft (32% vs. 37%, P = 0.04). Alemtuzumab recipients were less likely to receive tacrolimus (35% vs. 47%, P < 0.0001). The 1-, 3-, and 5-year cumulative incidence of antibody-mediated rejection (AMR) in alemtuzumab-treated patients was 19%, 24%, and 27%, vs. 11%, 15%, and 18% for the other group (P < 0.0001). The 1-, 3-, and 5-year allograft survival in the alemtuzumab group was 88%, 75%, and 67%, vs. 91%, 82%, and 74% for the other group (P < 0.0001). Patient survival was equivalent. Alemtuzumab was an independent risk factor for living donor allograft loss (HR 2.0, P = 0.004), opportunistic infections (HR 1.3, P = 0.01), CMV infections (HR 1.6, P = 0.001), and AMR (HR 1.5, P = 0.002). The significantly worse graft survival in the alemtuzumab cohort may be due to the increased rates of AMR and infectious complications., (© 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.)

Background and Objectives: There is little information on chronic kidney disease (CKD) stage progression rates and outcomes in liver transplant recipients. Identifying modifiable risk factors may help prevent CKD progression in liver transplant recipients., Design, Setting, Participants, & Measurements: We performed a retrospective review of 1151 adult, deceased-donor, single-organ primary liver transplants between July 1984 and December 2007 and analyzed kidney outcomes and risk factors for CKD stage progression. Seven hundred twenty-nine patients had an available estimated GFR at 1 year posttransplant to establish a baseline stage. The primary end point was the CKD progression from one stage to a higher stage (lower GFR)., Results: Kaplan-Meier estimates of patient survival were 91%, 74%, and 64% at 5, 10, and 15 years, respectively. Estimates of liver allograft survival were 89%, 71%, and 60% at the same time points. At 1 year, 7%, 34%, 56%, 3%, and 1% of patients were in CKD stages 1, 2, 3, 4, and 5. The incidence of stage progression was 28%, 40%, and 53% at 3, 5, and 10 years. The incidence of ESRD was 2.6%, 7.5%, and 18% at 5, 10, and 20 years. Multivariable Cox regression analyses demonstrated that CKD stage at 1 year, pretransplant diabetes and urinary tract infections/hypercholesterolemia in the first year proved to be independent risk factors for stage progression (hazard ratio 1.9, 0.28, 1.39, and 1.46, respectively, P < 0.05)., Conclusions: Future studies will determine whether treatment of risk factors in the first posttransplant year prevent CKD progression in liver transplant recipients.

Although the use of donation after cardiac death (DCD) donor organs has been shown to be a viable option for liver and kidney transplant recipients, outcomes after simultaneous liver and kidney (SLK) transplantation using DCD donors are less clear. We performed a retrospective analysis of 37 adult, primary SLK transplants performed at our center between January 1, 1998 and December 31, 2008. Thirty-two patients received donation after brain death (DBD) organs, and 5 patients received DCD organs. SLK recipients in the 2 groups were similar with respect to age, gender, race, body mass index, donor race, and donor body mass index. The calculated Model for End-Stage Liver Disease scores and pretransplant glomerular filtration rates were similar between the groups. DCD donors were younger and had shorter liver cold ischemia times. The median DCD donor warm ischemia time was 19.0 minutes (6.0-25.0 minutes). The recipient surgical times and hospital lengths of stay were comparable between the groups. Delayed graft function was more frequent in DCD renal allografts (80% versus 31%, P = 0.06). The 1-year graft survival rates for liver allografts (100% for the DCD group versus 94% for the DBD group) and kidney allografts (100% for the DCD group versus 94% for the DBD group) were similar. In conclusion, patients undergoing DCD SLK transplantation have comparable 1-year patient and graft survival rates and acceptable perioperative morbidity in comparison with DBD SLK transplant recipients. Although long-term outcomes remain unknown, the utilization of DCD organs for SLK transplantation should be considered a valid approach to safely expanding the donor organ pool., (Copyright © 2011 American Association for the Study of Liver Diseases.)

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)