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Background and Aims: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight. Methods: Adult (≥18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0–90 days) and longer-term (90 days–5 years) outcomes. Results: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days–5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49–0.80); graft failure HR: UK: 0.72, 95% CI: 0.58–0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p

To report the clinical outcomes of liver transplants from donors after MAiD versus donors after cardiac death (DCD) and deceased brain death (DBD).In North America, number of patients needing liver transplant exceeds the number of available donors. In 2016, medical assistance in dying (MAiD) was legalized in Canada.All patients undergoing deceased donor liver transplantation (DDLT) at Toronto General Hospital between 2016 and 2021 were included in the study. Recipient peri- and post-operative variables as well as donor physiologic variables were compared among three groups.807 patients underwent DDLT during the study period including DBD (n=719; 89%), DCD (n=77; 9.5%) and MAiD (n=11; 1.4%). Overall incidence of biliary complications was 6.9%(n=56), most common being strictures (n=55;6.8%), highest among the MAiD recipients [5.8%(DBD) vs. 14.2% (DCD) vs. 18.2% (MAiD); P=0.008]. There was no significant difference in 1-year (98.4% vs. 96.4% vs. 100%) and 3-year (89.3% vs. 88.7% vs. 100%) (P=0.56) patient survival among 3 groups. The 1- and 3- year graft survival rates were comparable (96.2% vs. 95.2% vs. 100% and 92.5% vs. 91% vs. 100%; P=0.37).With expected physiologic hemodynamic challenges among MAiD and DCD compared to DBD donors, higher rate of biliary complications was observed in MAiD donors, with no significant difference noted in short-and long-term graft outcomes amongst the three groups. While ethical challenges persist, good initial results suggest that MAiD donors can be safely used in liver transplantation, with results comparable to other established forms of donation.

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86%8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Hepatocellular carcinoma (HCC) is rare in children and there is limited data on its imaging features. To describe imaging features of pediatric HCC and correlate them with clinical and laboratory findings. We retrospectively reviewed imaging in all pediatric HCC cases seen between January 2000 and January 2019. Imaging features defined in LI-RADS (Liver Imaging Reporting and Data System) and tumor extent by PRETEXT (pretreatment extent of disease) criteria were noted by two radiologists. Patient charts were reviewed to collect clinical features, alpha-fetoprotein (AFP) level and pathology findings. Of the 15 children (7 boys, 8 girls; mean age: 11.8 years, age range: 6–17 years) included in the study, 12/15 had computed tomography, 9/15 had magnetic resonance imaging and 9/15 had ultrasound exams available for review. Pathological types of HCC included classic (11/15, 73%), fibrolamellar (3/15, 20%) and mixed cholangiocarcinoma-HCC (1/15, 7%). Eighty percent occurred de novo in normal liver and 67% showed elevated AFP levels. Arterial phase hyperenhancement was seen in 83% of cases, washout in 86%, capsule in 50% and tumor-in-vein in 33%. The mean tumor size was 9.8 cm and 40% were multifocal on imaging. Staging revealed PRETEXT II tumors in 47%, III in 20% and IV in 33%. There were no PRETEXT I tumors. The two most common PRETEXT annotation factors were portal vein and caudate lobe involvement in 71% and 43% of cases, respectively. Fibrolamellar HCC demonstrated central scar, normal AFP levels and normal background liver. Pediatric HCC are large heterogeneous tumors, as reflected by high PRETEXT staging, and commonly include portal vein and caudate involvement. This affects resectability of these tumors at presentation. Central scar, normal AFP level and normal liver background may help differentiate fibrolamellar HCC from other types of HCC.

Paired organ exchange can be used to circumvent living donor-recipient ABO incompatibilities. Herein, we present the first case of successful liver paired exchange in North America. This 2-way swap required 4 simultaneous operations: 2 living donor hepatectomies and 2 living donor liver transplants. A nondirected anonymous living donor gift initiated this domino exchange, alleviating an ABO incompatibility in the other donor-recipient pair. With careful attention to ethical and logistical issues, paired liver exchange is a feasible option to expand the donor pool for incompatible living liver donor-recipient pairs.

Grady Memorial Hospital is a pillar of public medical and surgical care in the Southeast. The evolution of this institution, both in its physical structure as well as its approach to patient care, mirrors the cultural and social changes that have occurred in the American South. Grady Memorial Hospital opened its doors in 1892 built in the heart of Atlanta's black community. With its separate and unequal facilities and services for black and white patients, the concept of “the Gradies” was born. Virtually, every aspect of care at Grady continued to be segregated by race until the mid-20th century. In 1958, the opening of the “New Grady” further cemented this legacy of the separate “Gradies,” with patients segregated by hospital wing. By the 1960s, civil rights activists brought change to Atlanta. The Atlanta Student Movement, with the support of Dr. Martin Luther King Jr., led protests outside of Grady, and a series of judicial and legislative rulings integrated medical boards and public hospitals. Eventually, the desegregation of Grady occurred with a quiet memo that belied years of struggle: on June 1, 1965, a memo from hospital superintendent Bill Pinkston read “All phases of the hospital are on a non-racial basis, effective today.” The future of Grady is deeply rooted in its past, and Grady's mission is unchanged from its inception in 1892: “It will nurse the poor and rich alike and will be an asylum for black and white.”

Background. Normothermic ex vivo kidney perfusion (NEVKP) has shown promising results for preservation, assessment, and reconditioning of kidney allografts in preclinical studies. Here, we report the first North American safety and feasibility study of deceased donor kidneys grafts transplanted following preservation with NEVKP. Methods. Outcomes of 13 human kidney grafts that received 1 to 3 h of NEVKP after being transported in an anoxic hypothermic machine perfusion device were compared with a matched control group of 26 grafts that were preserved with anoxic hypothermic machine perfusion alone. Results. Grafts were perfused for a median of 171 min (range, 44-275 min). The delayed graft function rate in NEVKP versus control patients was 30.8% versus 46.2% (P = 0.51). During the 1-y follow-up, no differences in postoperative graft function, measured by serum creatinine, necessity for dialysis, and urine production, were found between the study group and the control group. There were no differences in 1 y posttransplantation graft or patient survival between the 2 groups. Conclusions. Our study demonstrates the safety and feasibility of NEVKP for human deceased donor kidney transplantation. Further studies are warranted to explore how this technology can minimize cold ischemia, improve posttransplant graft function, and assess and repair expanded criteria kidney grafts.

The incidence and geographical distribution of cancers in children are dramatically different from the adult population. Consequent to improvements in postcancer survival, there is a progressive increase in the number of patients requiring liver transplantation (LT) who are in remission from pretransplant malignancy (PTM). Conventionally, however, PTM has been considered a relative contraindication to LT. Furthermore, with improving post-LT survival now extending beyond decades, the cumulative effect of immunosuppression and the increasing risk of de novo cancers need to be acknowledged. A working group was formed to evaluate, discuss, and retrieve all the evidence and provide guidelines with regards to best practices surrounding nonhepatic cancer in the pediatric LT (PLT) population. Further subsections of research included (a) extrahepatic solid tumors, leukemia, lymphoma, and other hematological disturbances before PLT and (b) malignancies following PLT (including posttransplant lymphoproliferative disorders). This guidance provides a collection of evidence-based expert opinions, consensus, and best practices on nonhepatic cancers in PLT.

In western countries, the timing of liver retransplantation depends on recipient prioritization on the wait-list, as determined by their model for end-stage liver disease (MELD) score, and the availability of an appropriate deceased donor graft. Unfortunately, the MELD score in these patients often does not reflect their medical condition accurately, resulting in an increased risk of wait-list mortality1 . Living-donor liver transplantation (LDLT) offers the potential of timely retransplantation with a high quality graft.

Extrahepatic portal vein obstruction (EHPVO) is a major cause of non-cirrhotic portal hypertension in children. Surgical procedures for EHPVO include portosystemic shunts (PSS) and meso-Rex bypass (MRB). We conducted a systematic review and meta-analysis to compare the effectiveness of MRB versus PSS in EHPVO patients. A systematic literature search was performed using four databases. Articles reporting EHPVO and comparing patients who received MRB and PSS were included in the analysis. We retrieved 851 papers, of which five observational studies met the inclusion criteria. There was no difference in shunt complications, mortality, or gastrointestinal bleeding after surgery between MRB and PSS in the meta-analysis. MRB had increased shunt complications compared with PSS in the non-comparative studies. MRB had a potential advantage over PSS in long-term prognosis in one comparative study. Overall, the quality of the evidence was low. Based on available data, our meta-analysis indicates that MRB does not increase shunt complications, mortality, or gastrointestinal bleeding after surgery. The present study did not reveal superiority for either MRB or PSS. The paucity of well conducted trials in this area justifies future multicenter studies and studies that examine long-term outcomes.

Background EPP is characterized by photosensitivity and by liver disease. When LT is performed in EPP, recurrence often occurs in the allograft due to ongoing protoporphyrin production in bone marrow. Therefore, curative treatment requires allogeneic HSCT after LT. Long-term immunosuppression could be spared by using the same donor for both transplants. Methods A 2-year-old girl with EPP in liver failure underwent liver transplant from her father. Transfusion and apheresis therapy were used to lower protoporphyrin levels before and after liver transplant. Ten weeks after liver transplant, she underwent HSCT, using the same donor. Conditioning was with treosulfan, fludarabine, cyclophosphamide, and ATG. GVHD prophylaxis was with abatacept, methotrexate, MMF, and tacrolimus. We followed the patient's erythrocyte protoporphyrin and liver and skin health for 2 years after transplant. Results After hematopoietic stem cell engraftment, a decline in protoporphyrin levels was observed, with clinical resolution of photosensitivity. Liver biopsies showed no evidence of EPP. Mild ACR occurred and responded to steroid pulse. Two years post-HSCT, the patient has been weaned off all immunosuppression and remains GVHD and liver rejection free. Conclusions Sequential liver and HSCT from the same haploidentical donor are feasible in EPP. This strategy can allow for discontinuation of immune suppression.

Background. Early allograft dysfunction (EAD) after liver transplantation has been associated with long-term reduced graft and patient survival. Methods. In this single-center cohort study, we aimed to compare incidence, risk factors, and outcomes in liver transplant recipients who developed EAD. Patients who received donation after circulatory death (DOD) or donation after brain death (DBD) grafts between January 2007 and December 2017 were included. EAD was defined as bilirubin of 10mg/dL (171 mu mol/L) or an international normalized ratio of >= 1.6 on postoperative day 7 or transaminases >2000 U\L in the first-week post-transplantation as previously described. Results. In our cohort of 1068 patients, incidence of EAD was 44%. EAD occurred more frequently in the DOD versus DBD group (71% versus 41%, P

Introduction Postoperative diaphragmatic hernia (DH) is a rare but potentially life-threatening complication following pediatric liver transplantation (LT). In the current literature, a total of 49 such hernias have been reported in 17 case series. We present eight additional cases, three of which reoccurred after surgical correction, and review the current literature with a focus on recurrence. Materials and Methods The study sample included children ( Results For the eight children with DH, the mean age at LT was 28.0 (5–132) months. All patients with a DH received left lateral segment split grafts except one, who received a full left lobe. The mean weight at time of LT was 11.8 (6.6–34) kg. Two patients had a primary abdominal muscle closure, and six had a temporary silastic mesh closure. All eight children presented with a right posterolateral DH. The small bowel was herniated in the majority of cases. Symptoms reported included nausea, vomiting, and respiratory distress. Two patients were asymptomatic, and discovery was incidental. All patients underwent prompt primary surgical repair. Three DH hernias (37.5%) recurred despite successful surgical correction. Conclusion DH following liver transplant with technical variant grafts may be underreported and is prone to recur despite surgical correction. A better understanding of the pathophysiology and more thorough reporting may help increase awareness. Early detection and prompt surgical management are the cornerstones of a successful outcome.

Hepatocellular carcinoma (HCC) is rare in children and there is limited data on its imaging features.To describe imaging features of pediatric HCC and correlate them with clinical and laboratory findings.We retrospectively reviewed imaging in all pediatric HCC cases seen between January 2000 and January 2019. Imaging features defined in LI-RADS (Liver Imaging Reporting and Data System) and tumor extent by PRETEXT (pretreatment extent of disease) criteria were noted by two radiologists. Patient charts were reviewed to collect clinical features, alpha-fetoprotein (AFP) level and pathology findings.Of the 15 children (7 boys, 8 girls; mean age: 11.8 years, age range: 6-17 years) included in the study, 12/15 had computed tomography, 9/15 had magnetic resonance imaging and 9/15 had ultrasound exams available for review. Pathological types of HCC included classic (11/15, 73%), fibrolamellar (3/15, 20%) and mixed cholangiocarcinoma-HCC (1/15, 7%). Eighty percent occurred de novo in normal liver and 67% showed elevated AFP levels. Arterial phase hyperenhancement was seen in 83% of cases, washout in 86%, capsule in 50% and tumor-in-vein in 33%. The mean tumor size was 9.8 cm and 40% were multifocal on imaging. Staging revealed PRETEXT II tumors in 47%, III in 20% and IV in 33%. There were no PRETEXT I tumors. The two most common PRETEXT annotation factors were portal vein and caudate lobe involvement in 71% and 43% of cases, respectively. Fibrolamellar HCC demonstrated central scar, normal AFP levels and normal background liver.Pediatric HCC are large heterogeneous tumors, as reflected by high PRETEXT staging, and commonly include portal vein and caudate involvement. This affects resectability of these tumors at presentation. Central scar, normal AFP level and normal liver background may help differentiate fibrolamellar HCC from other types of HCC.

Optimal diagnostic and surgical approaches for patients with bile duct injuries (BDI) remain debated. This study reviews results from a standardized approach to management of high-grade BDIs at a North American center. Patients undergoing surgical repair for BDIs over a 15-year period were included. Post-operative outcomes and biliary patency rates were calculated using imaging, laboratory values, and patient interviews. A total of 107 consecutive patients underwent repair for BDIs. Bismuth grade I/II injuries were identified in 46 patients (41%), grade III/IV in 41 (38%), grade V in 11 patients (10%), and 9 (10%) were unclassified. BDI anatomy was commonly identified using magnetic resonance imaging (MRI) (75%). Concomitant arterial injuries were identified in 30 (28 with formal angiography). Fifteen had early repairs (within 4 days) and remainder interval repairs (median: 65 days). Hepp-Couinaud repair was method of choice (83%). Estimated primary biliary patency was 100% at 30 days and 87% at 5 years. With appropriate referral to a specialist, surgical reconstruction of BDIs can have excellent outcomes, even with accompanying arterial injuries. Based on our experience, MR as first imaging modality and supplemental angiography served as the optimal diagnostic strategy. Delayed repair, using Hepp-Couinaud technique, with selective liver resection results in high long-term patency rates.

Grady Memorial Hospital is a pillar of public medical and surgical care in the Southeast. The evolution of this institution, both in its physical structure as well as its approach to patient care, mirrors the cultural and social changes that have occurred in the American South. Grady Memorial Hospital opened its doors in 1892 built in the heart of Atlanta's black community. With its separate and unequal facilities and services for black and white patients, the concept of "the Gradies" was born. Virtually, every aspect of care at Grady continued to be segregated by race until the mid-20th century. In 1958, the opening of the "New Grady" further cemented this legacy of the separate "Gradies," with patients segregated by hospital wing. By the 1960s, civil rights activists brought change to Atlanta. The Atlanta Student Movement, with the support of Dr. Martin Luther King Jr., led protests outside of Grady, and a series of judicial and legislative rulings integrated medical boards and public hospitals. Eventually, the desegregation of Grady occurred with a quiet memo that belied years of struggle: on June 1, 1965, a memo from hospital superintendent Bill Pinkston read "All phases of the hospital are on a non-racial basis, effective today." The future of Grady is deeply rooted in its past, and Grady's mission is unchanged from its inception in 1892: "It will nurse the poor and rich alike and will be an asylum for black and white."

Background & Aims In 2018, our team initiated a prospective pilot program to challenge the paradigm of the "6-month rule" of abstinence for patients with alcohol-related liver disease (ALD) requiring transplant. Our pilot involved an in-depth examination of patients' alcohol use, social support, and psychiatric comorbidity, as well as the provision of pre- and post-transplantation addiction treatment. Methods Patients with ALD were assessed for inclusion in the pilot by a multidisciplinary team. Relapse prevention therapy was provided directly to all patients deemed to meet the program's inclusion criteria. Random biomarker testing for alcohol was used pre and post transplantation. Results We received 703 referrals from May 1, 2018 to October 31, 2020. After fulfilling the program's criteria, 101 patients (14%) were listed for transplantation and 44 (6.2%) received transplants. There were no significant differences in survival rates between those receiving transplants through the pilot program compared with a control group with more than 6 months of abstinence (P = .07). Three patients returned to alcohol use during an average post-transplantation follow-up period of 339 days. In a multivariate analysis, younger age and lower Model for End-Stage Liver Disease scores at listing were associated with an increased likelihood of a return to alcohol use (P Conclusions Our prospective program provided direct monitoring and relapse prevention treatment for patients with ALD and with less than 6 months of abstinence and resulted in a reduction of post-transplantation return to drinking. This pilot study provides a framework for the future of more equitable transplant care.

Importance The Model for End-stage Liver Disease (MELD)-based organ allocation system has significantly decreased mortality on the transplant waiting list for patients with end-stage liver disease. However, women have remained at a disadvantage with respect to access to deceased donor liver transplant (DDLT) even after introduction of the MELD score for organ allocation. Objective To determine whether availability of living donation in a transplant program can offset inequity in liver transplant (LT) allocation for women. Design, Setting, and Participants This cohort study retrospectively analyzed adult patients listed for LT at the University Health Network in Toronto, Ontario, Canada. Patients included had a potential living donor (pLD) at the moment of listing. This study was performed from November 13, 2012, to May 31, 2019. A total of 1289 listed patients (830 men; 459 women) were analyzed during the study period. Main Outcomes and Measures This study performed survival analysis and competing-risk analysis to delineate how access to livers from living donors was associated with events in women vs men on the transplant waiting list (LT, death, or dropout). Results Of 1289 included patients, 459 (35.6%) were women, and the mean (SD) age was 56.1 (10.0) years at assessment and listing. A total of 783 of 1289 listed patients underwent LT. Among those with no pLD at assessment, there was a higher median (range) Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score at listing (22 [6-50] vs 19 [6-50]; P

Solid organ pancreas transplantation is a durable treatment for establishing normal blood glucose levels in patients with diabetes. Historically, younger patients with type 1 diabetes have been the primary recipients of pancreas transplants. As surgical techniques and post-operative immunosuppression regimens have continued to improve, indications have expanded such that non-traditional recipients are being evaluated for pancreas transplantation. These recipients include patients with type 2 diabetes, patients older than 50 years of age, and patients with chronic infectious diseases, including HIV and HCV. Despite limited literature in these patient populations, pancreas transplantation is a viable treatment for endocrine pancreas failure in appropriately selected patients, regardless of disease etiology or age. This review summarizes the current literature on pancreas transplantation in non-traditional recipients.

Preemptive kidney transplantation is the optimal treatment for pediatric End Stage Renal Disease (ESRD) patients to avoid increased morbidity and mortality associated with dialysis. It is unknown how race/ethnicity and poverty influence preemptive transplant access in pediatric ESRD. We examined the incidence of living donor (LD) or deceased donor (DD) preemptive transplantation among all black, white, and Hispanic children (< 18 years) in the United States Renal Data System from 2000–2009. Adjusted risk ratios for preemptive transplant were calculated using multivariable-adjusted models and examined across health insurance and neighborhood poverty levels. Among 8,053 patients, 1117 (13.9%) received a preemptive transplant (66.9% from LD, 33.1% from DD). In multivariable analyses, there were significant racial/ethnic disparities in access to LD preemptive transplant where blacks were 66% (RR=0.34; 95% CI: 0.28–0.43) and Hispanics 52% (RR=0.48; 95% CI: 0.35–0.67) less likely to receive a LD preemptive transplant vs. whites. Blacks were 22% less likely to receive a DD preemptive transplant vs. whites (RR=0.78, 95% CI: 0.57–1.05) although results were not statistically significant. Future efforts to promote equity in preemptive transplant should address the critical issues of improving access to pre-ESRD nephrology care and overcoming barriers in living donation, including obstacles partially driven by poverty.

PURPOSE OF REVIEW Advances in surgical technique and immunosuppression have significantly improved outcomes after pancreas transplantation, and as a result pancreas transplants increasingly are being performed for indications other than type 1 diabetes mellitus. This review summarizes the current literature on pancreas transplantation in unconventional recipient populations. RECENT FINDINGS An increasing body of work suggests that pancreas transplantation can be performed with good outcomes in patients with type 2 diabetes mellitus and those 50 years of age and older. Obesity appears detrimental to patient and pancreas graft survival, and bariatric surgery prior to transplantation may be of increasing interest and relevance. There are limited data yielding mixed outcomes on pancreas transplantation in patients with HIV or hepatitis C virus. However, rapidly improving antiviral therapies are prolonging survival in patients with HIV and chronic hepatitis C virus infections and may increase the number of candidates available for pancreas transplantation in these populations in the future. SUMMARY Despite limited literature in these patient populations, pancreas transplantation may be a viable treatment option for endocrine pancreas failure in appropriately selected patients regardless of disease cause or age.

Kidney transplantation is the preferred treatment for pediatric end-stage renal disease (ESRD). Preemptive transplantation avoids the increased morbidity and mortality of dialysis. Yet, previous studies have not demonstrated significant graft or patient survival benefits for children undergoing transplantation preemptively versus nonpreemptively. These previous studies were limited by small samples sizes and low rates of adverse events. Here we compared graft failure and mortality rates using Kaplan-Meier methods and Cox regression among a large national cohort of children with ESRD undergoing preemptive versus nonpreemptive kidney transplantation between 2000 and 2012. Among 7527 pediatric kidney transplant recipients in the United States Renal Data System, 1668 underwent preemptive transplantation. Over a median 4.8 years follow-up, 1314 experienced graft failure, and over a median 5.2 years of follow-up, 334 died. Dialysis exposure versus preemptive transplantation conferred a higher risk of graft failure (hazard ratio 1.32; 95% confidence interval: 1.10–1.56) and a higher risk of death (hazard ratio 1.69; 95% confidence interval: 1.22–2.33) in multivariable analysis. Compared with children undergoing preemptive transplantation, children on dialysis for >1 year had a 52% higher risk of graft failure and those on dialysis >18 months had an 89% higher risk of death, regardless of donor source. Thus, preemptive transplantation is associated with substantial benefits in allograft and patient survival among children with ESRD, particularly when compared with children who receive dialysis for >1 year. These findings support policies to promote early access to transplantation and avoidance of dialysis for children with ESRD whenever feasible.

[EN] Background and aims. The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD). The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD), we aimed to understand how ischemia/reperfusion (I/R) injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration. Methods Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13) and DBD (n = 10) livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22) and DBD (n = 13) livers. Results When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p

Screening recommendations for prostate cancer remain controversial, and no specific guidelines exist for screening in renal transplant candidates. To examine whether the use of prostate-specific antigen (PSA)–based screening in patients with ESRD affects time to transplantation and transplant outcomes, we retrospectively analyzed 3782 male patients ≥18 years of age undergoing primary renal transplant evaluation during a 10-year period. Patients were grouped by age per American Urological Association screening guidelines: group 1, patients 69 years. A positive screening test result was defined as a PSA level >4 ng/ml. We used univariate analysis and Cox proportional hazards models to identify the independent effect of screening on transplant waiting times, patient survival, and graft survival. Screening was performed in 63.6% of candidates, and 1198 candidates (31.7%) received kidney transplants. PSA screening was not associated with improved patient survival after transplantation (P=0.24). However, it did increase the time to listing and transplantation for candidates in groups 1 and 2 who had a positive screening result (P

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Although mast cells have long been considered the integral effector cell in allergy and atopic disease, the paradigm of mast cell function is now evolving to incorporate data showing that mast cells make innumerable contributions to both protective and pathologic immune responses. Mast cells express cell surface molecules with costimulatory or co-inhibitory activity and produce a multitude of mediators that can direct dendritic cell (DC) or T-cell differentiation and function. In addition, mast cells exhibit a widespread distribution and are in close proximity to DCs and T cells at several critical sites. While there has been amazing progress in characterizing mast cell populations in vitro, only recently has the ability to monitor their in vivo effects become a reality. In this review, we discuss the evolution of our understanding of mast cell biology with an emphasis on their established and hypothesized roles in influencing T-cell differentiation and function. The fact that T-cell and mast cell interactions exist and are a normal component of most adaptive immune responses is one of the best illustrations of the now established concept that innate and adaptive immunity are not completely independent entities.

Following intranasal inoculation, Vibrio cholerae KFV101 (Δ ctxAB Δ hapA Δ hlyA Δ rtxA ) colonizes and stimulates tumor necrosis factor alpha and interleukin 1β (IL-1β) in mice, similar to what occurs with isogenic strain P4 (Δ ctxAB ), but is less virulent and stimulates reduced levels of IL-6, demonstrating a role for accessory toxins in pathogenesis. Morbidity is enhanced in C3H/HeJ mice, indicating that Toll-like receptor 4 is important for infection containment.

Mast cells (MCs) exert a significant pathologic influence on disease severity in C57BL/6 (B6) strain-dependent experimental allergic encephalomyelitis (EAE), a model of primary progressive multiple sclerosis (MS). However, relapsing–remitting MS, which is modeled in SJL mice, is the more prevalent form. Given genetically determined heterogeneity in numbers and responsiveness of MCs from various strains of mice, we asked whether these cells also influence this more clinically relevant MS model using SJL-KitW/W-v mice. Similar to the commercially available WBB6F1-KitW/W-v mice, SJL-KitW/W-v mice are MC-deficient, anemic, and neutropenic and have normal T cell compartments. They exhibit significantly reduced disease severity, but retain the relapsing–remitting course, a phenotype reversed by selective MC reconstitution. These data confirm that MC influence is not confined to an isolated model of EAE and reveal a new system to study the effects of MC heterogeneity on relapsing–remitting EAE and other SJL strain-specific diseases.

The idea that the innate and adaptive immune systems are not separate entities is no longer new. In fact, it is surprising that this paradigm was accepted without question for so long. Many innate cells express cell surface molecules and soluble mediators that are essential for the development and activation of T cells and B cells. Yet among the innate cell populations, mast cells may play the major role in regulating adaptive immune cell function. This role first came to light in studies of mast cells and their involvement in the autoimmune disease experimental allergic encephalomyelitis, the major rodent model of multiple sclerosis and has subsequently been verified in many in vitro and in vivo model systems.

There are many parallels between allergic and autoimmune responses. Both are considered hypersensitivity responses: pathologies that are elicited by an exuberant reaction to antigens that do not pose any inherent danger to the organism. Although mast cells have long been recognized as central players in allergy, only recently has their role in autoimmunity become apparent. Because of the commonalities of these responses, much of what we have learned about the underlying mast cell–dependent mechanisms of inflammatory damage in allergy and asthma can be used to understand autoimmunity. Here we review mast cell biology in the context of autoimmune disease. We discuss the huge diversity in mast cell responses that can exert either proinflammatory or antiinflammatory activity. We also consider the myriad factors that cause one response to predominate over another in a particular immune setting.

Most immunology textbooks still promote the age-old idea that the sole function of mast cells is to mediate immunoglobulin E (IgE)-dependent responses in allergy and parasitic worm infections. But mast cells are extremely versatile cells and can be stimulated by numerous IgE-independent agonists, including pathogen-associated molecular pattern molecules (PAMPs), cytokines, hormones, and neuropeptides as well as through cell-cell interactions. Depending on the activation mode, mast cells exhibit varied and “tunable” responses, releasing unique arrays of preformed and newly synthesized pro- and/or anti-inflammatory mediators (Rao and Brown, 2008).

Although mast cells (MCs) are critical mediators of allergic and innate immune responses, they also modulate adaptive immune responses. Utilizing WBB6c-kitW/Wv mast cell-deficient mice, MCs have been implicated in the promotion of disease severity in several murine models of human autoimmune disease. WBB6c-kitW/Wv mice have two independent mutations that profoundly inhibit MC development. We previously demonstrated that MCs influence disease severity in a murine model of chronic-progressive multiple sclerosis (CP-MS), specifically by influencing cellular trafficking into the CNS and blood brain barrier permeability. However, this model does not mimic the most common form of the human disease, relapsing-remitting MS (RR-MS). Therefore, to test the effect of a MC deficiency on a RR form of disease, we transferred the c-kitW/Wv mutations onto the SJL background, a strain that is susceptible to RR disease. These animals are MC-deficient in all tissues examined, carry mild hematopoietic deficits, but have relatively normal thymic T cell compartments. SJLc-kitW/Wv mice display significantly decreased cumulative EAE disease scores and a delay in the day of peak acute disease compared to their wild type littermates. These differences in disease phenotypes are abrogated upon reconstitution of wild type bone marrow-derived MCs. Thus, MCs also influence disease severity in a RR murine model of MS, a finding with potential clinical relevance for the heterogeneous MS patient population.