Differences In Rejection Rates Research Articles

Cumulative rabbit anti-human thymocyte globulin dose to recipient weight during the peri-operative period is an independent risk factor for early postoperative urinary tract infection after kidney transplantation

Anti-human thymocyte globulin-Fresenius (ATG-F) is frequently utilized to achieve successful induction for kidney transplantation recipients. This study aimed to examine the association between the ATG-F dose-to-recipient-weight ratio (ADR) and the risk of developing urinary tract infections (UTIs) following kidney transplantation. Data of kidney transplant recipients who underwent ATG-F-induction peri-operatively in a medical center were retrospectively collected, and the incidence of UTIs during the first postoperative year was also recorded. The risk of UTI associated with ADR was analyzed, and receiver operating characteristic curves were drawn to determine the optimal ADR, followed by Cox regression models. In total, 131 recipients were included, with an UTI incidence of 19.08% and a mean interval of 3.08 months. The optimal ADR was 6.34, involving 41 and 90 patients in the low ADR and high ADR groups, respectively. The UTI-free rate in the low ADR group was significantly higher than that in the high ADR group (p = 0.007). Cox regression analysis indicated that a high ADR independently increased the risk of UTI following kidney transplantation (hazard ratio: 5.306, 95% confidence interval: 1.243–22.660, p = 0.024). There was no significant difference in rejection rate between the high ADR and low ADR groups. In conclusion, a high ADR increased the incidence of early postoperative UTI among kidney transplant recipients.

Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry

IntroductionData on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a tacrolimus-based immunosuppressive regimen are scarce. MethodsWe performed a large-scale analysis of 802 pKTR from the CERTAIN registry from 40 centers in 14 countries. Inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least two years of follow-up. The patient population was divided into three age groups (infants and young children <6 years, school-aged children 6-12 years, and adolescents >12 years) to assess age-related differences in outcome. ResultsMedian follow-up was 48 months (IQR, 36-72). Within the first 2 years post-transplant, infants and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P<0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first year post-transplant (21.7%) than infants and young children (12.6%, P=0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus intra-patient variability (all P < 0.01) than adolescents. ConclusionsThis largest study to date in European pKTR on a tacrolimus-based immunosuppressive regimen shows important age-related differences in rejection rates, infection episodes, tacrolimus exposure and clearance. These data suggest that immunosuppressive therapy in pKTR should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may also serve as a benchmark for future studies with novel immunosuppressive drugs.

Comparative Analysis of Ischemia-Reperfusion Injury in Heart Transplantation: A Single-Center Study Evaluating Conventional Ice-Cold Storage versus the Paragonix SherpaPak Cardiac Transport System.

Since the 2018 allocation system change in heart transplantation (HT), ischemic times have increased, which may be associated with peri-operative and post-operative complications. This study aimed to compare ischemia reperfusion injury (IRI) in hearts preserved using ice-cold storage (ICS) and the Paragonix SherpaPak TM Cardiac Transport System (CTS). From January 2021 to June 2022, consecutive endomyocardial biopsies from 90 HT recipients were analyzed by a cardiac pathologist in a single-blinded manner: 33 ICS and 57 CTS. Endomyocardial biopsies were performed at three-time intervals post-HT, and the severity of IRI manifesting histologically as coagulative myocyte necrosis (CMN) was evaluated, along with graft rejection and graft function. The incidence of IRI at weeks 1, 4, and 8 post-HT were similar between the ICS and CTS groups. There was a 59.3% statistically significant reduction in CMN from week 1 to 4 with CTS, but not with ICS. By week 8, there were significant reductions in CMN in both groups. Only 1 out of 33 (3%) patients in the ICS group had an ischemic time >240mins, compared to 10 out of 52 (19%) patients in the CTS group. During the follow-up period of 8 weeks to 12 months, there were no significant differences in rejection rates, formation of de novo donor-specific antibodies and overall survival between the groups. The CTS preservation system had similar rates of IRI and clinical outcomes compared to ICS despite longer overall ischemic times. There is significantly more recovery of IRI in the early post operative period with CTS. This study supports CTS as a viable option for preservation from remote locations, expanding the donor pool.

Modifying Tacrolimus-related Toxicity After Liver Transplantation Comparing Life Cycle Pharma Tacrolimus Versus Extended-released Tacrolimus: A Multicenter, Randomized Controlled Trial.

The aim of this open-label, multicenter, randomized controlled study was to investigate whether the life cycle pharma (LCP)-tacrolimus compared with the extended-release (ER)-tacrolimus formulation results in a difference in the prevalence of posttransplant diabetes, hypertension and chronic kidney disease (CKD) at 12 mo after liver transplantation. Patients were 1:1 randomized to either of the 2 tacrolimus formulations. The primary endpoint was defined as a composite endpoint of any of 3 events: sustained (>3 mo postrandomization) posttransplant diabetes, new-onset hypertension, and/or CKD, defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 for >3 m during the follow-up. In total, 105 patients were included. In the intention-to-treat analysis, a statistically significant lower proportion of liver transplant recipients in the LCP-tacrolimus group reached the composite primary endpoint at 12 mo compared with the ER-tacrolimus group (50.9% [27/53], 95% confidence interval [CI], 37.9%-63.9% versus 71.2% [37/52], 95% CI, 57.7%-81.7%; risk difference: 0.202; 95% CI, 0.002-0.382; P = 0.046). No significant difference was found in the per protocol analysis. In the intention-to-treat and per protocol population, fewer liver transplant recipients in the LCP-tacrolimus group developed CKD and new-onset hypertension compared with the ER-tacrolimus group. No differences in rejection rate, graft and patient survival were found. A statistically significant and clinically relevant reduction in the prevalence of the composite primary endpoint was found in the LCP-tacrolimus group compared with the ER-tacrolimus group in the first year after liver transplantation with comparable efficacy.

Short-term decreased post transplant lymphoproliferative disorder risk after kidney transplantation using two novel regimens

BackgroundBelatacept is employed alongside calcineurin inhibitor (CNI) therapy to prevent graft rejection in kidney transplant patients who are Epstein-Barr virus (EBV) seropositive. Preliminary data suggested that rates of post-transplant lymphoproliferative disorder (PTLD) were higher in individuals treated with belatacept compared to CNI therapy alone. MethodsThe records of 354 adults who underwent kidney only transplantation from January 2015 through September 2021 at one medical center were evaluated. Patients underwent treatment with either low-doses of mycophenolate, tacrolimus and sirolimus (B0, n = 235) or low-doses of mycophenolate, tacrolimus and belatacept (B1, n = 119). All recipients underwent induction with antithymocyte globulin and a rapid glucocorticosteroid taper. Relevant donor and recipient information were analyzed and endpoints of PTLD were assessed. ResultsThere were no cases of PTLD in either cohort within the study period. Recipients in the belatacept cohort experienced lower estimated glomerular filtration rates at 12 months (B0: 67.48 vs. B1: 59.10, p = 0.0014). Graft failure at 12 (B0: 1.28% vs. B1: 0.84%, p = 1.0) and 24 months (B0:2.55% vs. B1: 0.84%, p = 0.431) were similar. There was no difference in rejection rates at 12 (B0: 1.27% vs. B1: 2.52%, p = 0.408) or 24 months (B0: 2.12% vs. B1: 2.52%, p = 1.000). Both groups had similar rates of malignancy, mortality and CMV/BK viremia. ConclusionNon-belatacept (MMF, tacrolimus and sirolimus) and belatacept-based (MMF, tacrolimus and belatacept) regimens do not appear to pose any increased risk of early onset PTLD. Both cohorts benefited from low rates of rejection, malignancy, mortality and graft failure. Recipients will continue to be monitored as PTLD can manifest as a long-term complication.

407.8: Preventing Encephalopathy After Isolated Small Bowel Transplantation Through Portal Graft Drainage

Introduction: In isolated small bowel transplantation (SBTx), two methods of drainage have traditionally been described: systemic and portal. Although portal drainage (PD) is more physiological, allowing for the liver ‘first pass effect’, systemic drainage (SD) is often technically more feasible and has been shown in previous studies to have no significant side effects. In this single-centre study, we analyzed our experience over the years with both techniques. Methods: We performed a retrospective analysis of our prospectively maintained data collected between 2007 and 2022. The following data was included in the study: age, gender, cause of intestinal failure, indication for transplantation, type of portal anastomosis (SD vs PD), infection rate, rejection rate, rate of encephalopathy and patient/graft survival. Results: Between October 2007 and March 2022, 38 isolated SBTx were performed in 37 patients (n=15, 41%) males, median age 47 years (21-65)). The most common indication was short bowel (n=32, 86%) with either impending loss of vascular access (n= 10, 27%), IFALD (n=11, 30% or a combination (n = 5, 14%). Twenty-six patient (68%) had SD, while 12 had PD (32%). PD drainage was performed with a venous jump graft in 10 patients and directly in 2. Postoperatively, there were 12 patients (29%) with either transient or permanent encephalopathy (median ammonia level: 79 μmol/l (42-204)) and 8 patients (24%) with asymptomatic, raised ammonia levels (>30 μmol/l) but without clinical symptoms (38 μmol/l (34-64). All but one patient with clinical encephalopathy had SD. Median ammonia levels double in SD versus PD patients (71 vs 33.5 μmol/l; p=0.0076). One patient underwent a conversion from a systemic to portal drainage due to severe, intractable encephalopathy using a third-party venous graft. This resulted in a complete reversal of her symptoms and normalization of her ammonia levels from 136 to <10 μmol/l). In three additional patients, conversion from systemic to portal is being considered. Conversely, two patients underwent portal to systemic conversion due to insufficient portal inflow. There were no differences in rates of rejection or patient survival. Conclusion: Although, PD and SD yielded equal results in terms rejection and survival rates, encephalopathy was very frequent and occurred only after SD. Given this data, we advocate for PD whenever technically feasible, especially in patient with borderline liver function.

Enabling successful transition-Evaluation of a transition to adult care program for pediatric liver transplant recipients.

This study aimed to evaluate the transition to adult care program instituted for liver transplant recipients (LTRs) at a large tertiary pediatric hospital in Melbourne, Australia. Evaluation included the change in a Global Assessment Measure (GAM) before and after the transition program, satisfaction with the program, and measures of transition success including rejection rates and attendance at appointments post-transfer. We hypothesized that the introduction of our structured transition program would improve disease understanding, health system understanding, and self-care. We also hypothesized that those who had undergone the transition program would have lower failure to attend rates and lower rates of rejection than historical controls. A LTR transition program was instituted at our service from 2013 to 2015. The program involved initial assessment of competencies with a Global Assessment Measure (GAM), followed by the introduction of a personalized goal setting program addressing issues identified in dedicated transition clinics. Assessment of competencies was compared between the commencement of the program and immediately prior to transfer. Patient satisfaction with the transition process was assessed at an interview 6-12months after transfer to the adult service. Rejection rates and failure to attend rates were compared between the intervention group and a group of LTRs who did not receive the intervention. Twenty-eight LTRs participated in the study; 20 received the transition intervention and 8 served as controls. Within the intervention group, all domains of transition competency and reported anxiety regarding transferring had significantly improved at the conclusion of the intervention and all reported satisfaction with the transition program with most (81%) reporting readiness to transfer. There were no significant differences in rejection rates or failure to attend rates between those who did and did not receive the transition intervention. A longitudinal holistic transition program has the potential to positively impact the competencies and readiness of LTRs to successful transition and transfer to adult care.

Immunologic benefits of maternal living donor allografts in pediatric liver transplantation: fewer rejection episodes and no evidence of de novo allosensitization.

Pediatric liver transplant (LT) recipients of maternal living liver donor (LLD) grafts have been reported to experience fewer rejection episodes. However, it is unclear whether this benefit translates to reduction in developing donor-specific antibody (DSA) among maternal-LLD recipients. The aim of this study was to compare immunologic outcomes among maternal-LLD, non-maternal-LLD, and deceased donor liver transplant (DDLT) recipients. Children (≤18years) who underwent LT between 1/1998 and 12/2019 at two high-volume LT centers in North America were evaluated. Patients were divided into three groups by type of graft received (maternal-LLD, non-maternal LLD, and DDLT). Clinical variables and outcomes were compared according to each graft type. A total of 450 pediatric primary LT were analyzed: 275 (61.1%) DDLT, 73 (16.2%) maternal-LLD, and 102 (22.6%) non-maternal-LLD. Children receiving LLD grafts were less likely to develop rejection when compared to the DDLT group (DDLT 46.9% vs. maternal-LLD 31.5% vs. non-maternal-LLD 28.4%, p=0.001). There was no difference in rejection rates between maternal and non-maternal-LLD recipients. A higher percentage of maternal-LLD recipients were on immunosuppression monotherapy compared to non-maternal-LLD and DDLT recipients (6.7% vs. 1.2 vs. 2.4%, respectively). A subgroup of 68 patients were tested for DSA post-LT. Maternal-LLD recipients were less likely to develop de novo DSA (maternal-LLD 11.8% vs. non-maternal-LLD 19.3% vs. DDLT 43%, p=0.018). None of the maternal-LLD recipients developed antibody-mediated rejection. These data support the concept of immunologic benefit of maternal-LLD in pediatric LT, with lower rates of rejection and allosensitization post-LT when compared to DDLT recipients.

COMPARISON OF SINGLE-DOSE VS DOUBLE DOSE ALEMTUZUMAB IN RENAL TRANSPLANT RECIPIENTS: A SINGLE CENTRE EXPERIENCE

Introduction: Alemtuzumab is used as an induction agent at our centre for higher immunological risk kidney transplants. Aim of this study was to compare the effects of single-dose and two-dose Alemtuzumab on rejection and infection rates. Methods: Patients receiving Alemtuzumab between 1st April 2015 to 19th November 2018 were included. As per protocol, patients ≤ 60 years received two doses (Group 1) and ≥ 60 years received single-dose (Group 2) Alemtuzumab. The maintenance immunosuppression was similar in both groups (Tacrolimus and Mycophenolate Mofetil). Primary endpoints were biopsy-proven rejection and infection rates (viral (CMV, BK and EBV) and urine infections) at one year. Descriptive statistics and parametric survival analysis (Weilberg distribution) to account for the reducing risk of rejection and infection overtime after transplant. Results: 231 Renal Transplant recipients received Alemtuzumab with 158 (68.4%) and 73 (31.6%) patients receiving double and single-dose, respectively. The mean age of recipients was 46.6 years (95% CI 45.2-47.9) and 66.9 years (95% CI 64.9-60.1) in Group 1 and 2 respectively. There was no difference in rejection rates between the two groups (Table 1). There was also no difference between the groups either with regards to infection rates (Table 1).Discussion: RCT comparing standard basiliximab-based treatment with alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection and infection in alemetuzumab group(1). However, there are no studies to compare the optimum dose of Alemetuzumab for induction. Hurst et al. concluded that in the elderly, alemtuzumab is associated with an escalating risk of death and graft loss in recipients of kidney transplantations (2).Considering the reduced immunity in elderly patients, high risk recipients (age>60years) receive single dose as a protocol at our centre. Our present study comparing single dose versus double dose Alemetuzumab showed similar biopsy proven rejection and infection among the groups. Conclusion: For patients requiring Alemtuzumab induction, due consideration should be given to switching to single-dose as the rejection and infection rates are comparable.

DCD donations and outcomes of heart transplantation: the Australian experience.

There is increasing clinical utilization of hearts from the donation after circulatory death (DCD) pathway with the aim of expanding the donor pool and mitigating the ever-present discrepancy between the inadequate availability of good quality donor hearts and the rising number of patients with end-stage heart failure. This article reviews the rationale, practice, logistical factors, and 5-year experience of DCD heart transplantation at St Vincent's Hospital, Sydney. Between July 2014 and July 2019, 69 DCD donor retrievals were undertaken resulting in 49 hearts being instrumented on an ex situ normothermic cardiac perfusion device. Seventeen (35%) of these hearts were declined and the remaining 32 (65%) were used for orthotopic DCD heart transplantation. At 5years of follow-up, the 1-, 3-, and 5-year survival was 96%, 94%, and 94% for DCD hearts compared with 89%, 83%, and 82% respectively for donation after brain death (DBD) hearts (n.s). The immediate post-implant requirement for temporary extra-corporeal membrane oxygenation (ECMO) support for delayed graft function was 31% with no difference in rejection rates when compared with the contemporaneous cohort of patients transplanted with standard criteria DBD hearts. DCD heart transplantation has become routine and incorporated into standard clinical practice by a handful of pioneering clinical transplant centres. The Australian experience demonstrates that excellent medium-term outcomes are achievable from the use of DCD hearts. These outcomes are consistent across the other centres and consequently favour a more rapid and wider uptake of heart transplantation using DCD donor hearts, which would otherwise be discarded.

Hepatitis C donor viremic cardiac transplantation: A practical approach.

Patients with end-stage heart failure eligible for orthotopic heart transplantation (OHT) exceed the number of available donor organs. With highly effective hepatitis C virus (HCV) antiviral therapy now available, HCV+ organs are increasingly utilized. We seek to describe our experience with patients receiving HCV viremic organs as compared to non-HCV transplant recipients. Our center began utilizing HCV hearts in February 2018. We retrospectively reviewed baseline demographics, laboratory data and outcomes for those undergoing OHT with majority being from a viremic HCV donor. Twenty-three of 25 HCV recipients received hearts from NAT+ donors with 22 of 23 seroconverting within 7days. Fifteen recipients have completed HCV treatment, with the longest duration of follow-up being 13months. No differences in rates of rejection, hospitalizations or death were seen between non-HCV and HCV transplant patients. With the advent of available direct-acting antivirals (DAAs), viremic HCV hearts provide an opportunity to increase organ availability. Moreover, treatment for HCV in the setting of immunosuppression is well-tolerated and results in sustained viremic response. Viremic, discordant HCV OHT can be performed in a safe and effective manner utilizing a systematic, multidisciplinary approach without an effect on short-term outcomes.

APRIL/BLyS Blockade Reduces Donor-specific Antibodies in Allosensitized Mice.

Highly sensitized candidates on the transplant waitlist remain a significant challenge, as current desensitization protocols have variable success rates of donor-specific antibody (DSA) reduction. Therefore, improved therapies are needed. A proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) are critical survival factors for B-lymphocytes and plasma cells, which are the primary sources of alloantibody production. We examined the effect of APRIL/BLyS blockade on DSA in a murine kidney transplant model as a possible novel desensitization strategy. C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 10 BALB/c splenocytes. Twenty-one days following sensitization, animals were treated with 100 μg of BLyS blockade (B-cell activating factor receptor-immunoglobulin) or APRIL/BLyS blockade (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), administered thrice weekly for an additional 21 days. Animals were then euthanized or randomized to kidney transplant with Control Ig, BLyS blockade, or APRIL/BLyS blockade. Animals were euthanized 7 days posttransplant. B-lymphocytes and DSA of BLyS blockade only or APRIL/BLyS blockade-treated mice were assessed by flow cytometry, immunohistochemistry, and enzyme-linked immunospot. APRIL/BLyS inhibition resulted in a significant reduction of DSA by flow crossmatch compared with controls (P < 0.01). APRIL/BLyS blockade also significantly depleted IgM- and IgG-secreting cells and B-lymphocyte populations compared to controls (P < 0.0001). APRIL/BLyS blockade in transplanted mice also resulted in decreased B-lymphocyte populations; however, no difference in rejection rates were seen between groups. APRIL/BLyS blockade with transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin significantly depleted B-lymphocytes and reduced DSA in this sensitized murine model. APRIL/BLyS inhibition may be a clinically useful desensitization strategy for sensitized transplant candidates.

Gender and language use in scientific grant writing

Women in science, technology, engineering, and math are not equally represented across tenure-track career stages, and this extends to grant funding, where women applicants often have lower success rates compared with men. While gender bias in reviewers has been documented, it is currently unknown whether written language in grant applications varies predictably with gender to elicit bias against women. Here we analyse the text of ∼2000 public research summaries from the 2016 Natural Sciences and Engineering Research Council (NSERC) individual Discovery Grant (DG) program. We explore the relationship between language variables, inferred gender and career stage, and funding levels. We also analyse aggregated data from the 2012–2018 NSERC DG competitions to determine whether gender impacted the probability of receiving a grant for early-career researchers. We document a marginally significant gender difference in funding levels for successful grants, with women receiving $1756 less than men, and a large and significant difference in rejection rates among early-career applicants (women: 40.4% rejection; men: 33.0% rejection rate). Language variables had little ability to predict gender or funding level using predictive modelling. Our results indicate that NSERC funding levels and success rates differ between men and women, but we find no evidence that gendered language use affected funding outcomes.

Retrospective review of malignancy in liver transplant recipients

Background: Multiple studies demonstrate an increased incidence of malignancy following solid organ transplantation. Due to steady improvements in post-transplant survival, the proportion of recipient deaths secondary to these malignancies is increasing. While cancer in kidney recipients is well researched, studies of cancer in liver recipients are relatively few and limited by small numbers of patients. In this study, we analyze the frequencies, treatments, and outcomes of different malignancies in adult liver transplant recipients from a single high-volume transplant center and suggest appropriate management strategies. Methods: A retrospective review was performed of all adult liver transplant recipients at a single liver transplant center between January 2002 and December 2016. Data regarding treatment, outcome, and survival was collected and analyzed from a previously established institutional database. Results: We identified 1221 adult liver transplants, of which 108 developed at least one post-transplant malignancy, with 45 cases of cutaneous malignancy and 67 cases of solid organ malignancy. Three patients developed recurrent hepatocellular carcinoma and one developed de novo hepatocellular carcinoma. A history of cancer prior to transplant was positive in 85/1061 (8.0%) patients that did not develop cancer and 14/108 (13.0%) patients that did (p = 0.10). Overall 1-, 3- and 5- and 10-year survival were 96.3%, 87.9%, 80.1% and 50.7% for the patients who developed cancer and 90.1%, 83.5%, 77.7% and 67.2% for those who did not (p = 0.0209). For patients who developed cutaneous cancer only, corresponding survival was 100%, 100%, 97.1% and 86.4% compared to 94.3%, 81.4%, 71.0% and 32.1% for patients developing other cancers. (p < 0.0001). 24 (22.2%) patients that developed cancer experienced biopsy-proven rejection, compared to 227 (21.4%) for patients without cancer (p = NS). 41 patients with cutaneous malignancy received local excision, while four developed local invasion and required invasive surgery or radiation. Only one of these patients developed metastatic disease. 50 patients with solid organ tumors received surgery, chemotherapy, radiation, hormone therapy, and/or targeted therapy while the rest received hospice, surveillance, or were lost to follow up. Lung, colorectal, and hematologic cancer patients that received chemotherapy (n = 17) tolerated treatment poorly with 14/17 (82.4%) regimens reduced or stopped due to toxicity and progression. Those with other cancers (n = 7) tolerated chemotherapy well and completed their prescribed courses. One patient treated with surgery required re-operation for a hematoma, one with radiation developed a bleeding ulcer, and one with targeted therapy developed a GI bleed. Conclusion: Outcomes varied based on the type of malignancy and degree of systemic involvement. Cancer patients demonstrated significantly worse 10-year survival relative to those without cancer but comparable 1-, 3-, and 5-year rates, indicating risk of mortality due to cancer does not increase until well after transplantation. As expected, patients with solid organ cancers had significantly worse survival than those with cutaneous cancer, whose survival was similar to those without cancer. There were no differences in rates of rejection, suggesting a judicious reduction of immunosuppression is an appropriate component of oncologic treatment. Patients with non-metastatic disease amenable to local surgery or radiation tolerated treatment well, while patients with hematologic, lung, and colorectal cancer requiring chemotherapy developed higher rates of toxicity than patients with other cancers.

Heart transplant outcomes in recipients of Centers for Disease Control (CDC) high risk donors.

A lack of donor hearts remains a major limitation of heart transplantation. Hearts from Centers for Disease Control (CDC) high-risk donors can be utilized with specific recipient consent. However, outcomes of heart transplantation with CDC high-risk donors are not well known. We sought to define outcomes, including posttransplant hepatitis and human immunodeficiency virus (HIV) status, in recipients of CDC high-risk donor hearts at our institution. All heart transplant recipients from August 2010 to December 2014 (n = 74) were reviewed. Comparison of 1) CDC high-risk donor (HRD) versus 2) standard-risk donor (SRD) groups were performed using chi-squared tests for nominal data and Wilcoxon two-sample tests for continuous variables. Survival was estimated with Kaplan-Meier curves. Of 74 heart transplant recipients reviewed, 66 (89%) received a SRD heart and eight (11%) received a CDC HRD heart. We found no significant differences in recipient age, sex, waiting list 1A status, pretransplant left ventricular assist device (LVAD) support, cytomegalovirus (CMV) status, and graft ischemia times (p = NS) between the HRD and SRD groups. All of the eight HRD were seronegative at the time of transplant. Postoperatively, there was no significant difference in rejection rates at six and 12 months posttransplant. Importantly, no HRD recipients acquired hepatitis or HIV. Survival in HRD versus SRD recipients was not significantly different by Kaplan-Meier analysis (log rank p = 0.644) at five years posttransplant. Heart transplants that were seronegative at the time of transplant had similar posttransplant graft function, rejection rates, and five-year posttransplant survival versus recipients of SRD hearts. At our institution, no cases of hepatitis or HIV occurred in HRD recipients in early follow-up.

This issue of ACTA, printed and electronic

This issue of ACTA, printed and electronic

A Randomized 2x2 Factorial Trial: Part 1, Single-Dose rATG Induction Improves Long-Term Renal Transplant Outcomes.

Background We conducted a randomized/unblinded 2x2 sequential-factorial trial of intensive induction with single-dose (SD) vs. divided-dose (DD) rabbit anti-thymocyte globulin (rATG) and early steroid withdrawal (ESW) (Part 1), and Part 2, tacrolimus minimization vs. withdrawal. Here we report the long-term Part 1 safety and efficacy of SD-rATG induction combined with ESW and tacrolimus/sirolimus (tac/srl) minimization. Methods 180 patients received 6 mg/kg rATG, either single-dose or four alternate-day doses (1.5 mg/kg/dose), with ESW and tac/srl maintenance. Maintenance immunosuppression after 6 months was minimized in patients without evidence of rejection. Targeted maintenance levels were tac, 2-4 ng/ml and srl, 4-6 ng/ml. Primary endpoints were renal function and graft histopathology. Results Follow-up averaged 51.8 ± 15.1 months; tac/srl levels reached 4.6 ± 2.3/6.6 ± 2.7 ng/ml. SD-rATGassociated significantly with fewer patient deaths and infections, quicker lymphocyte, CD4 T-cell, and CD4/CD8 recovery, and better renal function (all donors, days 1-4 and weeks 3-26; deceased donors, months 6-36). The risk of multiple infections decreased in association with rising absolute CD4 counts and CD4/CD8 ratio. In a multivariate regression model fewer occurrences of severe viral infections associated with SD-rATG induction and higher 12-month absolute lymphocyte counts. Chronic graft histopathology in protocol biopsies progressed from 12 to 24 months but was not significantly different between groups. Induction groups had no differences in rejection rates or death-censored graft survival. Conclusions Intensive SD-rATG induction improves patient survival and infection rates, with better graft function among deceased-donor kidney recipients.Figure: No Caption available.Figure: No Caption available.

Assessment of Long-Term Outcomes After Kidney Retransplantation.

[Introduction] In recent years it has become possible to prevent antibody-mediated rejection by performing desensitization with a combination of preoperative plasma exchange, rituximab (RIT), and g-globulin (IVIG).In the present study we assessed the long-term outcome of initial kidney transplantation and retransplantation. [Subjects and Methods] Between 2001 and 2013 kidney transplantation was performed in 1026 cases (initial kidney transplantation: 965 cases; kidney retransplantation: 61 cases) in the Department of Urology of Tokyo Women's Medical University. The assessment was conducted by dividing the cases into an initial kidney transplantation group and a kidney retransplantation group and comparing them. [Results] No significant differences between the groups were seen in their 1-year, 5-year, or 10-year graft survival or patient survival rates, and no significant differences were seen in their serum creatinine values. The pre-transplantation donor-specific antibody (DSA)-positive rate was 169/965 (18%) in the initial transplantation group and 22/61 (36%) in the retransplantation group, and DSA-positive cases tended to be more common in the retransplantation group. The rate of occurrence of chronic antibody-mediated rejection was higher in the retransplantation group, and the difference in rejection rates was significant. The frequency of de novo detection was 31/965 (3%) in the initial transplantation group and 1/61 (2%) in the retransplantation group, and it tended to be higher in the initial transplantation group. [Conclusion] By performing an adequate preoperative immunologic evaluation with flow cytometry crossmatch (FCXM), Luminex, etc., and performing preconditioning when necessary, it appeared possible to achieve outcomes that are not inferior to the outcomes of initial transplantation.

Sickle Cell Anemia and HSCT: Relation Between ATG, Chimerism, Gvhd and Outcome In Myeloablative Genoidentical Transplants For The SFGM-TC

BackgroundSickle Cell Anemia (SCA) remains a disease with high risk of morbidity and early death. HSCT is currently the only curative treatment for SCA, but its use has been limited by the risks of transplant-related mortality (TRM) and GVHD. We have previously demonstrated that antithymocyte globulin (ATG) efficiently decreases the rejection rate in HSCT for SCA; however, its optimal dose has not been defined, prompting us to retrospectively analyse outcomes in patients from the SFGM-TC cohort receiving different ATG doses. Patients and MethodsThe cohort includes 236 SCA-patients (109F, 127M), (229 SS, 5 Sb0, 2 SDPunjab) transplanted in France (1988-2012) with geno-identical donors after homogeneous myeloablative conditioning regimen (CR; BU-CY), and rabbit ATG (n=215) at 5-15 mg/kg (n=35), 20 mg/kg (n=160) or no ATG (n=20). Cell sources were bone marrow (BM, n=197), cord blood (CB, n=30), CB+BM (n=8), and peripheral blood cells (PBC, n=1). Chimerism was assessed by quantitative real-time PCR from PBC at Day-30, 60, 90, Month-6, 12 and every year post-transplant, and defined as total donor chimerism (TDC): >95% donor (D); low (5-50%D) or high (50-95%D) mixed chimerism (MC),; or rejection (< 5%D). Disease-free survival (DFS) was defined as the absence of HSCT-related death and rejection. GVHD prophylaxis consisted of CSA-short MTX for BMT and CSA alone for CBT.ResultsMean age at transplant was 9.7yr (range: 2.2-28.9), with 33 patients older than 15. With a mean follow-up of 5.6yr (range 0.5-22.5), TRM was not different with or without ATG (3.4%; 0.8-6%) whereas DFS was higher (p=0.004) with ATG (95.4%; 92-4-98.4) than without (72.7%; 51.7-93.7), due to differences in rejection rates (p<0.001). DFS was similar whether the cell source was CB or BM. No lymphoma was observed, and only one post-transplant death at 5m was virus-related (adenoviral meningo-encephalitis). Incidences of AGVH ≥2, 3-4 and chronic-GVHD (cGVHD) were 19%, 6% and 8.7%, respectively. Univariate Cox analysis showed that significant risk factors affecting DFS were low dose of ATG, AGVH grade, and cGVHD, whereas cell source, ABO compatibility, donor's and recipient's (DR) age, and CMV status were not. Risk factors associated with cGVHD (Logistic regression) were ATG dose (20% incidence with no ATG, 15.6% with 5-15 mg/kg and only 6.4% with 20), DR age (even after exclusion of CBT), whereas DR genders, DR CMV status, and cell source doses (NC, CD34, CD3+) were not. Multivariate analysis only retained ATG dose (OR=0.9/mg/kg increase, 95% CI:0.8-1, p=0.007) and donor's age>15 (OR=7.9, 95%CI: 2.5-25.6,p<0.001) as significant independent risk factors for cGVHD. Chimerisms (n=165) (Figure) were significantly associated with ATG dose and cGVHD occurrence. Among the 6 patients with low MC at 1yr, 3 had not received ATG and rejected at 2, 2.2 and 8yr post-HSCT whereas the 3 others who had received ATG remained stable. All patients with high MC at 1yr (n=54) and TDC (n=80) are doing well with the same electrophoretic profile as their donor, excepted one patient who experienced appearance of MC with hemolysis (D/R group U+/U-) 5yr post-CBT, requiring donor lymphocyte infusion (DLI), which reversed chimerism to TDC but induced cGVHD. [Display omitted] ConclusionThis study confirms that myeloablative CR with ATG offers 95% DFS to SCA-patients and that stable MC in absence of SCA-symptoms does not require intervention such as DLI. It reports for the first time in HSCT for SCA that donor's age significantly increases GVHD risk, suggesting to choose the youngest sibling when possible, and that high ATG dose (20 mg/kg), which significantly reduces cGVHD risk without enhancing viral risk, should be recommended. Disclosures:Bernaudin:Novartis: Research Funding. Bertrand:ERYTECH Pharma: Principal Investigator Other. Gluckman:Cord use: Honoraria; gamida: Honoraria.

Computational Substrates of Norms and Their Violations during Social Exchange

Social norms in humans constrain individual behaviors to establish shared expectations within a social group. Previous work has probed social norm violations and the feelings that such violations engender; however, a computational rendering of the underlying neural and emotional responses has been lacking. We probed norm violations using a two-party, repeated fairness game (ultimatum game) where proposers offer a split of a monetary resource to a responder who either accepts or rejects the offer. Using a norm-training paradigm where subject groups are preadapted to either high or low offers, we demonstrate that unpredictable shifts in expected offers creates a difference in rejection rates exhibited by the two responder groups for otherwise identical offers. We constructed an ideal observer model that identified neural correlates of norm prediction errors in the ventral striatum and anterior insula, regions that also showed strong responses to variance-prediction errors generated by the same model. Subjective feelings about offers correlated with these norm prediction errors, and the two signals displayed overlapping, but not identical, neural correlates in striatum, insula, and medial orbitofrontal cortex. These results provide evidence for the hypothesis that responses in anterior insula can encode information about social norm violations that correlate with changes in overt behavior (changes in rejection rates). Together, these results demonstrate that the brain regions involved in reward prediction and risk prediction are also recruited in signaling social norm violations.