Severe Rejection Research Articles

Assessing causality by means of the Naranjo scale in a paediatric patient with life threatening respiratory failure after alemtuzumab administration: a case report

BackgroundAlemtuzumab is a T cell depleting antibody agent used as induction immunosuppressant therapy in solid organ transplant recipients. In addition, it is being increasingly used to treat severe or glucocorticoid-resistant graft rejection. Despite the effectiveness of the treatment, severe adverse events have been reported related to alemtuzumab administration. We present a similar event illustrating the severity of this adverse drug reaction (ADR) and we highlight the structure causality assessment provides in approaching such a case.Case presentationWe report a case of life-threatening respiratory failure after alemtuzumab administration in a 17 year old paediatric kidney transplant recipient. He developed near fatal severe respiratory and circulatory failure based on acute respiratory distress syndrome (ARDS) with diffuse alveolar oedema and haemoptysis hours after his second alemtuzumab administration. As it was questionable whether alemtuzumab could be regarded as the origin of his reaction and in order to assess the causality of this reaction as well as to structure clinical reasoning, we applied a widely used ADR probability scale to systematically review our case.Discussion and conclusionsOur case shows a severe ADR after alemtuzumab administration. It illustrates the importance of proper causality assessment, the structure it provides and the benefit of a clinical pharmacology consultation when a severe reaction is suspected to be an ADR. By taking our case as an example, we demonstrate the added value of structured causality assessment to clinical reasoning and in generating differential diagnoses.

Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report

Background: Antibodies directed against donor mismatched Human Leucocyte Antigens (HLA) are known to cause antibody-mediated rejection and affect the graft survival of transplanted organs. The influence of donor-directed antibodies against the products of HLA class I and II genes in renal transplantation are well described for class I (HLA-A, B and C), but still not clear for class II notably HLA DP. The clinical effects of donor-specific antibodies (DSA) directed against HLA-DP are still controversial.Methods: We report the outcome of kidney transplants in three highly sensitised individuals with significant sensitisation with donor-directed HLA-DP antibody. These recipients were on the waiting list for 6, 14 and 4 years, respectively and had kidney transplants from donors after brain death (DBD) with positive B cell flow cytometry crossmatch (FCXM). Two cases received induction therapy with a depleting antibody (Thymoglobulin®) while the third received Alemtuzumab followed by standard immunosuppression.Results: The clinical course of these three patients were different. The first patient developed transplant glomerulopathy, but the graft is still functioning with eGFR 29 mL/min/1.73 m2. The second patient did not have any adverse event with eGFR 26 mL/min/1.73 m2, while the third patient had severe antibody-mediated rejection (AMR), which was treated successfully with eGFR 32 mL/min/1.73 m2.Conclusion: Patients waiting for a deceased allograft with HLA-DP DSA and a positive FCXM can be transplanted successfully with depleting antibody or Alemtuzumab induction without prior antibody removal followed by standard immunosuppression.

Efficacy and Safety of Immunosuppression Withdrawal in Pediatric Liver Transplant Recipients: Moving Toward Personalized Management.

Tolerance is transplantation's holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long-term pediatric liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance. We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3-4). For-cause biopsies were done at investigators' discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1year after stopping immunosuppression. Among 88 subjects (median age 11years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval [CI] 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n=32) occurred at ≤32% of the trial-entry immunosuppression dose and was treated with corticosteroids (n=32) and/or tacrolimus (n=38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4years for either tolerant or nontolerant subjects. Immunosuppression withdrawal showed that 37.5% of selected pediatric liver-transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.

Cardiac sarcoidosis evaluation and characterization with cardiac magnetic resonance

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Sarcoidosis is a multisystemic inflammatory disease, which accounts for substantial morbimortality. Cardiac involvement portends a worse prognosis. A major limitation in the evaluation of cardiac sarcoidosis is that no gold standard clinical diagnostic criteria exists. Cardiac magnetic resonance (CMR) may be indicated in patients with suspected cardiac involvement as a diagnostic and prognostic tool. Purpose The aim of this study was to characterize the features of cardiac involvement of sarcoidosis in patients with stablished diagnosis of the systemic disease, as well as to describe changes observed. Methods A multicenter, 6-years prospective study of all patients with sarcoidosis who performed CMR to evaluate possible cardiac involvement. We followed a protocol to evaluate the left and right ventricles (VE; RV) both anatomically and functionally, T2- weighted STIR sequences to evaluate myocardial edema and presence of late gadolinium enhancement(LGE). Results A total of 20 patients were included. Female patients accounted for 75% of the cases, and the mean age was 53 ± 15 years old. A majority of the patients (90%) had preserved LV (mean LV ejection fraction(EF)63 ± 6%) and RV ejection fraction (mean RV EF 62 ± 7%). Patients observed presented with mean LV end diastolic indexed volume(EDIV) of 72 ± 19 mL/m2 and mean RV EDIV of 63 ± 18mL/m2, with only one patient presenting with LV dilation(LV EDIV 138mL/m2) and two with RV dilation (mean RV EDIV 107 ± 6mL/m2). Possible features of cardiac sarcoidosis were present in 10% (n = 2) of patients. One of them presented with biventricular dilation and severe ejection fraction depression(LV EF 22% and RV EF 28%). LGE was observed in these two patients, with one presenting with an intramyocardial lesion with nodular appearance on the apical inferior segment and the other patient having its distribution characterized with two different patterns: linear appearance on the septal intramyocardium and subepicardial on the basal and mid segments of the inferior wall. On STIR sequences none of the patients presented with hypersignal suggestive of edema. None of them presented with left atrium dilation. Conclusion CMR provides a noninvasive and multidimensional assessment of the heart for evaluation of cardiac sarcoidosis. In our population of patients with sarcoidosis but without established cardiac involvement diagnosis, CMR allowed a 10% increasement on the diagnosis of cardiac sarcoidosis. CMR myocardial fibrosis detection allowed a better stratification of patients with sarcoidosis.

De Novo Human Leukocyte Antigen Allosensitization in Heartmate 3 Versus Heartmate II Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVADs) are associated with the development of antihuman leukocyte antigen (HLA) antibodies, which can create a challenge for future transplantation in these patients. The differential effects of Heartmate 3 (HM3) versus Heartmate II (HMII) on de novo HLA allosensitization remain unknown. Patients who underwent HMII or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing were included in this study. Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels and Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. Electronic medical records were reviewed to examine posttransplant outcomes. Thirty-eight HM3 and 34 HMII patients with complete data were followed for 1.5 ± 1.1 years on device support. HM3 and HMII groups had similar age at implant, female gender, ischemic heart failure etiology, bridge strategy at implant, as well as intraoperative and postoperative transfusion requirements. 39.5% of HM3 and 47.1% of HMII patients developed detectable HLA antibodies by Luminex testing (p = 0.516). Development of high-level (mean fluorescence intensity >10,000) antibodies was significantly lower in HM3 than HMII patients (5.3 vs. 20.6%, p = 0.049). CDC PRA testing showed fewer HM3 patients with a positive result (PRA > 0%) than HMII patients (39.4 vs. 70.0%, p = 0.015). Among transplanted patients, those who had developed de novo sensitization on LVAD support showed a trend toward incidence of moderate to severe grade rejection compared with unsensitized patients (23.8 vs. 4.8%, p = 0.078). HM3 is associated with lower risk of de novo HLA sensitization compared with HMII.

Tacrolimus time-in-therapeutic range is associated with freedom from acute rejection and graft failure following intestinal transplantation.

Trough-adjusted tacrolimus is commonly prescribed following intestinal transplantation to prevent allograft rejection. Despite established practice, there remains limited direct evidence linking tacrolimus levels with improved clinical outcomes. This was a single-center review of all adult non-liver containing intestinal allograft recipients from 2011 to 2018. Patients received lymphocyte depleting induction and maintenance immunosuppression consisting of tacrolimus and a corticosteroid taper. Tacrolimus time-in-therapeutic range (TAC-TTR) was calculated for all patients from the date of transplant until 1-year post-transplant using Rosendaal's method. Cox-Proportional hazards modeling was utilized to assess freedom from acute rejection and graft failure stratified by TAC-TTR quartile. 47 patients were included in the review. Mean TAC-TTR for the cohort was 30.2% ± 11.4. Fifteen episodes of acute rejection were observed, 8 of which were severe. Patients in the highest TAC-TTR quartile >36% had a lower incidence of acute rejection and graft failure relative to patients with a TAC-TTR <20%. Cox-Proportional hazards modeling found a 10% decrease in TAC-TTR was associated with an increased hazard for acute rejection (2.03), severe acute rejection (2.19), and graft loss (3.33). The results of this study suggest that decreasing TAC-TTR is a risk factor for both acute rejection as well as intestinal allograft failure.

Retrospective Evaluation of Rabbit Anti-Thymocyte Globulin (rATG) Induction in Heart Transplant Patients

<h3>Purpose</h3> The use and dosing intensity of rATG as induction therapy in heart transplantation remains controversial. We sought to evaluate the efficacy and safety of rATG at a total dose of 4.5mg/kg compared to less than 4.5mg/kg. <h3>Methods</h3> This study was a cross-sectional retrospective chart review of adults who underwent heart transplantation from January 1, 2016 - December 31, 2018 at a single quaternary care center. Exposure was defined as a full rATG (4.5mg/kg total) induction per institutional protocol compared to partial (less than 4.5mg/kg) induction. The primary outcome was the incidence of ISHLT 1990 defined acute cellular rejection (ACR) at two years. Secondary outcomes were all-cause mortality, proportion of infections, and time to therapeutic tacrolimus levels. <h3>Results</h3> A total of 201 patients met inclusion criteria. 61 received partial rATG induction and 140 received full rATG induction. When comparing partial vs full induction, there was no difference in any-grade of ACR (78.7% vs 88.6%, p=0.11). There was a trend toward a higher cumulative incidence of ACR grade 2 or above over two years in the partial as compared to the full induction group (18% vs 11.4%, p=0.21). On multivariate Cox PH analysis, partial vs full induction, the estimated hazard ratio was 1.45 (CI 0.62-3.37, p=0.39). Adjusted landmark survival analysis conditional on survival to 1 month showed no difference between the two groups. The number of patients with at least one infection within 3 months of transplant was similar between the groups (partial 29.5% vs full 20.0% p=0.20). Both groups achieved therapeutic tacrolimus levels by day 7 after initiation. <h3>Conclusion</h3> The dose of rATG does not appear to affect the overall incidence of biopsy-proven rejection, though there appears to be a trend towards severe rejection with rATG induction doses less than 4.5mg/kg. The total cumulative dose of rATG induction did not impact medium-term survival. Prospective, randomized, controlled trials are needed to validate these observations.

Release the Pressure! Does Jugular Venous Pressure Predict Rejection in Cardiac Biopsy?

<h3>Purpose</h3> Rejection in heart transplant recipients is often diagnosed by surveillance biopsies as most patients are asymptomatic. Nevertheless, rejection, if left untreated, can produce progressive diastolic dysfunction followed by systolic heart failure. This in turn will cause an increase in central venous pressure due to decreased ventricular compliance. With this in mind we sought out to determine if elevated central venous pressures measured invasively at the time of the biopsy correlated with the presence of rejection. <h3>Methods</h3> Patients undergoing an endomyocardial biopsy between June and October 2020 were included. The invasive JVP was measured before and after the procedure by measuring the height of the blood column in the side port of the sheath open to the atmospheric pressure. The biopsy results were reported according to the 2004 ISHLT revision. Differences in median JVP for each biopsy result group (0, 1R, 2R, 3R) were compared using a Mann-Whitney test. The histogram density for each biopsy group was graphed using a Kernel density plot. <h3>Results</h3> Eighty-four patients underwent one or more endomyocardial biopsies, with a total of 374 biopsies performed. Of all procedures, 187 were grade 0 for rejection, 168 were grade 1R and 18 were grade 2R. One patient had Grade 3R rejection (not shown in illustration) The median JVP was not statistically different between the three groups and the numerical difference was not clinically meaningful (figure 1 A). The Kernel density plot (figure 1 B) demonstrates the similarities between the groups. The lack of correlation between invasive JVP and rejection persists if data from the first 2 weeks post heart transplant are excluded. <h3>Conclusion</h3> In our dataset, there was no clinical or statistical difference in median invasive JVP and rejection grade between the biopsy result groups. One limitation is that we only had one patient with severe rejection (3R). Overall, our findings reinforce the need for surveillance biopsies.

Daratumumab as Salvage Therapy in Pediatric Thoracic Organ Transplantation: An Addition to the Antibody Mediated Rejection Toolbox?

Purpose Antibody mediated rejection (AMR) is difficult to treat and often results in death or graft loss. Therapies targeted at antibodies or B cells are inadequate for decreasing donor specific antibodies (DSA), particularly to MHC class II. Bortezomib, a small molecule proteasome inhibitor targets plasma cells, but has many side effects and unsatisfactory results. Alternatively, we used Daratumumab (DAR), an anti-CD38 monoclonal antibody, in two pediatric transplant (Tx) recipients. Methods Chart review. Results An 18-year-old female with cystic fibrosis had a lung-liver Tx at 12-years-old. Twenty months post-Tx she developed severe AMR and Acute cellular rejection (ACR) treated with ATG, rituximab, TPE, photopheresis, and steroids. She ultimately required redo lung Tx. She did well for three years, but then developed AMR. She again received TPE, ATG, photopheresis, and rituximab. She was not considered a candidate for third lung Tx so all attempts were made to salvage her graft. She had no B cells, but continued to make DSA, so a plasma cell targeted therapy was desired. She received three doses of DAR 16 mg/kg on days 0, 7 and 21 with no infusion reactions. She developed neutropenia 2 months later which resolved with 3 weeks of GCSF. Both total PRA and DSA significantly decreased after DAR and have not returned 7 months later. PRA class I dropped from peak of 96% to 0, class II from peak 34% to 3%. She is maintained on subcutaneous IgG replacement for secondary hypogammaglobulinemia. Her graft function is poor, but has stabilized since DAR. She had one episode of presumed line associated sepsis and MSSA pneumonia without sequalae. A 3-year-old girl two years post heart Tx developed refractory AMR (by C4d and elevated DSA) despite ATG, TPE, IVIG, eculizumab, and ofatumumab. She then received two doses of DAR, 16 mg/kg each on days 0 and 14. She tolerated the infusions without any initial side effects. Not enough time has elapsed to follow up antibody levels or graft function. Conclusion Treatment for AMR remains challenging, especially when due to class II HLA antibodies. We safely administered DAR to two pediatric patients without infusion reactions or significant infectious complications to date. One patient had a decline in antibodies, while the other is too soon to determine. While more studies are needed, DAR may be a promising addition to the AMR toolbox.

Low AlloSure® Despite Discordance with High AlloMap® Associated with Low Risk of Moderate to Severe Cardiac Allograft Rejection

Low AlloSure® Despite Discordance with High AlloMap® Associated with Low Risk of Moderate to Severe Cardiac Allograft Rejection

AlloMap versus Endomyocardial Biopsy: The Patient Experience

<h3>Purpose</h3> Endomyocardial biopsy (EMB), the gold standard for rejection surveillance following heart transplantation, is an invasive test requiring right heart catherization and may be stressful and painful for patients. Alternatively, AlloMap is the only commercially available non-invasive rejection test. ISHLT guidelines include AlloMap to rule out moderate to severe rejection in low-risk patients 6 months - 5 years post-transplantation. We compared patients' experiences of AlloMap and EMB surveillance at our transplant center. <h3>Methods</h3> Heart transplant recipients undergoing rejection surveillance via EMB and via AlloMap testing on different visits quantified their anxiety on the GAD-7 scale (scored from 0-21) and their pain level on the Polyclinic Pain Scale (scored from 0-10) for each test; higher scores signified poorer results. Within-subject differences between EMB and AlloMap tests for pain and anxiety scores and adverse event rates were determined using Wilcoxon Rank Sum tests and McNemar's test. <h3>Results</h3> The 43 subjects had a median age of 60.5 [quartile 1=54, quartile 3=66] years; 35 (81%) were men. The majority (27, 63%) was Caucasian; 11 (26%) were African American, and 5 (11%) were a different race/ethnicity. The median GAD for undergoing EMB was 1 [0, 4] and 2 [0, 5] for AlloMap testing, with no significant within-subject difference 0 [-1, 1] (P=0.323). The median pain score was 1 [0, 1] for EMB and 0 [0, 0] for AlloMap testing. Most patients experienced less pain while undergoing AlloMap testing compared to EMB (EMB - AlloMap; 1 [0, 1], P=0.006). Seven (16%) subjects experienced a total of 9 adverse events (pain, bruising, bleeding, swelling) at the access site from EMB vs 2 (5%) subjects who experienced a total of 3 adverse events (pain, bruising ) from AlloMap testing (P=0.059). <h3>Conclusion</h3> These results suggest that AlloMap testing may be preferred over EMB in terms of patient experience and adverse events. Home testing via AlloMap test can reduce high-risk patients' infectious exposures during the pandemic.

Pneumonia With Scedosporium apiospermum and Lomentospora prolificans in a Patient After Bilateral Lung Transplantation for Pulmonary Hypertension: A Case Report

Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum β-D-glucan elevated without any sign of fungal infection by other tests. The serum β-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum β-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.

Clinical usefulness of T1-weighted MR cholangiography with Gd-EOB-DTPA for the evaluation of biliary complication after liver transplantation.

Backgrounds/AimsBiliary complications continue to be the major morbidity and mortality causes following living donor liver transplantation (LT). Endoscopic retrograde cholangiopancreatography (ERCP) has been performed to identify the biliary leakage source. However, this can lead to retrograde cholangitis and pancreatitis, and is not sufficient to diagnose bile leakage from cuts’ surface. This study aimed to describe the use of T1-Weighted Magnetic Resonance (MR) Cholangiography with Gd-EOB-DTPA (Primovist) examination for evaluating the bile duct complication following LT.MethodsFrom March 2012 to December 2018, 869 adult LT were performed at the Seoul National University Hospital. Forty-three recipients had undergone MR Cholangiography with Gd-EOB-DTPA. We reviewed these cases with their clinical outcomes and described the utility of the MR cholangiography with Gd-EOB-DTPA.ResultsIn radiologic examinations performed in the patients suspected of bile duct complication, 95% had bile leakage and stricture. Cut surface leakage was diagnosed in two cases, and biliary leakage from the anastomosis site was diagnosed in the others. Most patients with leakage had undergone percutaneous drainage and ERCP, which was performed to evaluate the bile secretion function of the hepatocytes. There was no contrast-enhanced bile duct image in one case with severe rejection, and it might have been related to hepatocyte secretary dysfunction.ConclusionsT1-Weighted MR Cholangiography with Gd-EOB-DTPA 40-minute delay examination is a feasible and safe non-invasive procedure for identifying biliary leakage sites.

Follicular T cells mediate donor-specific antibody and rejection after solid organ transplantation.

Following solid organ transplantation, a substantial proportion of chronic allograft loss is attributed to the formation of donor-specific antibodies (DSAs) and antibody-mediated rejection (AbMR). The frequency and phenotype of T follicular helper (Tfh) and T follicular regulatory (Tfr) cells is altered in the setting of kidney transplantation, particularly in patients who develop AbMR. However, the roles of Tfh and Tfr cells in AbMR after solid organ transplantation is unclear. We developed mouse models to inducibly and potently perturb Tfh and Tfr cells to assess the roles of these cells in the development of DSA and AbMR. We found that Tfh cells are required for both de novo DSA responses as well as augmentation of DSA following presensitization. Using orthotopic allogeneic kidney transplantation models, we found that deletion of Tfh cells at the time of transplantation resulted in less severe transplant rejection. Furthermore, using inducible Tfr cell deletion strategies we found that Tfr cells inhibit de novo DSA formation but only have a minor role in controlling kidney transplant rejection. These studies demonstrate that Tfh cells promote, whereas Tfr cells inhibit, DSA to control rejection after kidney transplantation. Therefore, targeting these cells represent a new therapeutic strategy to prevent and treat AbMR.

Human Uterus Transplantation from Living and Deceased Donors: The Interim Results of the First 10 Cases of the Czech Trial.

Introduction: Uterus transplantation (UTx) is a rapidly evolving treatment of uterine-factor infertility. We report the results of the first 10 UTx procedures performed at our institution. Methods: The program started in April 2016 as a two-arm study comparing the efficacy of UTx from live donors (LD) and deceased donors (DD). Results: Between April 2016 and April 2018, we performed five DD UTx and five LD UTx. Two grafts had to be removed early due to thrombosis. One graft was removed due to chronic rejection and previous herpes simplex infection at month 7. Graft survival is 70% at one year. Recipient survival is 100% at two years. Live donor survival is 100% at three years. Three live-births have been achieved, two from a LD and one from a graft from a nulliparous DD. Vaginal anastomotic stenosis occurred in 63% (5/8) of grafts. Self-expanding stents have shown preliminary suitability for the treatment of vaginal stenosis. Three recipients developed severe acute rejection. Conclusion: The interim results of our study demonstrate mid-term viability in 70% of grafts. The LD UTx produced two live births and the DD UTx produced one live birth. Nulliparous donors should be considered for donation.

Anorectal Transplantation: The First Long-term Success in a Canine Model.

Objective:Anorectal transplantation is a challenging procedure but a promising option for patients with weakened or completely absent anorectal function.Summary Background Data:We constructed a canine model of anorectal transplantation, evaluated the long-term outcomes, and controlled rejection and infection in allotransplantation.Methods:In the pudendal nerve function study, 6 dogs were randomly divided into 2 groups, transection and anastomosis, and were compared with a control using anorectal manometry, electromyography, and histological examination. In the anorectal transplantation model, 4 dogs were assigned to 4 groups: autotransplant, allotransplant with immunosuppression, allotransplant without immunosuppression, and normal control. Long-term function was evaluated by defecography, videography, and histological examination.Results:In the pudendal nerve function study, anorectal manometry indicated that the anastomosis group recovered partial function 6 months postoperatively. Microscopically, the pudendal nerve and the sphincter muscle regenerated in the anastomosis group. Anorectal transplantation was technically successful with a 3-stage operation: colostomy preparation, anorectal transplantation, and stoma closure. The dog who underwent allotransplantation and immunosuppression had 2 episodes of mild rejection, which were reversed with methylprednisolone and tacrolimus. The dog who underwent allotransplantation without immunosuppression had a severe acute rejection that resulted in graft necrosis. Successful dogs had full defecation control at the end of the study.Conclusions:We describe the critical role of the pudendal nerve in anorectal function and the first long-term success with anorectal transplantation in a canine model. This report is a proof-of-concept study for anorectal transplantation as a treatment for patients with an ostomy because of anorectal dysfunction.

Birth Cohort Changes in Chinese Primary School Students’ Perceptions of Parental Rearing Patterns: A Cross-temporal Meta-analysis, 1999–2017

Parental rearing patterns are important factors affecting children’s development. In recent decades, China has experienced dramatic social changes in family structures, which may influence parental rearing patterns. This research aims to examine the birth cohort changes in parental rearing patterns as perceived by Chinese primary school students. To examine the birth cohort changes in parental rearing patterns as perceived by Chinese primary school students, a cross-temporal meta-analysis was conducted on 71 studies (79 data points, N = 22,415). The results showed that Chinese primary school students’ scores on the Egna Minnen Betraffande Uppfostran (EMBU) scale changed significantly from 1999 to 2017. Data-collection year was significantly positively correlated with paternal severe punishment, paternal rejection, maternal overprotection and excessive interference and significantly negatively correlated with maternal rejection and maternal emotional warmth. The d values of the eleven scale dimensions varied from −0.93 to 1.09, indicating that the r squared varied from 0 to 23%. Furthermore, boys perceived more severe punishment, excessive interference, and rejection from fathers than girls.

Perioperative Management for Liver Transplantation with DSA Positive Patients

Background: Liver transplantation is an accepted treatment for end-stage liver disease. Despite improvements of the surgical techniques, organ preservation methods, and immunosuppressive therapy, antibody mediated rejection is still big problem. It has been reported that the existence of donor-specific antibodies (DSA) is correlated with rejection and with an increased risk of early mortality. We described our treatment and prognosis about the patient who has undergone liver transplantation with DSA. Methods: 16 patients among 87 patients of recipient who has undergone liver transplantation in our department from September 2011 to December 2018. In each patient, the type of DSA and the MFI were measured before liver transplantation. A high DSA titer was defined as a normalized, trimmed MFI value ≥10000. Patients received the standard immunosuppressive protocol for liver transplantation, including steroids, tacrolimus, and mycophenolate mofetil, with addition of rituximab more than two weeks before transplantation and took medication such as tacrolimus and mycophenolate mofetil one week before the transplantation. During operation, each patient underwent splenectomy. Results: 7 patients have high titer DSA, and each patient has a desensitization method that described before. Only one patient was dead because of other disease. 9 patients are still arrived without severe rejection. Conclusion: If the patients who has DSA was undergone right desensitization methods, we can get good survival rate.

5-Year outcomes of the prospective and randomized CISTCERT study comparing steroid withdrawal to replacement of cyclosporine with everolimus in de novo kidney transplant patients.

Withdrawal of either steroids or calcineurin inhibitors are two strategies to reduce treatment-related side effects and improve long-term outcomes of kidney transplantation. The CISTCERT study compared the efficacy and safety of these two strategies. In this multicenter, randomized controlled trial, 151 incident kidney transplant recipients received cyclosporine (CsA), mycophenolic acid (MPA), and steroids during three months, followed by either steroid withdrawal (CsA/MPA) or replacement of cyclosporine with everolimus (EVL) (EVL/MPA/steroids). 5-year patient survival (89% vs. 86%; P=NS) and death-censored graft survival (95% vs. 96%; P=NS) were comparable in the CsA/MPA and EVL/MPA/steroids arm, respectively. 51 CrEDTA clearance was comparable in the intention-to-treat analysis, but in the on-treatment population, the EVL/MPA/steroids arm exhibited a superior 51 CrEDTA clearance at 1 and 5years after transplantation (61.6 vs. 52.4, P=0.05 and 59.1 vs. 46.2ml/min/1.73m2 , P=0.042). Numerically more and more severe rejections were observed in the EVL/MPA/steroids arm, which also experienced a higher incidence of posttransplant diabetes (26% vs. 6%, P=0.0016) and infections. No significant differences were observed in cardiovascular outcomes and malignancy. Both regimens provide an excellent long-term patient survival and graft survival. Regarding graft function, EVL/MPA/steroids is an attractive strategy for patients with good tolerability who remain free of rejection. (ClinicalTrials.gov number: NCT00903188; EudraCT Number 2007-005844-26).

Intestinal transplantation: an overview of the recent experimental studies

Experimental intestinal transplantation (ITx ) has generated invaluable knowledge that has ultimately benefited the clinical activity. Herein, we appraise the recent publications pertaining to experimental ITx and highlight the main current research topics. During the recent years, ischemia-reperfusion injury (IRI) and Graft-versus-host disease (GVHD) have gradually replaced acute rejection as the main research topic. New additives to established preservation solutions and relatively novel approaches such as luminal interventions during cold storage may prolong the storage time and alleviate IRI. High donor age does not seem to worsen preservation injury. The ischemic susceptibility seems to differ between species, which may impact the translatability of the experimental findings. A new experimental model of modified multivisceral transplantation including the donor spleen may offer a new tool with which to study GVHD, besides the classical Lewis-Brown Norway rat combination. Flushing the graft with fludarabine may mitigate GVHD in rats. T-cell activation inhibitor-mitochondrial was downregulated in the peripheral blood leukocytes before other signs of acute and severe chronic rejection could be observed. Experimental research in ITx has largely shifted focus from acute rejection to IRI and GVHD. Several lines of research have matured toward clinical translation, yet no breakthrough is imminent.