Refractory Rejection Research Articles

Role of mTOR Inhibitors in Pediatric Liver Transplant Recipients: A Systematic Review.

Immunosuppressive medications play a crucial role in determining both organ and patient survival following liver transplantation (LT). Typically, immunosuppressive protocols for pediatric LT patients rely on calcineurin inhibitors (CNIs). While inhibitors of mammalian target of rapamycin (mTOR) have demonstrated beneficial outcomes in adult recipients of liver allografts, such as improved renal function post-LT, their application in pediatric liver transplant recipients is a subject of debate due to uncertain efficacy and potential adverse effects. This review evaluates the potential roles of mTOR inhibitors in the context of pediatric LT patients. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for conduct and reporting. Databases until 31 August 2023 were searched using specific terms and keywords. All clinical studies focusing on mTOR inhibitors in pediatric LT were included. Out of 888 identified articles, 30 studies, involving 386 children who had undergone liver transplantation and received mTOR-inhibitor-based immunosuppressive regimens, met the inclusion criteria. The beneficial impacts of switching from a CNI to an mTOR inhibitor or adding an mTOR inhibitor to CNI-reduced immunosuppression in LT pediatric patients with impaired kidney function are controversial, and high-powered clinical studies are need. It appears that enhancing immunosuppression by adding an mTOR inhibitor to CNI is helpful for pediatric LT recipients who are experiencing refractory acute rejection or chronic rejection. mTOR-inhibitor-containing regimens failed to reduce the occurrence of post-transplant lymphoproliferative disorders (PTLD) among children with LT that may be due to concomitant high CNI concentration among studied patients. The effectiveness of mTOR inhibitors in treating PTLD remains uncertain; however, in patients with PTLD who are at high risk of rejection, mTOR inhibitors may be administered. Conversion to or the addition of mTOR inhibitors to maintenance immunosuppression seems to be suitable for pediatric patients who received a transplant due to hepatic malignancies such as hepatoblastoma or hepatocellular carcinoma or for those with post-transplant primary or recurrent malignancies. Switching to an mTOR inhibitor may improve some CNI-related adverse effects such as gingival hyperplasia, neurotoxicity, nephropathy, hypertrophic cardiomyopathy, or thrombotic microangiopathy. Although the exact role of mTOR inhibitors among pediatric patients who have received a liver transplant needs further study, two algorithms are presented in this review to guide conversion from CNIs to mTOR inhibitors or the addition of mTOR inhibitor to a CNI-minimization immunosuppressive regimen for pediatric patients who may benefit from this class of drugs. This review mainly consisted of retrospective studies with inadequate sample sizes and lacked a control group, which represents the main limitation of this study.

Pediatric Combined Heart-liver Transplantation: A Single-center Long-term Experience.

Combined heart liver transplant (CHLT) continues to gain attention as a surgical treatment for patients with end-stage heart and liver disease but remains rare. We present our institutional longitudinal experience with up to 14 y of follow-up, focused on long-term outcomes in CHLT recipients. We conducted a single-institutional, retrospective review from January 1, 2010, to December 31, 2023, including 7 patients ages 7-17 y who underwent CHLT. Most patients were surgically palliated via Fontan procedure pretransplant (n = 6), and all had evidence of advanced fibrosis or cirrhosis before transplant. The 30-d mortality was 14.3% (n = 1, multiorgan failure). During the follow-up period, 1 patient developed acute heart rejection which required treatment and 2 developed acute liver rejection. In all cases, rejection was successfully treated. Two patients developed acute heart rejection which did not require treatment (grade 1R). No patients developed chronic or refractory rejection. No patients developed allograft coronary artery vasculopathy. CHLT remains a rarely performed treatment for pediatric patients with end-stage heart and liver disease, but our long-term data suggest that this treatment strategy should be considered more frequently.

Recurrent treatment of refractory acute cellular rejection with alemtuzumab after lung transplantation

We present an exceptional case of a lung transplant recipient successfully treated by multiple courses of alemtuzumab for refractory acute cellular rejection.The patient experienced multiple episodes of acute cellular rejection following the transplantation procedure. Alemtuzumab was initiated as third-line rejection treatment and was repeated six times. Each treatment course resulted in complete recovery of the pulmonary function and depletion of T- and B-lymphocytes and NK cells. The onset of rejection was consistently preceded by the recovery of NK cells, while T- and B-lymphocytes remained depleted. This suggests a rejection process mediated by NK cells.This case contributes to recent research findings suggesting that NK cells play a significant role in acute cellular rejection in lung transplant recipients and stresses the importance to further investigate the role of NK cells in rejection. Furthermore, it demonstrates that acute cellular rejection following lung transplantation can be repeatedly managed by treatment with alemtuzumab. Data availability statementThe authors confirm that the data supporting the findings of this study are available within the article.

CORNEAL TRANSPLANTATION

Corneal transplantation is an ophthalmic surgery that aims to restore vision in patients with corneal diseases. Advances in transplantation techniques and in the treatment of rejection have improved the results of this procedure, making it more effective and safer. This paper seeks to analyze the latest developments in transplantation techniques and treatments for rejection in corneal transplantation, highlighting not only scientific advances, but also the emotional and social aspects involved in this procedure, providing a comprehensive overview of the latest innovations in the field of corneal transplantation, highlighting improvements in surgical techniques and post-operative treatments, which are helping to transform the lives of thousands of patients around the world. This is a bibliographical review, using qualitative premises, with the PubMed, Scopus, Web of Science and Scielo databases. The health descriptors “corneal transplantation”, “corneal graft rejection” and “penetrating keratoplasty” were used to better refine the research. Corneal transplantation is indicated for various conditions, such as keratoconus, corneal dystrophies, corneal opacities, among others. The most common transplant techniques include complete (penetrating) corneal transplantation, anterior lamellar transplantation and endothelial transplantation (DSAEK/ DMEK). In recent years, there have been significant advances in lamellar transplantation techniques, which allow specific layers of the cornea to be replaced while preserving the healthy layers. This has resulted in better success rates and faster visual recovery compared to penetrating transplantation. Treatment of corneal graft rejection includes the use of topical and systemic corticosteroids, immunosuppressants and anti-inflammatory agents. New approaches, such as biological and immunomodulatory therapies, are also being investigated to improve results in cases of refractory graft rejection. In conclusion, corneal transplantation remains an important option for restoring vision in patients with corneal diseases. Updates in transplantation techniques and advances in the treatment of rejection have improved the results of this procedure, providing patients with a better quality of life and faster and more effective visual recovery.

Rabbit Antithymocyte Globulin for Treatment of Corticosteroid Refractory Acute Cellular Rejection After Lung Transplantation.

Chronic lung allograft dysfunction (CLAD) remains a major cause of death after the first year posttransplant, with acute cellular rejection (ACR) being a major risk factor for CLAD. We evaluated the use of rabbit antithymocyte globulin (rATG) for corticosteroid refractory ACR in lung transplant recipients. We retrospectively identified 112 adult lung transplant recipients who received rATG for refractory ACR after lung transplantation. The primary endpoint was the incidence of ACR on follow-up transbronchial biopsy. Secondary endpoints included freedom from ACR within 1 y post-rATG, CLAD progression at 1 y post-rATG, and all-cause mortality at 1 y post-rATG. A complete resolution of ACR was observed in 60.2% of patients, an improvement but not complete resolution in 22.1%, and no response on follow-up biopsy in 17.8%. Mean A grade 1 y post-rATG was 0.51 in complete responders, 1.01 in partial responders, and 2.19 in nonresponders ( P < 0.001). Complete responders had significantly less new or worsening CLAD at 1 y than partial responders (17% versus 40%; P = 0.02). All-cause mortality rate was 14.9% in complete responders, 40% in partial responders, and 30% in nonresponders ( P < 0.01). rATG appears to be an effective treatment of refractory ACR in lung transplant recipients. Failure to respond to rATG carries an increased risk of early CLAD and death.

Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats.

Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR.

Evaluation of Antithymocyte Globulin Efficacy in Reversing Refractory Graft Rejection Using Retrospective Event-Based Sequential Graft Biopsy Analysis in Living Related Donor Renal Transplant.

The main risk factor for poor graft outcomes is refractory acute rejection and its consequences. In this study, we compared the efficacy of antithymocyte globulins versus other antirejection strategies in reversing refractory acute graft rejection after living donor renal transplant. We retrospectively reviewed the records of 745 patients who received living-donor kidney transplants and experienced acute rejection episodes at Mansoura Urology and Nephrology Center in Egypt over the past 20 years. Based on the type of antirejection medication that they received, we divided patients into 2 groups, with 80 patients in the antithymocyte globulin group and 665 patients who had other antirejection strategies. By using event-based sequential graft biopsy histopathology analysis, we compared the efficacy of antithymocyte globulins in reversing refractory rejection in terms of graft and patient complications and survival. Patient survival was comparable in both groups; however, graft survival was better in the antithymocyte globulin group than in the other group; in addition, event-based sequential graft biopsies revealed a lower incidence of acute and chronic rejection episodes after treatment of severe acute rejection in the antithymocyte globulin group compared with the other group. Incidence of posttreatment complications, particularly infection and malignancy, was comparable in both groups. Our retrospective analysis of event-based sequential graft biopsy allowed us to track graft rejection resolution or worsening. Antithymocyte globulins are highly effective in reversing acute graft rejection when compared with other approaches, with no increased risk of infection or malignancy.

Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation.

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18y) after rituximab introduction (2004-2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without ( p =0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63-16.3], p =0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05-10.0], p =0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not ( p =0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009-2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development ( p <0.001); however, it did not affect the 5-year recipient survival compared with those without ( p =0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.

Extracorporeal photopheresis for refractory rejection in intestinal transplantation

Extracorporeal photopheresis for refractory rejection in intestinal transplantation

Short-Course Total Lymphoid Irradiation in Management of Pediatric Heart Transplant Rejection

<h3>Purpose/Objective(s)</h3> To evaluate short-course total lymphoid irradiation (TLI) as treatment for refractory heart transplant rejection in pediatric patients. <h3>Materials/Methods</h3> Pediatric patients who received short-course TLI for treatment of recurrent heart transplant rejection at a single institution were retrospectively reviewed. Radiotherapy consisted of 448 cGy in 4 fractions delivered once daily consecutively. This regimen was previously reported in a small series of adults but has not been reported in children. Potential advantages of short-course TLI compared to a more standard 800 cGy in 10 fractions delivered twice weekly (over 5 weeks) include fewer anesthesia sessions, lower cumulative dose, and patient convenience. <h3>Results</h3> Between 2019-2021, 3 pediatric patients (ages 4, 15, 17; 1 girl, 2 boys) received short-course TLI for chronic or recurrent rejection after cardiac allograft transplant. TLI was delivered between 5-51 months after heart transplantation, and time from initial rejection to TLI was 4-30 months. All patients were critically ill with limited medical options to manage rejection at time of TLI. They all received TLI as planned without need for modification due to acute toxicity. Two patients achieved resolution of rejection after TLI. One of these patients was rejection free on endomyocardial biopsy 3 months later and was alive 6 months after TLI with no complications related to TLI. The other patient's endomyocardial biopsy at 3 months also demonstrated no evidence of rejection and was able to undergo a second heart transplant 8 months after TLI for heart failure that was present prior to TLI. This patient was alive 3 years after TLI with no complications related to TLI. One patient died within 1 month of TLI due to multi-organ failure and thus the effects of TLI were not able to be fully assessed. <h3>Conclusion</h3> Short-course TLI was well-tolerated and significantly reduced the duration of the radiation treatment course in comparison to standard course; this is particularly advantageous in young patients who require anesthesia as well as acutely ill patients with poor performance status. Fortunately, alternative anti-rejection therapies are often effective and TLI is rarely requested, but if required a short-course TLI regimen remains an option.

The Microbiome and Metabolomic Profile of the Transplanted Intestine with Long-Term Function.

We analyzed the fecal microbiome by deep sequencing of the 16S ribosomal genes and the metabolomic profiles of 43 intestinal transplant recipients to identify biomarkers of graft function. Stool samples were collected from 23 patients with stable graft function five years or longer after transplant, 15 stable recipients one-year post-transplant and four recipients with refractory rejection and graft loss within one-year post-transplant. Lactobacillus and Streptococcus species were predominant in patients with stable graft function both in the short and long term, with a microbiome profile consistent with the general population. Conversely, Enterococcus species were predominant in patients with refractory rejection as compared to the general population, indicating profound dysbiosis in the context of graft dysfunction. Metabolomic analysis demonstrated significant differences between the three groups, with several metabolites in rejecting recipients clustering as a distinct set. Our study suggests that the bacterial microbiome profile of stable intestinal transplants is similar to the general population, supporting further application of this non-invasive approach to identify biomarkers of intestinal graft function.

Improvement in Coronary Allograft Vasculopathy Following Treatment with a Regimen Including Extracorporeal Photophoresis in a Heart Transplant Recipient

<h3>Introduction</h3> Extracorporeal photophoresis (ECP) has been used for select heart transplant (HT) recipients with acute cellular rejection, recurrent or refractory rejection, antibody-mediated rejection (AMR) and as prophylactic therapy. Effects of ECP on coronary allograft vasculopathy (CAV) are not as well-described. <h3>Case Report</h3> A 48 year-old man with a history of familial cardiomyopathy required left ventricular assist device therapy and ultimately HT in 2001. He developed ISHLT CAV 1 (40% stenosis of LCx and RCA) with severe microvascular dysfunction detected on PET scan (MFR Total 1.14, LAD 1.11, LCx 0.98, RCA 1.40). He was started on treatment with everolimus, but progressive chronic kidney disease necessitated a change back to mycophenolate mofetil. Following this change, his chronic Class II DSA increased significantly and his renal function worsened requiring dialysis, during which time he also had COVID-19. He then presented in cardiogenic shock with ISHLT CAV 3 and pAMR 2 in July 2020 and was treated with an IABP, plasmapheresis, and thymoglobulin. He had recurrent pAMR 2 three months later, for which he was treated with plasmapheresis, bortezomib, rituximab, and ECP. Prior to initiation of ECP, his coronary angiogram demonstrated rapidly progressive ISHLT CAV 3 (80% proximal LAD, 80% ostial LCx, 70% OM1, and 80% mid RCA). Right heart catheterization demonstrated restrictive filling pressures and echocardiogram demonstrated normal graft systolic function. Four months following initiation of ECP therapy, repeat coronary angiography showed improvement of his CAV: the stenosis in the pLAD had regressed to 50%, the proximal LCX stenosis had regressed to 50%, and disease in the distal circumflex artery had also improved (Figure). <h3>Summary</h3> In our patient, ECP along with multiple other therapies was associated with significant regression of CAV. Even many years post-HT, CAV may be amenable to some therapies.

Rabbit Anti-Thymocyte Globulin for Treatment of Corticosteroid Refractory Acute Cellular Rejection After Lung Transplantation

<h3>Purpose</h3> Chronic Lung Allograft Dysfunction (CLAD) is the major cause of graft failure and death after the first-year post-transplant. Acute Cellular Rejection (ACR) of grade A2 or higher is a major risk factor for CLAD. Rabbit anti-thymocyte globulin (rATG) is often used when ACR is nonresponsive to pulse-dose corticosteroids. Data is lacking regarding the impact of rATG on steroid refractory ACR (rACR) after lung transplantation. The objective of this retrospective study was to evaluate the use of rATG for rACR in lung transplant recipients and define its success in improving or resolving ACR. <h3>Methods</h3> Adult patients were included if they had received a single or double lung transplant as identified by ICD 9 and 10 procedure codes between January 2010 and August 2019 and had received rATG after the date of transplantation through September 2020. rATG treatment was identified using medication charge data. Patients were included if rATG was administered for ACR. The primary endpoint was the incidence of ACR on follow-up transbronchial biopsy. ACR was classified by complete resolution, improvement but not complete resolution, or no response in A grade. Secondary endpoints included freedom from ACR at one-year post-rATG, CLAD incidence or progression at one-year post-rATG, and all-cause mortality at one-year post-rATG. <h3>Results</h3> 112 patients were included in the primary outcome analysis. 60.2% of patients had a complete resolution, 22.1% had an improvement but not complete resolution, and 17.8% had no response on follow-up biopsy. Mean A grade one-year post-rATG was 0.51 in complete responders, 1.01 in partial responders, and 2.19 in non-responders (p < 0.001). There was no statistical difference in new or worsening CLAD depending on response to rATG (17% vs 40% vs 30%; p = 0.09). All-cause mortality was significantly lower in patients who had a complete histologic response to rATG (14.9% vs 40% in partial responders, and 30% in non-responders (p < 0.01). <h3>Conclusion</h3> rATG appears to be an effective treatment of rACR in lung transplant recipients. Response to rATG appears to be sustained at one-year post-rATG. Patients that do not respond to rATG for rACR may have an increased risk of mortality.

Long-term outcomes in pediatric patients who underwent living donor liver transplantation for biliary atresia

BackgroundThere is no consensus about long-term outcomes in patients with biliary atresia. We retrospectively reviewed the long-term outcomes in pediatric patients who underwent living donor liver transplantation for biliary atresia. MethodsBetween May 2001 and December 2020, 221 (73%) of 302 pediatric patients who underwent living donor liver transplantation had biliary atresia. The median age at living donor liver transplantation was 1.2 (range 0.2–16.5) years, and follow-up was 10.3 ± 5.5 years. ResultsThe 10-year graft survival rates in patients with and without biliary atresia were 94% and 89%, respectively (P = .019). The 10-year graft survival was significantly poorer in patients ≥12 years of age (84%) versus those <12 years of age at living donor liver transplantation (0–2 years: 95%; 2–12 years: 96%) (P = .016). The causes of graft failure in patients with biliary atresia included late-onset refractory rejection (n = 6), bowel perforation (n = 2), and acute encephalitis (n = 2), as well as cerebral hemorrhage, hepatic vein thrombosis, and sepsis (n = 1 for all). All 7 patients with graft failure due to refractory rejection and hepatic vein thrombosis underwent repeated liver transplantation and are alive in 2021. The rates of post-transplant portal vein complications and early-onset acute cellular rejection in patients with biliary atresia were higher than in those without biliary atresia (P = .042 and P = .022, respectively). In 2021, of 60 adolescents with biliary atresia, 14 (23%) reported medication nonadherence. The rate of liver dysfunction due to late-onset acute cellular rejection and graft failure due to late-onset refractory rejection in patients with nonadherence was higher than in patients with satisfactory adherence (P = .009). ConclusionThe long-term prognosis after living donor liver transplantation in pediatric patients with biliary atresia is quite good. However, long-term support to enhance medication adherence is required in adolescents with biliary atresia.

Group Contribution as Selection Criteria for Nutrients Fermentation Media in the Production of Tacrolimus

Group contribution methods are suitable tools for estimating many physicochemical properties of pure compounds and mixtures. The classical group contribution method decomposes each chemical compound into first, second, and third-order functional groups based on its molecular structure. The most significant advantage of these methods is that they need only the compounds chemical structure without any other input information. From these approaches, structural fragments and subsequent group contribution methods can be established. The knowledge of the molecular structure and its decomposing into molecular fragments can optimize the production of biosynthesis compounds for chemical and pharmaceutical industries. The current research proposes an innovative group contribution application as selection criteria to culture media carbon and nitrogen sources. The concept is based on group contribution to identifying molecular fragments present in tacrolimus structure. Tacrolimus is a macrolide lactone originally obtained from fermentation of Streptomyces tsukubaensis broth. This drug decreases the occurrence and severity of refractory rejection episodes. In addition, tacrolimus is recommended for the treatment of autoimmune diseases. In order to investigate the application of the group contribution, tacrolimus molecular structure and fermentation results of this macrolide were analyzed. This approach can enhance productivity of this important immunosuppressant.

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.

Coronary Thrombosis after Rabbit-ATG in LTx Recipient

Introduction Rabbit anti-thymocyte globulin (rATG) is a polyclonal antibody that targets human T lymphocytes; it can be used as an induction agent at the time of lung transplant (LTx) or as treatment for steroid refractory allograft rejection. rATG-induced platelet activation and hypercoagulability has been reported. Herein, we report a case of acute thrombotic myocardial infarction (MI) after the first dose of rATG in an LTx recipient with steroid refractory rejection. Case Report The patient is a 60-year-old man with COPD who underwent a bilateral LTx in May 2018. He had an uneventful post-LTx course, but presented 18 months later with dyspnea and a 600-cc decline in FEV1. A CT scan of the chest showed diffuse bronchial thickening and a bronchoscopy with bronchoalveolar lavage and transbronchial biopsies showed rhinovirus, but no evidence of acute cellular rejection. Donor specific antibodies were absent. The patient was empirically treated with high-dose corticosteroids, but presented a month later with another 400-cc decline in FEV1, prompting admission and treatment with rATG for presumed steroid refractory rejection. During admission, his labs were remarkable for mild anemia and thrombocytosis (781 K/µL). Thirty minutes into his rATG infusion, the patient complained of shortness of breath, chest discomfort, diaphoresis, and right-arm numbness. The infusion was stopped. His labs revealed elevated troponin (0.382 ng/mL), and his EKG showed an ST elevation in leads II, III and aVF along with ST depression in leads I and aVL suggestive of inferior wall MI. Emergent cardiac catheterization and ventriculogram showed 100% occlusion of the mid-distal right coronary artery with heavy clot burden, inferior wall hypokinesis, and a mildly reduced ejection fraction. A drug-eluting stent was placed, which resulted in near resolution of ST elevation. Of note, his prior pre-LTx cardiac catheterization had no angiographic evidence of coronary artery disease (CAD). Summary rATG activates platelets and establishes a link between complement and coagulation cascades, which may explain the clinically observed phenomenon of rATG-induced hypercoagulability. To the best of our knowledge, this is the first report of rATG-induced coronary arterial thrombosis in an LTx recipient with no prior CAD, but with thrombocytosis at the time of rATG infusion.

Modest Improvements in Refractory Antibody-Mediated Rejection After Prolonged Treatment

Active and chronic active antibody-mediated rejection (ABMR) are major causes of allograft loss after kidney transplantation.1 There is no standard treatment approach for ABMR, but intravenous immunoglobulin (IVIG), steroids, and targeted B-cell therapies have been found to have relative success in reducing allograft injury and preserving function.2–4,S1 In contrast, outcomes for patients with refractory or resistant, chronic active ABMR (cABMR) are generally poor with limited success reported with the addition of bortezomib, eculizumab, or IVIG and rituximab to the standard of care.

Extracorporeal photopheresis in solid organ transplantation

Despite the use of up-to-date immunosuppressive agents, graft rejection episodes are quite common and pose a serious threat to thousands of solid organ recipients. Continuous use of various combinations of immunosuppressants cause serious complications, such as arterial hypertension, post-transplant diabetes mellitus, renal failure, increased risk of infections, malignant neoplasms, etc. The attempts to achieve the desired or forced minimization of the graft immunosuppression are associated with the threat of its rejection, which makes it necessary to search for less toxic, non-medical, immunological, including cellular, management methods. One of the promising methods based on cell technology is extracorporeal photopheresis (ECP). ECP is a well-established second line therapy recommended for the prevention and treatment of refractory rejection of a heart transplant. ECP improves the pulmonary allograft functioning in patients with treatment resistant obliterating bronchiolitis syndrome. However, its value as a preventive method has not yet been established. ECP effectiveness for induction, maintenance, or anti-crisis therapy in transplantation of kidney, liver or other solid organs has been rather convincing, but the lack of randomized multicenter studies limits its use. The optimal ECP strategy has not been yet established. Nevertheless, current understanding of the pathophysiological and immunological aspects of ECP is sufficient to develop a standard methodology and technology for the procedure, as well as for a quality control system for ECP in kidney and liver transplant recipients. The review discusses possible mechanisms of the immunomodulating effect of ECP. ECP is being increasingly studied in prospective randomized trials with larger samples. This allows for an extension of its clinical indications with clear criteria, as well as for studying its multifactorial underlying immunomodulating mechanism of action. Further research is needed to identify biomarkers that could predict ECP effectiveness in solid organ transplantation.

Risk Factors and Outcomes of Acute and Refractory Antibody-Mediated Rejection

Risk Factors and Outcomes of Acute and Refractory Antibody-Mediated Rejection