Serum MicroRNA Transcriptomics and Acute Rejection or Recurrent Hepatitis C Virus in Human Liver Allograft Recipients: A Pilot Study.

Background: Acute rejection (AR) and recurrent hepatitis C virus (R-HCV) are significant complications in liver allograft recipients. Noninvasive diagnosis of intragraft pathologies may improve their management.

Methods: We performed small RNA sequencing and microRNA (miRNA) microarray profiling of RNA from sera matched to liver allograft biopsies from patients with nonimmune, nonviral (NINV) native liver disease.

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

Background And Aims: 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.

Approach And Results: We conducted a multicenter, single-arm trial of immunosuppression withdrawal over 36-48 weeks.

Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective, randomized clinical trial.

In a phase 2 multicenter open-label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)-based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low-dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled.

Hospital readmission following pediatric heart transplantation.

The frequency, indications, and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC-04) multi-institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge.

Perceived barriers to medication adherence remain stable following solid organ transplantation.

Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post-transplant while their guardians completed PMBS.

Early outcomes for low-risk pediatric heart transplant recipients and steroid avoidance: A multicenter cohort study (Clinical Trials in Organ Transplantation in Children - CTOTC-04).

Background: Immunosuppression strategies have changed over time in pediatric heart transplantation. Thus, comorbidity profiles may have evolved. Clinical Trials in Organ Transplantation in Children-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after pediatric heart transplantation.

Accelerated Allograft Vasculopathy With Rituximab After Cardiac Transplantation.

Background: The CTOT-11 (Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation [Clinical Trials in Organ Transplantation-11]) study was a randomized, placebo-controlled, multicenter, double-blinded clinical trial in nonsensitized primary heart transplant (HTX) recipients.

Objectives: The study sought to determine whether B cell depletion therapy would attenuate the development of cardiac allograft vasculopathy.

Methods: A total of 163 HTX recipients were randomized to rituximab 1,000 mg intravenous or placebo on days 0 and 12 post-transplant.

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups.

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism.

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population.

Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation.

Genetic Variants Associated With Immunosuppressant Pharmacokinetics and Adverse Effects in the DeKAF Genomics Genome-wide Association Studies.

Background: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.

Methods: We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.

Analysis of 75 Candidate SNPs Associated With Acute Rejection in Kidney Transplant Recipients: Validation of rs2910164 in MicroRNA MIR146A.

Background: Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR.

Early immune biomarkers and intermediate-term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation-18.

Clinical Trials in Organ Transplantation-18 (CTOT-18) is a follow-up analysis of the 200-subject multicenter heart transplant CTOT-05 cohort. CTOT-18 aimed to identify clinical, epidemiologic, and biologic markers associated with adverse clinical events past 1 year posttransplantation. We examined various candidate biomarkers including serum antibodies, angiogenic proteins, blood gene expression profiles, and T cell alloreactivity.

Evidence of Chronic Allograft Injury in Liver Biopsies From Long-term Pediatric Recipients of Liver Transplants.

Background & Aims: A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic features and identified associated immunologic profiles.

Methods: We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.

Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant.

Noninvasive biomarkers are needed to monitor stable patients after kidney transplant (KT), because subclinical acute rejection (subAR), currently detectable only with surveillance biopsies, can lead to chronic rejection and graft loss. We conducted a multicenter study to develop a blood-based molecular biomarker for subAR using peripheral blood paired with surveillance biopsies and strict clinical phenotyping algorithms for discovery and validation. At a predefined threshold, 72% to 75% of KT recipients achieved a negative biomarker test correlating with the absence of subAR (negative predictive value: 78%-88%), while a positive test was obtained in 25% to 28% correlating with the presence of subAR (positive predictive value: 47%-61%).

Pediatric heart transplantation across a positive crossmatch: First year results from the CTOTC-04 multi-institutional study.

Sensitization is common in pediatric heart transplant candidates and waitlist mortality is high. Transplantation across a positive crossmatch may reduce wait time, but is considered high risk. We prospectively recruited consecutive candidates at eight North American centers.

Study rationale, design, and pretransplantation alloantibody status: A first report of Clinical Trials in Organ Transplantation in Children-04 (CTOTC-04) in pediatric heart transplantation.

Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality.

Incidence, characterization, and impact of newly detected donor-specific anti-HLA antibody in the first year after pediatric heart transplantation: A report from the CTOTC-04 study.

Data on the clinical importance of newly detected donor-specific anti-HLA antibodies (ndDSAs) after pediatric heart transplantation are lacking despite mounting evidence of the detrimental effect of de novo DSAs in solid organ transplantation. We prospectively tested 237 pediatric heart transplant recipients for ndDSAs in the first year posttransplantation to determine their incidence, pattern, and clinical impact. One-third of patients developed ndDSAs; when present, these were mostly detected within the first 6 weeks after transplantation, suggesting that memory responses may predominate over true de novo DSA production in this population.

Epstein-Barr viral loads do not predict post-transplant lymphoproliferative disorder in pediatric lung transplant recipients: A multicenter prospective cohort study.

Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation.

Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept.

The intent of this National Institutes of Health-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein-Barr virus-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil.

Discrepant serological assays for Pneumococcus in renal transplant recipients - a prospective study.

Vaccine immunoprotection for Streptococcus pneumoniae is mediated by opsonizing antibodies targeting serotype-specific capsular polysaccharides. Quantitative antibody levels enzyme-linked immunosorbent assay (ELISA) and antibody-mediated opsonophagocytic assays (OPA) measure vaccine-induced protection; correlation of these assays in transplantation requires investigation. This study examines the laboratory assessment of antibody titers in vaccinated renal recipients.

Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients.

Background: Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV.

Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R.

Unlabelled: Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments.

Perceived barriers to medication adherence in pediatric and adolescent solid organ transplantation.

Comparisons of perceived barriers to adherence in pediatric and adolescent SOT have not been systematically conducted despite association between medication non-adherence and poor outcome. Fifteen centers in CTOT-C enrolled patients in a cross-sectional study. Subjects' guardians completed the PMBS and subjects over eight completed the Adolescent Scale (AMBS).

Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type.

Objective: To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response.

Methods: Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper.