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Purpose: Evaluate cytomegalovirus (CMV) post-prophylaxis surveillance in high-risk (D+/R-) kidney and liver transplant recipients., Methods: Adult D+/R- patients were included if transplanted between 6/1/15 and 11/30/22 and divided into a pre-CMV-stewardship-era (6/1/15-5/31/18), CMV-stewardship-era (6/1/18-6/30/20), and a surveillance-era (7/1/2020-11/30/2022) then followed through 12 months. The primary objective was to evaluate CMV-related outcomes. The secondary objective was to assess graft and patient survival by era., Results: There were 328 patients in the study period; 133 in the pre-stewardship-era, 103 in the stewardship-era, and 92 in the surveillance-era. Replication rates in the surveillance-era were significantly higher, as anticipated due to increased sampling (pre 38.4%, stewardship 33.0%, surveillance 52.2%, p = 0.02). Time from transplant to first replication was similar (pre 214.0 ± 79.0 days, stewardship 231.1 ± 65.5, surveillance 234.9 ± 61.4, p = 0.29). CMV viral load (VL) at first detection, maximum-VL, and incidence of VL > 100 000 IU/mL were numerically lower in the surveillance era, although not statistically significant. CMV end-organ disease (p < 0.0001) and ganciclovir-resistance (p = 0.002) were significantly lower in the surveillance era than in both previous eras. Rejection was not different between eras (p = 0.4). Graft (p = 0.0007) and patient survival (p = 0.008) were significantly improved in the surveillance era., Conclusions: Post-prophylaxis surveillance significantly reduced CMV end-organ disease and resistance. Despite observing increased replication rates in the surveillance era, rejection was not significantly different and there was no graft loss or patient mortality at 12 months., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Tocilizumab prevents the clinical worsening of chronic active antibody-mediated rejection (CAAMR) in kidney transplant recipients. Following a global shortage of the intravenous pharmaceutical form in 2022, patients were switched from monthly intravenous administration of 8 mg/kg to weekly subcutaneous injection of 162 mg, raising the question of bioequivalence between these schemes of administration., Aims: We aimed to compare the areas under the curve (AUC) of tocilizumab in virtual simulations of populations treated with the two administration schemes and to identify the covariates that could contribute to pharmacokinetic variability of tocilizumab in kidney transplant patients with CAAMR who received tocilizumab as salvage treatment., Methods: This retrospective monocentric study included 43 kidney transplant patients (202 tocilizumab concentrations) with CAAMR treated with intravenous or subcutaneous tocilizumab between December 2020 and January 2023. We developed a population pharmacokinetic model using nonlinear mixed effects modeling and identified the covariates that could contribute to tocilizumab AUC variability. Monte Carlo simulations were then performed to assess the subcutaneous and intravenous tocilizumab AUC for 0-28 days (M1), 56-84 days (M3), 140-168 days (M6), and 308-336 days (M12). Bioequivalence was defined by SC/IV AUC geometric mean ratios (GMRs) between 0.80 and 1.25., Results: A two-compartment model with parallel linear and nonlinear elimination best described the concentration-time data. Significant covariates for tocilizumab clearance were body weight, urinary albumin-to-creatinine ratio (ACR), and inflammation status [C-reactive protein (CRP) ≥ 5 mg/L]. The GMR values and their 90% confidence intervals at M3, M6, and M12 were within the 0.8-1.25 margin for equivalence. Conversely, the 90% prediction intervals of the GMR were much wider than the 90% confidence intervals and did not fall within 0.8 and 1.25., Conclusions: From month 3 of treatment, the subcutaneous and intravenous tocilizumab administration schemes provided average bioequivalent pharmacokinetic exposure at the population level but not at the individual level. Body weight, inflammation, ACR, and administration scheme should be considered to personalize the dose of tocilizumab for patients with CAAMR. Further studies are required to determine the target of tocilizumab exposure in kidney transplant patients with CAAMR., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression., Methods: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation., Results: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17)., Conclusions: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Despite advancements in short-term outcomes since the inception of intestinal transplant, significant long-term graft failure persists. Early successes are attributed to the utilization of tacrolimus for maintenance therapy, coupled with T-cell modulating induction regimens, which effectively reduce the incidence of acute cellular rejection. However, the challenge of chronic allograft injury remains unresolved. There is increasing evidence indicating a correlation between donor-specific antibodies and the survival of visceral allografts. Strategies aimed at reducing the presence or load of these antibodies may potentially enhance long-term outcomes. Consequently, our focus is now turning toward B-cell induction therapies as a possible solution., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this review, the authors outlined concepts and strategies to achieve immune tolerance through inducing hematopoietic chimerism after solid organ transplantation and introduced challenges and opportunities in harnessing two-way alloresponses to improve outcomes after intestinal transplantation (ITx). Next, the authors discussed the dynamics and phenotypes of peripheral blood and intestinal graft T-cell subset chimerism and their association with outcomes. The authors also summarized studies on other types of immune cells after ITx and their potential participation in chimerism-mediated tolerance. The authors further discussed strategies and future directions to promote chimerism-associated tolerance after ITx to overcome rejection and minimize immunosuppression., Competing Interests: Disclosure JF served as a Scientific Consultant for Adaptive Biotechnologies Corp. from June 2022 to May 2023. J.F. is a co-investigator for a research grant provided by Ossium Heath Inc. and a co-inventor for a patent issued to Ossium Heath Inc. and the Trustees of Columbia University in the City of New York. KC and KDL have no conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The history of intestinal transplantation can be traced back to the turn of the twentieth century. Although advancements have been made, the intestine still presents a greater challenge to transplantation than does that of other solid organs, experiencing higher rates of graft rejection and lower long-term survival. Increasingly, intestinal re-transplantation (re-ITx) is seen as a viable option and is now the fourth most common indication for ITx. Changes to immunosuppression protocols, technical modifications, and infectious disease monitoring have contributed to improved outcomes. The authors review the literature on re-ITx in regard to the history, management considerations, and future directions., Competing Interests: Disclosure The authors declare that they have no relevant or material financial interests that relate to the research described in this paper., (Published by Elsevier Inc.)

Outcomes in intestinal transplantation remain hampered by higher rates of rejection than any other solid organs. However, maintenance immunosuppression regimens have largely remained unchanged despite advances in therapies for induction and treatment of rejection and graft-versus-host disease. Recently, there have been a small number of new maintenance therapies attempted, and older agents have been used in new ways to achieve better outcomes. The authors herein review the traditional maintenance therapies and their mechanisms and then consider updates in new therapies and new ways of using old therapies for maintenance immunosuppression after intestinal transplantation., Competing Interests: Disclosure The authors declare no commercial or financial conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

For patients with intestinal failure, small bowel transplantation remains one of the most effective treatments despite continuous advancements in parenteral nutrition techniques. Long-term use of parenteral nutrition can result in serious complications that lead to metabolic dysfunction and organ failure. However, the small intestine is a highly immunogenic organ with a large amount of mucosa-associated lymphoid tissue and histocompatibility antigens; therefore, the small intestine is highly susceptible to severe immune rejection. This article discusses the mechanisms underlying immune rejection after small bowel transplantation and presents various options for prevention and treatment. Our findings offer new insights into the development of small bowel transplantation., (Copyright © 2024 Asian Surgical Association and Taiwan Society of Coloproctology. Published by Elsevier B.V. All rights reserved.)

Transplantation is the ideal therapy for end-stage organ failure, but outcomes for all transplant organs are suboptimal, underscoring the need to develop novel approaches to improve graft survival and function. The complement system, traditionally considered a component of innate immunity, is now known to broadly control inflammation and crucially contribute to induction and function of adaptive T-cell and B-cell immune responses, including those induced by alloantigens. Interest of pharmaceutical industries in complement therapeutics for nontransplant indications and the understanding that the complement system contributes to solid organ transplantation injury through multiple mechanisms raise the possibility that targeting specific complement components could improve transplant outcomes and patient health. Here, we provide an overview of complement biology and review the roles and mechanisms through which the complement system is pathogenically linked to solid organ transplant injury. We then discuss how this knowledge has been translated into novel therapeutic strategies to improve organ transplant outcomes and identify areas for future investigation. Although the clinical application of complement-targeted therapies in transplantation remains in its infancy, the increasing availability of new agents in this arena provides a rich environment for potentially transformative translational transplant research., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

There is no recent update on the clinical course of retransplantation (re-LT) after living donor liver transplantation (LDLT) in the US using recent national data. The UNOS database (2002-2023) was used to explore patient characteristics in initial LT, comparing deceased donor liver transplantation (DDLT) and LDLT for graft survival (GS), reasons for graft failure, and GS after re-LT. It assesses waitlist dropout and re-LT likelihood, categorizing re-LT cohort based on time to re-listing as acute or chronic (≤ or > 1 mo). Of 132,323 DDLT and 5955 LDLT initial transplants, 3848 DDLT and 302 LDLT recipients underwent re-LT. Of the 302 re-LT following LDLT, 156 were acute and 146 chronic. Primary nonfunction (PNF) was more common in DDLT, although the difference was not statistically significant (17.4% vs. 14.8% for LDLT; p = 0.52). Vascular complications were significantly higher in LDLT (12.5% vs. 8.3% for DDLT; p < 0.01). Acute re-LT showed a larger difference in primary nonfunction between DDLT and LDLT (49.7% vs. 32.0%; p < 0.01). Status 1 patients were more common in DDLT (51.3% vs. 34.0% in LDLT; p < 0.01). In the acute cohort, Kaplan-Meier curves indicated superior GS after re-LT for initial LDLT recipients in both short-term and long-term ( p = 0.02 and < 0.01, respectively), with no significant difference in the chronic cohort. No significant differences in waitlist dropout were observed, but the initial LDLT group had a higher re-LT likelihood in the acute cohort (sHR 1.40, p < 0.01). A sensitivity analysis focusing on the most recent 10-year cohort revealed trends consistent with the overall study findings. LDLT recipients had better GS in re-LT than DDLT. Despite a higher severity of illness, the DDLT cohort was less likely to undergo re-LT., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Pediatric valvar heart disease continues to be a topic of interest due to the common and severe clinical manifestations. Problems with heart valve replacement, including lack of adaptive valve growth and accelerated structural valve degeneration, mandate morbid reoperations to serially replace valve implants. Homologous or homograft heart valves are a compelling option for valve replacement in the pediatric population but are susceptible to structural valve degeneration. The immunogenicity of homologous heart valves is not fully understood, and mechanisms explaining how implanted heart valves are attacked are unclear. It has been demonstrated that preservation methods determine homograft cell viability and there may be a direct correlation between increased cellular viability and a higher immune response. This consists of an early increase in human leukocyte antigen (HLA)-class I and II antibodies over days to months posthomograft implantation, followed by the sustained increase in HLA-class II antibodies for years after implantation. Cytotoxic T lymphocytes and T-helper lymphocytes specific to both HLA classes can infiltrate tissue almost immediately after implantation. Furthermore, increased HLA-class II mismatches result in an increased cell-mediated response and an accelerated rate of structural valve degeneration especially in younger patients. Further long-term clinical studies should be completed investigating the immunological mechanisms of heart valve rejection and their relation to structural valve degeneration as well as testing of immunosuppressant therapies to determine the needed immunosuppression for homologous heart valve implantation., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response. Microbiome-mediated effects are referred to as drug-microbiome interactions (DMI). Rapid advances in the field of pharmacomicrobiomics have been driven by the availability of efficient bacterial genome sequencing methods and new computational and bioinformatics tools. The success of fecal microbiota transplantation for recurrent Clostridioides difficile has fueled enthusiasm and research in the field. This review focuses on the pharmacomicrobiome in transplantation. Alterations in the microbiome in transplant recipients are well documented, largely because of prophylactic antibiotic use, and the potential for DMI is high. There is evidence that the gut microbiome may alter the pharmacokinetic disposition of tacrolimus and result in microbiome-specific tacrolimus metabolites. The gut microbiome also impacts the enterohepatic recirculation of mycophenolate, resulting in substantial changes in pharmacokinetic disposition and systemic exposure. The mechanisms of these DMI and the specific bacteria or communities of bacteria are under investigation. There are little or no human DMI data for cyclosporine A, corticosteroids, and sirolimus. The available evidence in transplantation is limited and driven by small studies of heterogeneous designs. Larger clinical studies are needed, but the potential for future clinical application of the pharmacomicrobiome in avoiding poor outcomes is high., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no funding or conflicts of interest.

Objective: To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs)., Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant , and AMR ., Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered., Data Synthesis: Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described., Relevance to Patient Care and Clinical Practice: Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function., Conclusions: Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

On June 6, 2022, the FDA expanded the indications for mycophenolate mofetil (MMF) to include the prophylaxis of organ rejection in combination with other immunosuppressants in pediatric recipients of allogeneic heart or liver transplants aged 3 months and older. The approved oral dosing regimen for these patients was a starting dose of 600 mg/m 2 with titration up to a maximum of 900 mg/m 2 twice daily. Data to support efficacy in pediatric patients were derived from established pharmacokinetic (PK) relationships across approved populations, a PK study in pediatric liver transplant recipients, and information from the Scientific Registry of Transplant Recipients database. Information supporting safety was based on comparing mycophenolic acid (MPA) exposure with that in pediatric kidney transplant recipients, the published literature, and post-marketing safety reports. Efficacy in pediatric patients was established based on extrapolation of efficacy from studies in adult liver, adult heart, and pediatric kidney transplant populations, and similarity in MPA exposure between pediatric and adult patients. Review of the data supported an oral dosing regimen for pediatric heart transplant and liver transplant recipients consisting of a starting dose of 600 mg/m 2 up to a maximum of 900 mg/m 2 b.i.d. A dosage range for MMF is recommended recognizing that the MMF dose may be modified in clinical practice for myriad factors. The dosage recommendations in the labeling for pediatric liver and pediatric heart transplant patients are intended to permit individualized dosing based on clinical assessment of these factors., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Tacrolimus (TAC) has high pharmacokinetic (PK) variability during the early transplantation period. The relationships between whole-blood and intracellular TAC concentrations and clinical outcomes remain controversial. This study identifies the factors affecting the PK variability of TAC and characterizes the relationships between whole-blood and intracellular TAC concentrations. Data regarding whole-blood TAC concentrations of 1,787 samples from 215 renal transplant recipients (<90 days postoperative) across two centers and intracellular TAC concentrations (648 samples) digitized from previous studies were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were screened, and the distribution of whole-blood to intracellular TAC concentration ratios (R WB:IC ) was estimated. The final model was evaluated using bootstrap, goodness of fit, and prediction-corrected visual predictive checks. The optimal dosing regimens and target ranges for each type of immune cell subsets were determined using Monte Carlo simulations. A two-compartment model adequately described the data, and the estimated mean TAC CL/F was 23.6 L·h -1 (relative standard error: 11.5 %). The hematocrit level, CYP3A5*3 carrier status, co-administration with Wuzhi capsules, and tapering prednisolone dose may contribute to the high variability of TAC PK variability during the early post-transplant period. The estimated R WB:IC of all TAC concentrations in peripheral blood mononuclear cells (PBMCs) was 4940, and inter-center variability of PBMCs was observed. The simulated TAC target range in PBMCs was 20.2-85.9 pg·million cells -1 . Inter-center variability in intracellular concentrations should be taken into account in further analyses. TAC dosage adjustments can be guided based on PK/PD variability and simulated intracellular concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed in hematopoietic stem cells and dendritic cells (DCs). While FLT3 plays a critical role in the proliferation, development and maintenance of DCs, thus influencing immune responses under both normal and pathological conditions, there also exists some evidence that FLT3 + DC may be involved with immune responses in liver transplantation (LT). In this study, results from single-cell sequencing data analysis revealed a clear relationship between FLT3 + DCs and Regulatory T cells (Tregs) in liver tissue of LT recipients. In peripheral blood samples of LT patients, levels of FLT3 + DCs were decreased post-LT-surgery, while Tregs were increased. In a LT mouse model, levels of FLT3 + DCs in the liver and bone marrow exhibited an initial time-dependent decrease followed by an increase after LT surgery. Results as obtained with co-culture experiments using mature BMDCs and CD4 + T cells revealed fluctuations in Tregs in response to FLT3 inhibitors and the FLT3 ligand. These findings suggest that FLT3 + DCs could emerge as a novel target for mitigating immune rejection in LT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS., Methods: We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18-70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing., Findings: A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32-0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20-0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34-0·92)., Interpretation: Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE., Funding: XVIVO Perfusion., Competing Interests: Declaration of interests The sponsor provided the investigational devices and financial support for trial-specific investigational site costs to all participating centres. FR reports institutional research grants from XVIVO outside of the submitted work and receiving speakers fees from Atricure. GL reports receiving study materials from XVIVO as investigator in another clinical trial. SM reports research grants from German Center for Lung Research and German Research Foundation and honoraria from Berlin Heart. GD reports research grants from Astellas and Abbot and being a programme chair for ISHLT and a board member of XVIVO. AW is employed by the trial sponsor and may retain stock or stock options. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The transplantation of organ(s) across species may alleviate the shortage of available donor kidneys for an ever-growing number of patients on transplant waiting lists. However, this potential remains limited by uncharacterized physiologic and immune effects of xenotransplants in recipients, which Pan et al. 1 investigated in the current study., Competing Interests: Declaration of interests A.K.I. has served on an advisory board for Avera Pharmaceuticals and Novartis, receives consulting fees from the Medical Review Institute of America, and has family members that are employees of Novartis pharmaceutical company, all of which are unrelated to this work., (Copyright © 2024. Published by Elsevier Inc.)

Renal transplantation is a life-saving treatment for patients with end-stage renal disease. However, the challenge of transplant rejection and the complications associated with immunosuppressants necessitates a deeper understanding of the underlying immune mechanisms. T cell exhaustion, a state characterized by impaired effector functions and sustained expression of inhibitory receptors, plays a dual role in renal transplantation. While moderate T cell exhaustion can aid in graft acceptance by regulating alloreactive T cell responses, excessive exhaustion may impair the recipient's ability to control viral infections and tumors, posing significant health risks. Moreover, drugs targeting T cell exhaustion to promote graft tolerance and using immune checkpoint inhibitors for cancer treatment in transplant recipients are areas deserving of further attention and research. This review aims to provide a comprehensive understanding of the changes in T cell exhaustion levels after renal transplantation and their implications for graft survival and patient outcomes. We discuss the molecular mechanisms underlying T cell exhaustion, the role of specific exhaustion markers, the potential impact of immunosuppressive therapies, and the pharmaceutical intervention on T cell exhaustion levels. Additionally, we demonstrate the potential to modulate T cell exhaustion favorably, enhancing graft survival. Future research should focus on the distinctions of T cell exhaustion across different immune states and subsets, as well as the interactions between exhausted T cells and other immune cells. Understanding these dynamics is crucial for optimizing transplant outcomes and ensuring long-term graft survival while maintaining immune competence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Zhang, Zhong and Wei.)

Introduction: Angiotensin II (ATII) maintains blood pressure via RAAS with a beneficial adverse effect profile versus catecholamines and phenylephrine. Head-to-head data comparing ATII to phenylephrine are lacking regarding renal allograft function, hemodynamic efficacy, and safety within the perioperative period of kidney transplantation., Methods: This single-center, retrospective study included adult kidney transplant recipients who received continuous infusions of ATII or phenylephrine within a 24-h perioperative period as a first-line vasopressor according to an institutional algorithm. The primary endpoint was allograft function. Secondary endpoints were hemodynamic efficacy and adverse effects., Results: Among 105 patients, there was no significant difference in IGF (p = 0.545), SGF (p = 0.557), or DGF (p = 0.878) between patient cohorts. In the 34 patients with cold ischemia time (CIT) > 14-h, IGF was higher (p = 0.013) and DGF (p = 0.045) was lower in the ATII cohort versus phenylephrine. In all patients, ATII was associated with a decreased need for additional vasopressor agents (p < 0.001). Adverse effect profiles were similar between cohorts (p > 0.05)., Conclusion: Among kidney transplant recipients, ATII may be a suitable first-line alternative compared with phenylephrine in the perioperative period for hypotension management with a reduced need for additional vasopressor support. Allograft benefits were observed in patients with prolonged CIT., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Introduction: Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations., Methods: A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed., Results: Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion., Conclusion: Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation., Methods: We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays., Results: High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR., Conclusions: Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Organ transplantation is the preferred paradigm for patients with end-stage organ failures. Despite unprecedented successes, complications such as immune rejection, ischemia-reperfusion injury, and graft dysfunction remain significant barriers to long-term recipient survival after transplantation. Conventional immunosuppressive drugs have limited efficacy because of significant drug toxicities, high systemic immune burden, and emergence of transplant infectious disease, leading to poor quality of life for patients. Nanoparticle-based drug delivery has emerged as a promising medical technology and offers several advantages by enhancing the delivery of drug payloads to their target sites, reducing systemic toxicity, and facilitating patient compliance over free drug administration. In addition, nanotechnology-based imaging approaches provide exciting diagnostic methods for monitoring molecular and cellular changes in transplanted organs, visualizing immune responses, and assessing the severity of rejection. These noninvasive technologies are expected to help enhance the posttransplantation patient survival through real time and early diagnosis of disease progression. Here, we present a comprehensive review of nanotechnology-assisted strategies in various aspects of organ transplantation, including organ protection before transplantation, mitigation of ischemia-reperfusion injury, counteraction of immune rejection, early detection of organ dysfunction posttransplantation, and molecular imaging and diagnosis of immune rejection., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Exposure to HLA alloantigens through pregnancy, blood products, and previous transplantations induce powerful immunologic responses that create an immunologic barrier to successful transplantation. This is commonly detected through screening for HLA antibodies using Luminex beads coated with HLA antigens at transplant evaluation. Currently accepted approaches to desensitization include plasmapheresis/low-dose or high-dose intravenous Ig plus anti-CD20. However, these approaches are often unsuccessful because of the inability to remove high titer circulating HLA antibodies and limit rebound responses by long-lived anti-HLA antibody secreting plasma cells (PCs) and memory B cells (B MEM ). This is especially significant for patients with a calculated panel reactive antibody of 99%-100%. Newer desensitization approaches, such as imlifidase (IgG endopeptidase), rapidly inactivate IgG molecules and create an antibody-free zone by cleaving IgG into F(ab'2) and Fc fragments, thus eliminating complement and cell-mediated injury to the graft. This represents an important advancement in desensitization. However, the efficacy of imlifidase is limited by pathogenic antibody rebound, increasing the potential for antibody-mediated rejection. Controlling antibody rebound requires new strategies that address the issues of antibody depletion and inhibition of B MEM and PC responses. This will likely require a combination of agents that effectively and rapidly deplete pathogenic antibodies and prevent immune cell activation pathways responsible for antibody rebound. Here, using anti-IL-6 receptor (tocilizumab) or anti-IL-6 (clazakizumab) could offer long-term control of B MEM and PC donor-specific HLA antibody responses. Agents aimed at eliminating long-lived PCs (anti-CD38 and anti-B-cell maturation antigen×CD3) are likely to benefit highly HLA sensitized patients. Complement inhibitors and novel agents aimed at inhibiting Fc neonatal receptor IgG recycling will be important in desensitization. Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly HLA sensitized patients., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Purpose: Currently 80% of lung transplant centers use induction immunosuppression. However, there is a lack of standardization of induction protocols within and across lung transplant centers. This study explores the association of two different induction immunosuppression strategies used at our center [single dose rabbit antithymocyte globulin (rATG) vs. alemtuzumab] compared to no induction with immunologic and clinical outcomes after lung transplantation., Methods: A total of 174 consecutive lung transplant recipients (LTR) between 2016 and 2019 were included in the analysis. Twenty nine LTR (16.7%) received no induction, 22 LTR (12.6%) received alemtuzumab, 123 LTR (70.6%) received a single dose of rATG; 1.5 mg/kg within 24 h of transplant for induction. All LTR had a negative flow cytometry crossmatch on the day of the transplant. All LTR were assessed for de novo HLA donor-specific antibodies (DSA) development and clinical outcomes, including the risk of acute cellular rejection (ACR), antibody-mediated rejection (AMR), chronic lung allograft dysfunction (CLAD), and overall survival post-transplant., Results: The median lung allocation score (LAS) was significantly higher in LTR that did not receive Induction immunosuppression (76; range = 35.3-94.3) compared to induction with rATG (41.6; range = 31.6-91) and alemtuzumab (51; range = 33.1-88.2) (p < 0.001). De novo HLA DSA were detected in 50/174 (28.7%) LTR within 12 months post-transplant. They were detected in 13/29 (44.8%) LTR without induction immunosuppression compared to 28/123 (22.8%) and 9/22 (40.9%) LTR with rATG and alemtuzumab induction, respectively (p = 0.02). The percent freedom from ACR rates between LTR who received alemtuzumab induction was significantly higher compared to LTR who received rATG or no induction at 1 (p = 0.02), 2 (p = 0.01) and 3 (p = 0.05) years post-transplant. In addition, the overall 1-year survival rates were significantly higher in LTR who received rATG or alemtuzumab induction compared to LTR without induction immunosuppression (p = 0.02)., Conclusion: Induction immunosuppression strategies utilizing rATG or Alemtuzumab have unique and contrasting benefits in LTR. Combination of alemtuzumab induction and a lower dose of maintenance immunosuppression may reduce the incidence of ACR in LTR. Single-dose rATG or alemtuzumab induction immunosuppression may also improve the 1 year overall LTR survival compared to no induction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heart transplantation offers life-saving treatment for patients with end-stage heart failure; however, ischemia-reperfusion injury (IRI) and subsequent immune responses remain significant challenges. Current therapies primarily target adaptive immunity, with limited options available for addressing IRI and innate immune activation. Although plant-derived vesicle-like nanoparticles show promise in managing diseases, their application in organ transplantation complications is unexplored. Here, this work develops a novel reactive oxygen species (ROS)-responsive multifunctional fusion extracellular nanovesicles carrying rapamycin (FNVs@RAPA) to address early IRI and Ly6C + Ly6G - inflammatory macrophage-mediated rejection in heart transplantation. The FNVs comprise Exocarpium Citri grandis-derived extracellular nanovesicles with anti-inflammatory and antioxidant properties, and mesenchymal stem cell membrane-derived nanovesicles expressing calreticulin with macrophage-targeting ability. A novel ROS-responsive bio-orthogonal chemistry approach facilitates the active targeting delivery of FNVs@RAPA to the heart graft site, effectively alleviating IRI and promoting the polarization of Ly6C + Ly6G - inflammatory macrophages toward an anti-inflammatory phenotype. Hence, FNVs@RAPA represents a promising therapeutic approach for mitigating early transplantation complications and immune rejection. The fusion-targeted delivery strategy offers superior heart graft site enrichment and macrophage-specific targeting, promising improved transplant outcomes., (© 2024 Wiley‐VCH GmbH.)

Several reports have highlighted the dichotomous nature of the Interleukin-33 (IL-33) system in cardiac and lung disease, where this cytokine can exert both protective effects and drive pro-inflammatory responses in a context-specific manner. This State-of-the-Art review focuses on preclinical mechanistic studies of the IL-33 system in development of allograft rejection in heart and lung transplantation. We address the scope of potential cellular sources of IL-33 and pathways for cellular release that may impact the study of this cytokine system in transplant models. We then highlight soluble IL-33 receptor as a biomarker in cardiac allograft rejection and detail preclinical models that collectively demonstrate a role for this cytokine in driving type-2 immune programs to protect cardiac allografts. We contrast this with investigation of IL-33 in lung transplantation, which has yielded mixed and somewhat conflicting results when comparing human studies with preclinical models, which have implicated the IL-33 system in both allograft tolerance and acceleration of chronic rejection. We summarize and interpret these results in aggregate and provide future directions for study of IL-33 in heart and lung transplantation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19-49], 13 females) were transplanted. Median follow-up was 46.0 months (IQR 21.8-57.9). One-year overall survival and event-free survival (graft failure or death) were both 95% (95% confidence interval 86-100). Mean donor myeloid and T-cell chimerism 1-year post-transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid-responsive grade II intestinal acute graft-versus-host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event-free survival and robust donor T-cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The clinical impact of individual dose adjustment of mycophenolate mofetil is still debated, due to conflicting results from randomized clinical trials. This retrospective study aimed to compare 3-year rejection-free survival and adverse effects between adult kidney transplant recipients (KTRs) with or without mycophenolate mofetil model-informed precision dosing (MIPD). MIPD is defined here as mycophenolic acid area under the curve (AUC 0-12h ) estimation using a limited sampling strategy, pharmacokinetic models and Bayesian estimators; dose recommendation to reach AUC 0-12h  = 45 mg.h/L; using a widely used online expert system. The study, nested in two multicenter prospective cohort studies, focused on patients who received a mycophenolate drug and were followed up for 1-3 years. Mycophenolate mofetil MIPD was prescribed as per local practice, on a regular basis, when deemed necessary, or not at all. The MIPD group included 341 KTRs and the control group 392. At 3 years, rejection-free survival was respectively 91.2% and 80.6% (P < 0.001) and the cumulative incidence of rejection 5.08% vs. 12.7% per patient × year (hazard ratio = 0.49 (0.34, 0.71), P < 0.001), corresponding to a 2.5-fold reduction. Significant association with rejection-free survival was confirmed in patients at low or high risk of rejection (P = 0.017 and 0.013) and in patients on tacrolimus, but not on cyclosporine (P < 0.001 and 0.205). The mycophenolate mofetil MIPD group had significantly more adverse effects, but most occurred before the first AUC 0-12h , suggesting some may be the reason why MIPD was ordered., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The self-administered Kidney AlloTransplant Immunosuppressive Therapy Adherence (KATITA-25) questionnaire is a multidimensional scale for use in the pretransplant setting that evaluates the predisposition to nonadherence of patients who are candidates to kidney transplant. The scale has shown adequate internal consistency and test-retest reliability. This study presents the results of an external validation study of the KATITA-25 scale., Methods: Patients >18 y old scheduled for kidney transplant were included in this multicenter study. The KATITA-25 scale was administered before surgery and then at 3-mo posttransplantation for evaluation of scale sensitivity to change. At this time, 2 validated medication adherence scales were applied for assessment of concurrent validity. For evaluation of predictive validity, nonadherence to immunosuppressive medication was assessed at 6 and 12 mo after transplantation by 3 independent methods: patient self-report of nonadherence using the Morisky-Green-Levine Medication Assessment Questionnaire scale, serum trough levels of immunosuppressants, and pharmacy refills., Results: Three twenty-two patients were available for evaluation of concurrent validity and 311 patients of predictive validity. After kidney transplant, the median KATITA-25 score decreased from 20 to 8 ( P  < 0.001), demonstrating scale sensitivity to change, and the KATITA-25 score showed correlation with the Basel Assessment of Adherence to Immunosuppressive Medication Scale score (Spearman's ρ 0.18, P  = 0.002) and the Cuestionario para la Evaluación de la Adhesión al Tratamiento Antiretroviral scores (ρ -0.17, P  = 0.002), confirming concurrent validity. The nonadherence rate was 57.6%. The scale predictive validity was demonstrated by the area under the receiver operating characteristics curve (0.68), sensitivity (59.8%), specificity (68.2%), and positive predictive value (71.8%)., Conclusions: This external validation study of KATITA-25 scale provided evidence of sensitivity to change, and structural, criterion, and predictive validity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Type 1 diabetes mellitus (T1DM) is characterized by absolute insulin deficiency primarily due to autoimmune destruction of pancreatic β-cells. The prevailing treatment for T1DM involves daily subcutaneous insulin injections, but a substantial proportion of patients face challenges such as severe hypoglycemic episodes and poorly controlled hyperglycemia. For T1DM patients, a more effective therapeutic option involves the replacement of β-cells through allogeneic transplantation of either the entire pancreas or isolated pancreatic islets. Unfortunately, the scarcity of transplantable human organs has led to a growing list of patients waiting for an islet transplant. One potential alternative is xenotransplantation of porcine pancreatic islets. However, due to inter-species molecular incompatibilities, porcine tissues trigger a robust immune response in humans, leading to xenograft rejection. Several promising strategies aim to overcome this challenge and enhance the long-term survival and functionality of xenogeneic islet grafts. These strategies include the use of islets derived from genetically modified pigs, immunoisolation of islets by encapsulation in biocompatible materials, and the creation of an immunomodulatory microenvironment by co-transplanting islets with accessory cells or utilizing immunomodulatory biomaterials. This review concentrates on delineating the primary obstacles in islet xenotransplantation and elucidates the fundamental principles and recent breakthroughs aimed at addressing these challenges., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Graft survival is a critical end point in adult-to-adult living donor liver transplantation (ALDLT), where graft procurement endangers the lives of healthy individuals. Therefore, ALDLT must be responsibly performed in the perspective of a positive harm-to-benefit ratio. This study aimed to develop a risk prediction model for early (3 months) graft failure (EGF) following ALDLT. Donor and recipient factors associated with EGF in ALDLT were studied using data from the European Liver Transplant Registry. An artificial neural network classification algorithm was trained on a set of 2073 ALDLTs, validated using cross-validation, tested on an independent random-split sample (n=518), and externally validated on United Network for Organ Sharing Standard Transplant Analysis and Research data. Model performance was assessed using the AUC, calibration plots, and decision curve analysis. Graft type, graft weight, level of hospitalization, and the severity of liver disease were associated with EGF. The model ( http://ldlt.shinyapps.io/eltr&#95;app ) presented AUC values at cross-validation, in the independent test set, and at external validation of 0.69, 0.70, and 0.68, respectively. Model calibration was fair. The decision curve analysis indicated a positive net benefit of the model, with an estimated net reduction of 5-15 EGF per 100 ALDLTs. Estimated risks>40% and<5% had a specificity of 0.96 and sensitivity of 0.99 in predicting and excluding EGF, respectively. The model also stratified long-term graft survival ( p <0.001), which ranged from 87% in the low-risk group to 60% in the high-risk group. In conclusion, based on a panel of donor and recipient variables, an artificial neural network can contribute to decision-making in ALDLT by predicting EGF risk., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Donor blood transfusion may potentially affect transplant outcomes through an inflammatory response, recipient sensitization, or transmission of infection. The aim of this study was to evaluate the association of donor blood transfusion with outcomes of liver transplantation (LT)., Methods: From January 2004 to December 2022, donor blood transfusion information was available for 113,017 adult recipients of LT in the United Network for Organ Sharing database and was classified into 4 levels of transfusion: no-transfusion (N = 68,130), transfusion of 1-5 units (N = 33,629), 6-10 units (N = 8067), and >10 units (N = 5329). Recipient survival analysis was performed by Kaplan-Meier method and multivariable Cox-hazard model., Results: Among this cohort, 40.8% of donors (N = 46,261) received blood transfusion during the index hospitalization. Compared to no-blood transfusion donors, blood transfusion donors were younger (median age 37 versus 46 y P < 0.001) and were more brain death donors (94.5% versus 92.1%, P < 0.001). An increased risk of rejection at 6-mo (transfusion 10.3% versus no-transfusion 9.9%, P = 0.055) and 1 y (transfusion 12.5% versus no-transfusion 11.9%, P = 0.0036) post-LT was noted in this cohort. Multivariable Cox-hazard model showed blood transfusion was associated with increased 1-y mortality (transfusion 1.07; 95% CI 1.02-1.12, P = 0.007) and graft failure (transfusion 1.09; 95% CI 1.04-1.13, P < 0.001)., Conclusions: Donor blood transfusion was associated with an increased risk of rejection at 6 mo and 1 y among LT recipients and worse post-transplant graft and overall survival. Additional information regarding donor blood transfusion, along with other known factors, may be considered when deciding the optimization of overall immune suppression in LT recipients to decrease the risk of delayed rejection., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In the last decade, cell therapies have revolutionized the treatment of some diseases, earning the definition of being the "third pillar" of therapeutics. In particular, the infusion of regulatory T cells (Tregs) is explored for the prevention and control of autoimmune reactions and acute/chronic allograft rejection. Such an approach represents a promising new treatment for autoimmune diseases to recover an immunotolerance against autoantigens, and to prevent an immune response to alloantigens. The efficacy of the in vitro expanded polyclonal and antigen-specific Treg infusion in the treatment of a large number of autoimmune diseases has been extensively demonstrated in mouse models. Similarly, experimental work documented the efficacy of Treg infusions to prevent acute and chronic allograft rejections. The Treg therapy has shown encouraging results in the control of type 1 diabetes (T1D) as well as Crohn's disease, systemic lupus erythematosus, autoimmune hepatitis and delaying graft rejection in clinical trials. However, the best method for Treg expansion and the advantages and pitfalls with the different types of Tregs are not fully understood in terms of how these therapeutic treatments can be applied in the clinical setting. This review provides an up-to-date overview of Treg infusion-based treatments in autoimmune diseases and allograft transplantation, the current technical challenges, and the highlights and disadvantages of this therapeutic approaches.", Competing Interests: Declaration of competing interest The authors have no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Vascularized composite allotransplantation (VCA) is the transplantation of multiple tissue types as a solution for devastating injuries. Despite the highly encouraging functional outcomes of VCA, the consequences of long-term immunosuppression remain the main obstacle in its application. In this review, we provide researchers and surgeons with a summary of the latest advances in the field of cell-based therapies for VCA tolerance., Methods: Four electronic databases were searched: PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature , and Web of Science. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis as the basis of our organization., Results: Hematopoietic stem cells prolonged VCA survival. A combination of immature dendritic cells and tacrolimus was superior to tacrolimus alone. T cell Ig domain and mucin domain modified mature dendritic cells increased VCA tolerance. Bone marrow-derived mesenchymal stem cells prolonged survival of VCAs. A combination of adipose-derived mesenchymal stem cells, cytotoxic T-lymphocyte antigen 4 immunoglobulin, and antilymphocyte serum significantly improved VCA tolerance. Ex-vivo allotransplant perfusion with recipient's bone marrow-derived mesenchymal stem cells increased VCA survival. Recipient's adipose-derived mesenchymal stem cells and systemic immunosuppression prolonged VCA survival more than any of those agents alone. Additionally, a combination of peripheral blood mononuclear cells shortly incubated in mitomycin and cyclosporine significantly improved VCA survival. Finally, a combination of donor recipient chimeric cells, anti-αβ-T cell receptor (TCR), and cyclosporine significantly prolonged VCA tolerance., Conclusions: Evidence from animal studies shows that cell-based therapies can prolong survival of VCAs. However, there remain many obstacles for these therapies, and they require rigorous clinical research given the rarity of the subjects and the complexity of the therapies. The major limitations of cell-based therapies include the need for conditioning with immunosuppressive drugs and radiation, causing significant toxicity. Safety concerns also persist as most research is on animal models. While completely replacing traditional immunosuppression with cell-based methods is unlikely soon, these therapies could reduce the need for high doses of immunosuppressants and improve VCA tolerance., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intestinal transplantation is a complex technical procedure that provides patients suffering from end-stage intestinal failure an opportunity to enjoy improved quality of life, nutrition and survival. Compared to other types of organ transplants, it is a relatively new advancement in the field of organ transplantation. Nevertheless, great advances have been made over the past few decades to the present era, including the use of ischemic preconditioning, gene therapy, and addition of pharmacological supplements to preservation solutions. However, despite these strides, intestinal transplantation is still a challenging endeavor due to several factors. Notable among them is ischemia-reperfusion injury (IRI), which results in loss of cellular integrity and mucosal barrier function. In addition, IRI causes graft failure, delayed graft function, and decreased graft and recipient survival. This has necessitated the search for novel therapeutic avenues and improved transplantation protocols to prevent or attenuate intestinal IRI. Among the many candidate agents that are being investigated to combat IRI and its associated complications, nitric oxide (NO). NO is an endogenously produced gaseous signaling molecule with several therapeutic properties. The purpose of this mini-review is to discuss IRI and its related complications in intestinal transplantation, and NO as an emerging pharmacological tool against this challenging pathological condition. i., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Tacrolimus is the primary calcineurin inhibitor used in immunosuppressive regimens to prevent allograft rejection (AR) after organ transplantation. Recent studies have linked intrapatient variability (IPV) of tacrolimus with AR occurrence and reduced survival, especially in kidney transplant recipients. However, limited data are available on the impact of tacrolimus IPV on adverse outcomes after liver transplantation (LT)., Aims: The aim of this study was to assess the association between tacrolimus IPV using various methodologies with acute AR and long-term patient survival after LT., Methods: All patients who underwent LT from January 2010 to July 2021 were retrospectively evaluated. Tacrolimus IPV was calculated for each patient using the mean and SD, mean absolute deviation (MAD), coefficient of variation (CV), and time in therapeutic range (TTR). These measures were then compared with AR within the first 24 months after LT and to long-term survival., Results: Out of 234 patients, 32 (13.7%) developed AR and 183 (78.2%) survived, with a mean follow-up of 101 ± 43 months. Tacrolimus IPV, assessed by mean, SD, MAD, and CV, was 8.3 ± 2.1, 2.7 ± 1.3, 32.0% ± 11.7%, and 39.4% ± 15.4%, respectively. There was no statistically significant correlation between Tacrolimus IPV and AR or survival post-LT., Conclusions: In a large cohort of patients from diverse racial backgrounds, tacrolimus IPV was not associated with clinically relevant outcomes such as AR and survival after LT., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The purpose of this study was to assess off-label use of loteprednol etabonate 0.25% ophthalmic suspension for prevention of immunologic rejection after Descemet membrane endothelial keratoplasty (DMEK)., Methods: This prospective, open-label study enrolled 70 eyes of 70 participants without preexisting glaucoma 1 month after DMEK. Participants used topical loteprednol 0.25% 4 times daily for 2 months, tapered by 1 drop/month to once daily use, and continued use through 1 year after DMEK. Main outcomes were rate of intraocular pressure (IOP) elevation (defined as a relative increase of ≥10 mm Hg over the pretransplant IOP) and rate of initial allograft rejection episodes. The results were compared with historical data using the log-rank test., Results: All participants had Fuchs dystrophy, and 40 of 70 (57%) were female. None (0%) experienced an immunologic graft rejection episode, matching the previously reported efficacy of prednisolone acetate 1% suspension and loteprednol 0.5% gel (both 0% incidence). One study eye developed IOP elevation 3 months after DMEK (cumulative risk 1.5%). Compared with historical data, this was similar to the risk with loteprednol 0.5% gel (4%, P = 0.36) and significantly lower than the risk with prednisolone 1% suspension (18%, P = 0.0025). Two participants (3%) complained of instillation site discomfort, consistent with the 5% rate reported on package labeling., Conclusions: Loteprednol 0.25% suspension, approved for short-term treatment of dry eyes, effectively prevented immunologic rejection episodes with minimal risk of IOP elevation when used from 1 month until 12 months after DMEK in patients without preexisting glaucoma., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Organ transplantation requires the use of immunosuppressive medications that lack antigen specificity, have many adverse side effects, and fail to induce immunological tolerance to the graft. The safe induction of tolerance to allogeneic tissue without compromising host responses to infection or enhancing the risk of malignant disease is a major goal in transplantation. One promising approach to achieve this goal is based on the concept of "negative vaccination." Vaccination (or actively acquired immunity) involves the presentation of both a foreign antigen and immunostimulatory adjuvant to the immune system to induce antigen-specific immunity. By contrast, negative vaccination, in the context of transplantation, involves the delivery of donor antigen before or after transplantation, together with a "negative adjuvant" to selectively inhibit the alloimmune response. This review will explore established and emerging negative vaccination strategies for promotion of organ or pancreatic islet transplant tolerance. These include donor regulatory myeloid cell infusion, which has progressed to early-phase clinical trials, apoptotic donor cell infusion that has advanced to nonhuman primate models, and novel nanoparticle antigen-delivery systems., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The author declares no funding or conflicts of interest.

Background: Antibody-mediated rejection is one of the most significant risk factors for allograft dysfunction and failure in children and adolescents with kidney transplants, yet optimal treatment remains unidentified. To date, there are mixed findings regarding the use of Bortezomib, a plasma cell apoptosis inducer, as an adjunct therapy in the treatment of antibody-mediated rejection., Methods: In a retrospective single center study, we reviewed the efficacy and tolerability of bortezomib as adjunct therapy for treatment-refractory antibody-mediated rejection., Results: Six patients with a median age of 14.6 years (range 6.9-20.1 years) received bortezomib at a mean of 71 months (range 15-83 months) post-kidney transplant. Four patients experienced decline in estimated glomerular filtration rate (eGFR) from 4% to 42%. One patient started bortezomib while on hemodialysis and did not recover graft function, and another patient progressed to hemodialysis 6 months after receiving bortezomib. Although DSA did not completely resolve, there was a statistically significant decline in DSA MFI pre and 12-months post-BZ (p = .012, paired t-test) for the subjects who were not on dialysis at the time of bortezomib. Chronic Allograft Damage Index (CADI) score of ≥3 was seen in all six subjects at their biopsy prior to therapy. No adverse effects were reported., Conclusions: Bortezomib was well tolerated and resulted in improvements in MFI of DSA among four pediatric subjects without allograft failure, although no effects were observed on eGFR trajectory. Further studies are needed to clarify whether earlier intervention with bortezomib could prevent renal failure progression., (© 2024 Wiley Periodicals LLC.)

Recently published studies in both murine models and a meta-analysis of non-human primate renal transplant studies showed that anti-CD154 reagents conferred a significant survival advantage over CD40 blockers in both animal models and across multiple organs. Here we sought to compare the induction of donor-reactive forkhead box P3+-induced regulatory T cells (Foxp3 + iTreg) in mice treated with anti-CD154 versus anti-CD40 monoclonal antibodies (mAbs). Results indicated that while treatment with anti-CD154 mAb resulted in a significant increase in the frequency of donor-reactive CD4 + Foxp3 + iTreg following transplantation, treatment with anti-CD40 or Cd40 deficiency failed to recapitulate this result. Because we recently identified CD11b as an alternate receptor for CD154 during alloimmunity, we interrogated the role of CD154:CD11b interactions in the generation of Foxp3 + iTreg and found that blockade of CD11b in Cd40 -/- recipients resulted in increased donor-reactive Foxp3 + iTreg as compared with CD40 deficiency alone. Mechanistically, CD154:CD11b inhibition decreased interleukin (IL)-1β from CD11b + and CD11c + dendritic cells, and blockade of IL-1β synergized with CD40 deficiency to promote Foxp3 + iTreg induction and prolong allograft survival. Taken together, these data provide a mechanistic basis for the observed inferiority of anti-CD40 blockers as compared with anti-CD154 mAb and illuminate an IL-1β-dependent mechanism by which CD154:CD11b interactions prevent the generation of donor-reactive Foxp3 + iTreg during transplantation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mandy L. Ford reports financial support was provided by National Institutes of Health. Mandy L. Ford reports a relationship with Veloxis Pharmaceuticals Inc that includes: consulting or advisory. I am a deputy editor at the American Journal of Transplantation. I am on the Board of Directors of the American Society of Transplantation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Optimizing the immunosuppressive regimen is essential to improve the long-term outcomes of pediatric liver transplant recipients., Methods: We conducted a prospective, randomized, open-label study to compare the safety and efficacy of 2 treatment approaches during pediatric liver transplantation: tacrolimus monotherapy following basiliximab induction (the study group) and a dual regimen of tacrolimus plus steroids (the control group). A total of 150 patients were enrolled, with 75 patients allocated to each group., Results: In both groups, recipients achieved graft and recipient overall survival rates exceeding 93%, with no statistically significant differences between them. However, the study group exhibited a significantly lower incidence of acute cellular rejection (ACR), delayed occurrence of ACR, and an improved ACR-free survival rate at 2 y compared with the control group. Notably, the study group also showed a significant reduction in the incidence of de novo donor-specific antibodies at 3-mo and 2-y posttransplant. Furthermore, 6 mo after the transplant, the study group demonstrated significant improvements in weight-for-age Z score and height-for-age Z score. No notable differences were observed in postoperative complications or the incidence of liver fibrosis between the 2 groups., Conclusions: Basiliximab induction combine with tacrolimus (TAC) monotherapy is a safe and effective immunosuppressive regimen to reduce the episodes of ACR without influencing the development of liver fibrosis and graft and recipient survival rate after pediatric liver transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients., Methods: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen., Results: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type ( adjusted OR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above ( adjusted OR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant., Conclusions: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes., (© 2024 Wiley Periodicals LLC.)

Purpose: Kidney transplantation has a survival benefit for people with human immunodeficiency virus (HIV) and end-stage kidney disease, however increased rates of rejection remain an issue. Questions remain regarding the impact of induction immunosuppression therapy and antiretroviral (ARV) choice on long-term outcomes., Methods: We performed a multicenter retrospective analysis of outcomes in recipients with HIV who received kidneys from donors without HIV transplanted between 2004 and 2019. The association between induction and ARV regimens and long-term outcomes including rejection, graft, and recipient survival over 5 years was investigated using Cox regression modeling., Results: Seventy-eight kidney transplants (KT) performed in 77 recipients at five US transplant centers were included, with median follow up of 7.1 (4.3-10.7) years. Overall recipient and graft survival were 83% and 67%, respectively. Rejection occurred in 37% (29/78). Recipients with rejection were more likely to be younger, recipients of deceased donor organs, and Black. Receipt of rabbit anti-thymocyte globulin (rATG) induction without protease-inhibitor (PI)-based ARVs was associated with 83% lower risk of rejection (adjusted hazard ratio (aHR) 0.17 (95% CI 0.05-0.63), p =.007) and a non-statistically significantly lower risk of graft failure (aHR 0.18 (0.03-1.16), p =.07) when compared to those who received other induction and ARV combinations., Conclusions: In this multicenter retrospective study, we found a trend toward lower rejection and improved graft survival among those who received both rATG for induction and PI-sparing ARVs., (© 2024 Takeda Development Center Americas, Inc. Transplant Infectious Disease published by Wiley Periodicals LLC.)