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Objectives: To evaluate long-term renal graft prognosis and the role of rapamycin from a single-center in China over a 30-year follow-up., Methods: This study enrolled a total of 654 patients who underwent kidney transplantation between 1989 and 2020. The basic characteristics of the included patients were collected. Graft survival was described and compared using Kaplan-Meier curves (K-M curves). Both continuous and categorical variables were included in a multivariate Cox proportional-hazards model. Patients were divided into rapamycin-based quadruple immunosuppression regimen group (rapa group, n = 41) and conventional tacrolimus-based triple immunosuppression regimen group (control group, n = 218). The indication biopsy results of the two groups were further reviewed to compare the incidence of rejection, acute rejection, and banff score., Results: The overall 5, 10, 15, 20-year graft survival rate of our center is 87.5%, 62.4%, 46.4% and 20.9%, respectively. The median survival time after surgery is 14 years. Multiple Cox regression analysis identified BMI (p = 0.035), dialysis type (p < 0.001), immunosuppressants (p < 0.01), urine albumen (p < 0.001), globulin (p = 0.041), and blood glucose (p = 0.002) as risk factors. The 20-year, 10-year and 5-year AUC is 0.78, 0.75 and 0.75. The combination of FK506 and rapamycin was further suggested by the model to effectively improve the graft prognosis (p < 0.01, HR = 0.763). The K-M curve showed that the long-term survival rate of renal grafts in the rapa group was significantly better than that in the conventional group (p < 0.001). In addition, indication biopsy records revealed a lower possibility of immune rejection in the rapa group than that in the conventional group (p < 0.001). Banff score indicated that rapa group had less vascular inflammation in the transplanted kidney., Conclusions: In this study, a 30-year follow-up was performed in a single center, and a total graft 20-year survival rate of 20.9% was reported. The prognostic model and subgroup analysis suggested that FK506 combined with rapamycin could effectively improve the prognosis of renal transplantation, which could be explained by reduced acute rejection and less vascular inflammation., (© 2024. The Author(s).)

As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation., 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 Yue, Li, Yao, Song, Zhang and Wang.)

Paediatric heart transplant is an established treatment for end stage heart failure in children, however patients have to commit to lifelong medical surveillance and adhere to daily immunosuppressants to minimise the risk of rejection. Compliance with immunosuppressants can be burdensome with their toxic side effects and need for frequent blood monitoring especially in children. Though the incidence of early rejection episodes has significantly improved overtime, the long-term allograft health and survival is determined by Cardiac Allograft Vasculopathy (CAV) which affects a vast number of post-transplant patients. Once CAV has set in, there is no medical or surgical treatment to reverse it and graft survival is significantly compromised across all age groups. Current treatment strategies include novel immunosuppressant agents and drugs to lower blood lipid levels to address the underlying immunological pathophysiology and to manage traditional cardiac risk factors. Translational researchers are seeking novel immunological approaches that can lead to permanent acceptance of the allograft such as using regulatory T cell (Tregs) immunotherapy. Clinical trials in the setting of graft versus host disease, autoimmunity and kidney and liver transplantation using Tregs have shown the feasibility and safety of this strategy. This review will summarise current knowledge of the latest clinical therapies for CAV and pre-clinical evidence in support of Treg therapy for CAV. We will also discuss the different Treg sources and the considerations of translating this into a feasible immunotherapy in clinical practice in the paediatric population., 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 Aiyengar, Romano, Burch, Lombardi and Fanelli.)

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.

Background: Tacrolimus is a potent calcineurin inhibitor (CNI) that is principally used as a first-line immunosuppressant for the prophylaxis of allograft rejection in liver transplantation (LT) patients. In clinical practice, prescribing the optimal tacrolimus dosage is complicated by its narrow therapeutic index and high pharmacokinetic variability. Thus, performing therapeutic drug monitoring (TDM) of only tacrolimus may not provide optimal drug levels. However, other influential clinical factors affecting tacrolimus levels, such as hemoglobin (Hb), hematocrit, and total bilirubin (TBIL), should be considered while adjusting tacrolimus levels. This case report aims to introduce clinicians and their teams to taking the pharmacokinetic prediction equation into consideration for a better understanding of tacrolimus dosage adjustment during the early postoperative LT., Case Presentation: In this case report, an 18-year-old male patient of Thai ethnicity was admitted for orthotropic liver transplantation, and tacrolimus was prescribed as a cornerstone immunosuppressive agent. In the immediate postoperative period, which is the most challenging period in liver transplantation, the population pharmacokinetics predictive equation was clinically used to assist in dosage adjustment of tacrolimus by considering the significant clinical factors in this case. Hemoglobin and total bilirubin levels were deemed significant clinical factors affecting the oral clearance (CL/F) of tacrolimus. First, a decrease in the Hb concentration increases the free drug concentration and therefore increases the CL/F of tacrolimus. Second, an elevated TBIL decreases the biliary excretion of tacrolimus, resulting in a decrease in the CL/F of tacrolimus. Thus, dose optimization of tacrolimus would be accurate when taking the pharmacokinetic prediction equation into consideration. Moreover, the results may contribute to a better understanding of tacrolimus pharmacokinetic variability in each transplant patient during the immediate postoperative course., Conclusions: Hemoglobin and total bilirubin were significant clinical factors influencing the oral clearance of tacrolimus early after liver transplantation. A decrease in the hemoglobin concentration would increase the free drug concentration and therefore increase the oral clearance of tacrolimus. An elevated total bilirubin decreases the biliary excretion of tacrolimus, resulting in a decrease in the oral clearance of tacrolimus., (© 2024. The Author(s).)

Advances in hematopoietic cell transplantation have expanded the use of alternative donors such as haploidentical family donors or mismatched unrelated donors. However, donor-specific HLA antibodies (DSA) have been recognized as a significant risk factor of primary graft failure after HLA incompatible transplantation. Therefore, screening for HLA antibodies and taking DSA into consideration in the process of donor search play an increasingly important role in donor selection. If an HLA compatible donor is not available, desensitization may enable a successful transplantation. In this review, we describe the currently most widely used methods for HLA antibody detections including their pitfalls. In addition, we summarize the results of the studies on the impact of preformed DSA on transplant outcomes and their treatment options. Many more and larger studies are needed to clarify laboratory issues as well as immunological and clinical aspects in the management of DSA., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Though virtual care was widely adopted during the COVID-19 pandemic, evidence to support its use in kidney transplant recipients early after transplantation is limited., Methods: We conducted a retrospective cohort study comparing post kidney transplant outcomes in patients who received in-person transplant care before the COVID-19 pandemic with those who received mainly virtual transplant care during the COVID-19 pandemic. The usual-care group included 69 patients who received a kidney transplant from March 1, 2019 to September 1, 2019, and the virtual-care group included 64 patients who received a kidney transplant from September 1, 2020 to March 1, 2021., Results: At 6 months, five patients in the usual-care group and three patients in the virtual-care group died. There was one graft loss and one episode of acute rejection in the usual-care group, and two episodes of acute rejection in the virtual-care group (p = 0.60). Estimated glomerular filtration rate was higher for patients in the virtual-care group (59 mL/min/1.73 m 2 vs. 52 mL/min/1.73 m 2 , p = 0.046) and serum creatinine was not different (138 µmol/L vs. 127 µmol/L, p = 0.27). There was no difference in mean blood pressure or hospitalizations., Conclusion: Outcomes were similar among recipients of a kidney transplant prior to the COVID-19 pandemic when care was mainly in person and during the pandemic when care was mainly virtual, without a signal of harm. Patient and donor selection may have led to unmeasured differences between groups., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Background: Tacrolimus blood level variability is associated with reduced graft survival among kidney transplant recipients. To date, no practical approach for reducing variability has been validated. We defined specific tacrolimus blood level patterns correlated with variability and evaluated their independent association with reduced graft survival., Methods: In this single-center retrospective study, we predefined 12 patterns that exhibited correlation with high tacrolimus blood level variability. Subsequently, we utilized a multivariate Cox proportional hazard model, in conjunction with the Akaike information criteria, to evaluate the association between the predefined patterns and decreased graft survival., Results: Our cohort included 1305 kidney transplant recipients. The primary outcome of this trial was graft loss, defined as the initiation of chronic dialysis or the need for retransplantation. The secondary outcome was the combination of death-censored graft loss and death with a functioning graft. During the study's follow-up period, there were 131 events of graft loss. The number of episodes of subtherapeutic tacrolimus level during the first-year posttransplantation was significantly associated with graft loss (HR 1.208 per episode, 95% CI 1.075-1.356, p = 0.001) and significantly improved the relative likelihood of the model compared to the multivariate model as demonstrated by the delta AIC value (8.256, p = 0.016)., Conclusion: In addition to increased tacrolimus blood level variability, the number of episodes of subtherapeutic tacrolimus levels is independently associated with decreased graft survival among kidney transplant recipients., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

It is important for providers caring for kidney transplant recipients to be familiar with the common causes of allograft dysfunction. Early detection of allograft dysfunction leads to timely management, with the goal of preventing or delaying progression to allograft failure. Although transplant rejection is always a concern, the differential diagnoses for allograft dysfunction are broad and include perioperative complications, infections, recurrent disease, and calcineurin nephrotoxicity. In this review, we will go over early and late causes of allograft dysfunction and discuss the basic workup and principles of management for each condition., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the study was to determine outcomes after heart transplantation for cytomegalovirus (CMV) mismatched patients (D + /R - ) who underwent a surveillance and preemptive therapy protocol, compared to nonmismatch patients., Methods: A review of patient records from January 2010 to December 2020 with follow-up to October 2023 was done. The protocol consisted weekly surveillance with CMV PCR starting 4 weeks after transplant continuing up until the patient seroconverts or up to 3 months posttransplant if the patient does not seroconvert. Valganciclovir was given for 2 weeks to those who seroconverted., Results: Two hundred and twenty-one patients were included, and 23% were mismatched patients. Overall survival was not different between CMV groups (p = NS). Causes of death and morbidities were also not significantly different (p = NS). Sixty-six percent of mismatch patients seroconverted, and there was also a significantly older donor age in the seroconverted patients compared to nonseroconverted patients (41 ± 11 vs. 29 ± 12 years, p < 0.005), indicating a higher risk donor profile. A multivariate Cox regression including donor age showed that there was no increase in mortality in the seroconverted mismatches compared to nonmismatch patients (p = NS)., Conclusions: There is no significant increased mortality or morbidity using a CMV surveillance and preemptive therapy protocol. The effect of donor age on seroconversion of mismatches requires further validation., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Survival rates for allografts have improved over the last 2 decades, yet failing allografts remains a challenge in the field of transplant. The risks of mortality and morbidity associated with failed allografts are compounded by infectious complications and metabolic abnormalities, emphasizing the need for a standardized approach to management. Management of failing allografts lacks consensus, highlighting the need for unified protocols to guide treatment protocols and minimize risks with postdialysis initiation. The decision to wean off immunosuppression depends on various factors, including living donor availability and infectious risks, necessitating improved coordination of care and a standard guideline. Treatment of failed pancreas focuses on glycemic control, with insulin as the mainstay, while considering surgical interventions such as graft pancreatectomy in advanced symptomatic cases. Navigating the complexities of failed allograft management demands a multidisciplinary approach and standardized stepwise protocol. Addressing the gaps in management plans for failing allografts and employing a systematic approach to transplant decisions will enhance patient outcomes and facilitate informed decision-making., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Over the last 7 decades, kidney transplantation has evolved from an experiment between identical twins to becoming the gold standard treatment for end-stage kidney disease. To date, mycophenolate and calcineurin inhibitors, with or without prednisone, continue to constitute the backbone of modern maintenance immunosuppression. Despite major strides in improving acute rejection, long-term outcomes remain suboptimal with current regimens. Alternatives to calcineurin inhibitors such as belatacept and mammalian targets of rapamycin inhibitors exist; however, their wider-scale adoption remains relatively delayed due to concerns about increased rejection rates. In addition to continuing the investigation of steroid and calcineurin inhibitor sparing protocols, it is time to identify measurable surrogates for meaningful long-term graft survival. iBOX, a dynamic risk-prediction tool that predicts long-term death-censored graft failure could be a potential surrogate end point for future immunosuppression clinical trials. In this review, we summarize the landmark studies supporting current immunosuppression protocols and briefly discuss challenges and future directions., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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: Medication nonadherence (MNA) in organ transplant recipients is associated with increased risk of rejection, allograft loss, patient death, and higher healthcare costs. Various approaches have been used in an attempt to reduce MNA. A patient support program (PSP) can be an invaluable tool for improving patient outcomes. The aim of this study was to analyze available data of PSP for kidney transplant recipients., Methods: A total of 3352 patients from all over the country were prospectively enrolled in the Parichay PSP between January 2021 and April 2023. Baseline demographic details were recorded. A monthly call was made thereafter. Data were analyzed for demographic details, compliance rate, dropouts, and tacrolimus levels when available., Results: The Parichay PSP had enrolled a total of 1371 kidney transplant patients in 2021, 1620 in 2022, and 361 in 2023 (January-April) from different parts of India (North, 25%; East, 35%; South, 26%; West, 14%). (n=2626) Of the 2626 patients who received tacrolimus (Tacrograf), 2158 (82%) were male, with a mean age of 42 years. The majority of patients (61%) were age 28 to 48 years. A patient compliance rate of >90% was maintained for longer than 13 months (n = 1920; April 2022 to April 2023). Of the 3352 patients, 250 (7.4%) dropped out of the study. Thus, use of PSP ensured a compliance rate of 92.6% in this study., Conclusions: This analysis demonstrates that participation in a PSP can be a useful tool for monitoring compliance and tacrolimus therapeutic drug monitoring in kidney transplant recipients., 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 Inc. All rights reserved.)

Objective: We sought to determine if genetically modified porcine kidneys used for xenotransplantation had sufficient tissue integrity to support long-term function in a human recipient., Background: Kidney transplantation remains the best available treatment for patients with end-stage kidney disease. However, a shortage of available donor human kidneys prevents many patients from achieving the benefits of transplantation. Xenotransplantation is a potential solution to this shortage. Recent pre-clinical human studies have demonstrated kidneys from genetically modified pig donors can be transplanted without hyperacute rejection and are capable of providing creatinine and other solute clearance. It is unknown whether the porcine kidneys would tolerate the relatively higher resting blood pressure in an adult human recipient compared with the pig donor or non-human primate (NHP) recipients used in translational studies. Furthermore, previous experience in NHPs raised concerns about the tissue integrity of the porcine ureter and post-xenotransplant growth of the porcine kidney., Methods: Kidneys recovered from porcine donors with 10 gene edits were transplanted into decedent brain-dead recipients who were not eligible for organ donation. Decedents underwent bilateral native nephrectomy before transplant and were followed for 3 to 7 days. Standard induction and maintenance immunosuppression was used as previously reported. Vital signs, including blood pressure, were recorded frequently. Kidney xenografts were assessed daily, serially biopsied, and were measured at implantation and study completion., Results: Three decedents underwent successful xenotransplantation. Subcapsular hematomas developed, requiring incision of the xenograft capsules to prevent Page kidney. Blood pressures were maintained in a physiologic range for adult humans (median arterial pressures (MAP) 108.5 mm Hg (Interquartile Range (IQR): 97-114 mm Hg), 74 mm Hg (IQR: 71-78 mm Hg), and 95 mm Hg (IQR: 88-99 mm Hg, respectively) and no bleeding complications or aneurysm formation was observed. Serial biopsies were taken from the xenografts without apparent loss of tissue integrity despite the lack of a capsule. Ureteroneocystotomies remained intact without evidence of urine leak. Xenograft growth was observed, but plateaued, in 1 decedent with increased volume of the left and right xenografts by 25% and 26%, respectively, and in the context of human growth hormone levels consistently less <0.1 ng/ml and insulin-like growth factor 1 levels ranging from 34-50 ng/ml., Conclusions: The findings of this study suggest kidneys from 10-gene edited porcine donors have sufficient tissue integrity to tolerate xenotransplantation into a living human recipient. There was no evidence of anastomotic complications, and the xenografts tolerated needle biopsy without issue. Xenograft growth occurred but plateaued by the study end; further observation and investigation will be required to confirm this finding and elucidate underlying mechanisms., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Although severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid (SARS-CoV-2 mRNA) vaccines are effective in kidney transplant recipients (KTRs), their immune response to vaccination is blunted by immunosuppression. Other tools enhancing vaccination response are therefore needed. Interestingly, aligning vaccine administration with circadian rhythms (chronovaccination) has been shown to boost immune response. However, its applicability in KTRs, whose circadian rhythms are likely disrupted by immunosuppressants, remains unclear. To assess the impact of vaccination timing on seroconversion in the KTRs population, we analyzed data from 553 virus-naïve KTRs who received 2 doses of messenger ribonucleic acid (mRNA) vaccine. Bayesian logistic regression was employed, adjusting for previously identified predictors of seroconversion, including allograft function, maintenance immunosuppressants, or time since transplantation. SARS-CoV-2 immunoglobulin G (IgG) levels were measured with a median of 47 days after the second dose. The results did not reveal a reliable effect of timing of the first dose but did indicate that earlier timing for the second dose brings a notable benefit-every 1-hour delay in the application was associated with a 16% reduction in the odds of seroconversion (OR 0.84, 95% CI 0.71, 0.998). Similar results were obtained from quantile regression modeling IgG levels. In conclusion, morning vaccination is emerging as a promising and easily implementable strategy to enhance vaccine response in KTRs., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, Parabacteroides distasonis, as the most enriched following all Abx treatments. Oral administration of P.distasonis to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflict of interest to disclose as described by the American Journal of Transplantation. Yuk Man Lei currently holds a position at Exelixis Inc, Alameda, California, USA and Yang Chen currently holds a position at Veracyte, Inc, South San Francisco, California, USA., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Solid organ transplant recipients require ongoing immunosuppression to prevent acute rejection, which puts them at risk of opportunistic infections. Viral infections are particularly challenging to prevent and treat as many establish latency and thus cannot be eliminated, whereas targets for small molecule antiviral medications are limited. Resistance to antivirals and unacceptable toxicity also complicate treatment. Virus-specific T cell therapies aim to restore host-specific immunity to opportunistic viruses that is lacking due to ongoing immunosuppressive therapy. This minireview will provide a state-of-the-art update of the current virus-specific T cell pipeline and translational research that is likely to lead to further treatment options for viral infections in solid organ transplant recipients., Competing Interests: Declaration of competing interest The author of this manuscript has conflicts of interest to disclose as described by the American Journal of Transplantation. L. Schweitzer receives salary support from the Fonds de recherche du Québec – Santé and the Royal College of Physicians and Surgeons of Canada. The other author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier 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.)

Background: The optimal dose of rabbit anti-thymocyte globulin (r-ATG) in renal transplantation is still under debate. We previously reported that a low-dose r-ATG induction of 3 mg/kg can be used safely and effectively in low-risk kidney transplants with good results in the first year after transplantation compared to basiliximab induction., Aims: The purpose of this study is to evaluate the long-term impact of this trial of low-dose r-ATG versus basiliximab on post-transplant outcomes (patient and graft survival, biopsy-proven acute rejection incidence [BPAR], infectious complications, and side effects)., Methods: Observational study (three-year follow-up) of a 12-month single-center, open-label RCT in de novo kidney allograft recipients assigned to receive either thymoglobulin or basiliximab before transplantation., Results: Patients in the basiliximab group (BG) underwent more kidney transplant biopsies than patients in the low-dose r-ATG group (TG) (50 vs. 31.8%, p = 0.07). Although the 12-month cumulative incidence of BPAR was lower in BG, by the end of the three-year follow-up period this incidence was higher (22%) than in the low-dose TG (15%) (p = ns). Steroids were withdrawn more frequently in the TG group and sirolimus was most frequently indicated. Graft function and graft survival were higher in the low-dose TG than in the BG at three-year follow-up but not statistically significant. Patient survival was similar between groups (>90%)., Conclusions: These three-year follow-up data confirm the efficacy and favorable safety aspects of the low-dose r-ATG (3 mg/kg) in low-risk kidney transplantation., (Copyright © 2024 Instituto Mexicano del Seguro Social (IMSS). Published by 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.)

In kidney transplant recipients, delayed graft function increases the risk of graft failure and mortality. In a phase 3, randomized, double-blind, placebo-controlled trial, we investigated the hepatocyte growth factor mimetic, ANG-3777 (once daily for 3 consecutive days, starting ≤30 hours posttransplant), in 248 patients receiving a first kidney transplant from a deceased donor. At day 360, estimated glomerular filtration rate (primary endpoint) was not significantly different between the ANG-3777 and placebo groups. There were no significant between-group differences in the duration of dialysis through day 30 or in the percentage of patients with an estimated glomerular filtration rate of >30 mL/min/1.73 m 2 at day 360. The incidence of both delayed graft function and acute rejection was similar between ANG-3777 and placebo groups (68.5% vs 69.4% and 8.1% vs 6.5%, respectively). ANG-3777 was well tolerated, and there was a numerically lower incidence of graft failure versus placebo (3.2% vs 8.1%). Although there is insufficient evidence to support an indication of ANG-3777 for patients at risk of renal dysfunction after deceased-donor kidney transplantation, these findings indicate potential biological activity that may warrant further investigation., Competing Interests: Declaration of competing interests The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. F. Vincenti has research or consulting contracts with Egenesis, Eledon, Merck, Sanofi, Veloxis, and Viela/Horizon. J. Bromberg has research or consulting contracts with CareDx, Eurofins/TGI, Natera, and Pfizer. J. Kim has no conflicts of interest to disclose. A. Faravardeh has research or consulting contracts with Natera and Veloxia. N. Leca has received institutional funding for multicenter trials from Angion, CareDx, CSL Behring, Hansa Pharmaceuticals, Memo Therapeutics, Natera, Novartis, Transplant Genomics, and Verici. G. Alperovich and P.A. Csomor are employees of and hold equity in CSL Vifor. S. Aslam and J. Neylan were employees of and held equity in Angion Biomedica at the time of the study and are current employees of BioCryst Pharmaceuticals, Inc, and Akari Therapeutics, Plc, respectively., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Objective: The aim of this study was to analyze the effects of mindfulness-based cognitive therapy on the adherence of liver transplant recipients to immunosuppressive therapy with a randomized controlled design., Method: This randomized controlled trial was performed with 120 liver transplant recipients hospitalized at the liver transplant department of a research and practice hospital (n = 120). While we administered no intervention to the patients in the control group (n = 60), we provided Mindfulness-Based Cognitive Therapy to those in the experimental group (n = 60). We used the Mindful Attention Awareness Scale and the Immunosuppressant Therapy Adherence Scale to collect data. We utilized descriptive statistics, paired-samples t-tests, independent-samples t-tests, one-way analysis of variance, and chi-squared tests to analyze the data., Results: After the intervention, the immunosuppressive therapy adherence levels of the experimental group increased significantly (p < 0.01). On the other hand, the control group had significantly higher adherence to immunosuppressive therapy and significantly higher levels of mindfulness in the pretest phase than it did in the posttest phase (p < 0.01)., Conclusions: Complete adherence to immunosuppressive therapy is imperative for the prevention of graft rejection in liver transplant recipients. In our study, the experimental group equipped with enhanced mindfulness had higher adherence to immunosuppressive therapy. Therefore, the use of Mindfulness-Based Cognitive Therapy in the promotion of adherence to immunosuppressive therapy is recommended., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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

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.)

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.)

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.)

Post-transplantation immune rejection remains an important factor for transplant patients. However, conventional immunosuppressants are associated with substantial adverse effects. Natural immunosuppressants present a promising alternative to conventional counterparts, boasting exceptional biological activity, minimal toxicity and reduced side effects. We identified carvacrol as a prospective immunosuppressive agent following T cell proliferation experiment and validated carvacrol's immunosuppressive efficacy in the murine allogeneic skin graft model. T cell proliferation assay was used to screen natural small molecule compounds and the immunosuppressive effect of compounds was evaluated in MHC-mismatched murine allogeneic skin graft model. H&E and immunohistochemical staining were applied to evaluate the pathological grade. Furthermore, flow cytometry was uitlized to analyse the immunophenotype changes of immune cells. Western blotting and q-PCR were used to detect the expression of key molecules in macrophages. In vitro, carvacrol demonstrates significant inhibition of the proliferation of CD4 + T and CD8 + T cells. It notably reduces inflammatory factor expression within the allografts, suppresses T cell differentiation toward Th1 phenotype and expansion. Furthermore, carvacrol prominently hinders M1-type macrophages polarization by activating Wnt signaling. Notably, the anti-rejection efficacy of carvacrol was significantly weakened upon the removal of macrophages in mice using chlorophosphate liposomes. Carvacrol could significantly inhibit T cell proliferation, alleviate graft rejection and has outstanding toxicological safety. The molecular mechanism of the anti-rejection effect of carvacrol is closely related to its mediating activation of macrophage Wnt pathway, inhibiting M1 polarization and inducing T cell differentiation., (© 2024 John Wiley & Sons Ltd.)

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.)

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.)

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.)

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.)

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.)

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.)

Phytoestrogens are natural compounds found in plants and plant-based foods. When ingested, they can affect the human body in the same way as estrogen produced by the body. Phytoestrogens affect the regulation, differentiation, and production of immune cells. People who consume polyphenol and flavonoid-rich foods have lower incidences of inflammation, autoimmune diseases, and cancer. In organ transplantation, immune rejection is a lifelong problem for patients. In clinical practice, acute rejection is treated with hormonal shock or immunosuppressive drugs. However, effective reversal measures for chronic rejection, specifically for prevention, are still lacking. Recipients are also prone to post-transplant complications such as new tumors, diabetes, hyperlipidemia, hyperuricemia, and cardiovascular and cerebrovascular diseases, owing to the long-term use of immunosuppressive drugs. Phytoestrogens play a promising role in immune regulation and exert curative effects on cardiovascular diseases and cancer. In this study, we reviewed the use of phytoestrogens in the fields of immune regulation and organ transplantation., 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. Published by Elsevier B.V.)

Purpose: Tacrolimus is the cornerstone of current immunosuppressive strategies after lung transplantation. However, its narrow therapeutic range and considerable pharmacokinetic variability pose challenges for individualized treatment. Several tacrolimus population pharmacokinetic (popPK) models have been developed for precision dosing in adult lung transplant patients. However, their applicability across different clinical settings remains uncertain. The aim of this study was to evaluate the external predictability of these models and identify influential factors., Methods: Published models were systematically retrieved and assessed based on an external dataset of 39 patients (1240 tacrolimus trough concentrations) using three approaches: (1) prediction-based diagnosis using dosing records and patient characteristics; (2) simulation-based diagnosis, with prediction- and variability-corrected visual predictive checks (pvcVPC) and normalized prediction distribution error tests (NPDE); and (3) Bayesian forecasting using one to four observations for posterior predictions. We also investigated the impact of model structure and covariates on predictability., Results: The predictive performance of six published models was externally evaluated, but none demonstrated satisfactory accuracy in prediction- and simulation-based diagnosis. Bayesian forecasting yielded satisfactory results with only one prior observation and optimal predictive performance with 2-3 priors for all included models. The structural model parameterized on plasma tacrolimus concentration outperformed others. Significant correlations were observed between prediction-error and daily tacrolimus dose, postoperative day, and voriconazole co-administration., Conclusions: The overall predictive performance of all published models was unsatisfactory, making direct extrapolation inappropriate. However, Bayesian forecasting significantly improves predictive performance. Utilizing plasma tacrolimus concentration for parameter estimation can improve the predictive ability of tacrolimus popPK models., 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.)

Purpose of Review: Allograft vasculopathy in vascularized composite allografts (VCA) remains understudied. This review explores the vascular changes in VCA, focused on recent literature., Recent Findings: Allograft vasculopathy in VCA generally includes progressive concentric myointimal thickening and luminal narrowing of arterial vessels through endothelial deterioration and proliferation of smooth muscle cells. Microvascular changes are also noted, with thrombosis and lumen narrowing in microvessels of the skin even in the absence of large vessel vasculopathy. Histopathologic reports of skin containing VCA rejection document arteriosclerosis in deep vessels that are not always reflected in skin punch biopsies. The first revision of the Banff VCA scoring system 2022 was developed to include vascular changes in VCA. The scoring system for chronic changes and antibody mediated rejection continues to be under development., Summary: The study of vascular changes in VCA continues to progress. Important data and advances in experimental and clinical VCA have been reported and continue to take place. Challenges ahead include capture of clinical data that will evolve beyond transient report forms and approaching on the problem of graft failure well grounded in sound scientific methodology., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Despite significant advancements in the field of vascularized composite allotransplantation, challenges, particularly regarding the long-term viability and functionality of vascularized composite allotransplantation (VCA) grafts, persist. This paper provides a review of the current literature on the longevity of VCA grafts, focusing on factors influencing graft survival, immunological considerations and clinical outcomes., Recent Findings: Longevity of VCA grafts is influenced by a variety of peri- and postoperative factors including cold ischemia time, human leukocyte antigen matching, environmental exposure, psychosocial factors, adherence, immunosuppression, and complications. Due to the limited number of VCA transplants performed and heterogenous reporting, direct correlation of single factors with VCA outcomes remains inconclusive. Indirect evidence, however, supports their importance. High immunosuppressive burden, frequent occurrence of acute and accumulating cases of chronic rejection remain a significant challenge of the field., Summary: Insights gained from this review aim to inform clinical practice and guide future research endeavors with the goal of ameliorating outcomes after VCA transplantation and facilitate wider use of VCA grafts for restoration of tissue defects., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Primary graft dysfunction (PGD) and chronic lung allograft dysfunction (CLAD) are the leading causes of graft loss in lung transplant recipients. The development of mouse lung transplant models has allowed for the genetic dissection of cellular and molecular pathways that prevent graft survival. This review provides an overview into recent mechanistic insights into PGD and CLAD., Recent Findings: Mouse orthotopic lung transplant models and investigations of human lung transplant recipeints have revealed new molecular and cellular targets that promote PGD and CLAD. Donor and recipient-derived innate immune cells promote PGD and CLAD. PGD is driven by communication between classical monocytes and tissue-resident nonclassical monocytes activating alveolar macrophages to release chemokines that recruit neutrophils. Products of cell damage trigger neutrophil NET release, which together with NK cells, antibodies and complement, that further promote PGD. The development of CLAD involves circuits that activate B cells, CD8 + T cells, classical monocytes, and eosinophils., Summary: Effective targeted management of PGD and CLAD in lung transplant recipient to improve their long-term outcome remains a critical unmet need. Current mechanistic studies and therapeutic studies in mouse models and humans identify new possibilities for prevention and treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Significant advancements have been made in the field of vascularized composite allotransplantation (VCA); however, like solid organ transplantation, bypassing the recipient's immune response remains a significant obstacle to long-term allograft survival. Therefore, strategies to overcome acute and chronic rejection and minimize immunosuppressive therapy are crucial for the future of VCA. This review highlights recent attempts to induce tolerance in VCA and discusses key findings through a clinical lens., Recent Findings: Promising VCA tolerance protocols are being investigated, with five recent studies illustrating various successes. These preclinical approaches demonstrate a correlation between the presence of donor-derived T cells and VCA tolerance, the importance of using clinically available reagents within preclinical protocols, and the ability to induce sustained tolerance through nonmyeloablative methods. Furthermore, environmental factors, such as NB-UVB light are being investigated for their immunomodulation properties and may influence VCA graft rejection., Summary: To widen the scope of VCA, minimization of immunosuppression is needed. Overall, tolerance induction protocols should have a low-toxicity level, minimally invasive induction therapies, and utilize short-term immunosuppressive medications. By examining the milestones of recent studies, researchers can gain new technical approaches to immune modulation and make data-driven amendments to tolerance protocols in preparation for clinical translation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The purpose of this review is to explore the lessons learned from experimental and human tracheal transplantation to determine if this information may be applied to lung transplantation., Recent Findings: Experimental work in animal models and the recent human tracheal transplantation suggests that a robust tracheal vascular supply prevents anastomotic complications. Further, this work demonstrates that tracheal allografts undergo a progressive chimerism as recipient epithelium repopulates the allograft. In contrast to most vascularized composite allografts such as hand and face transplantation that experience high rates of rejection, the tracheal allograft did not demonstrate rejection. This may suggest that tissue chimerism plays a role in evading immune-mediated allograft rejection., Summary: While anastomotic complications and chronic allograft rejection are the most common complications related to lung transplantation, the findings associated with tracheal transplantation may have implications for both reducing complications associated with lung transplantation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Tacrolimus remains the mainstay of immunosuppression in kidney transplantation. Understanding the relationship between therapeutic tacrolimus levels and outcomes of acute rejection, patient/graft survival, and tolerability are important. The relationship between time to therapeutic tacrolimus levels and outcomes has not been well established, specifically with the use of extended release tacrolimus formulation (LCP-Tac). This study investigated time to therapeutic tacrolimus levels of 2 tacrolimus formulations, LCP-Tac and immediate release tacrolimus (IR-Tac), as a predictor of clinical outcomes. Methods: This was a single-center, retrospective, cohort study of kidney transplant recipients at Duke Hospital between 2013-2021. The primary objective evaluated the difference in time to therapeutic tacrolimus levels with LCP-Tac vs IR-Tac regimens. Secondary endpoints included time within therapeutic range during the first 3 months post-transplant, incidence of biopsy-proven rejection, development of de novo donor specific antibodies, and patient and allograft survival at 12 months post-transplant. Results: 128 patients were included (63 in LCP-Tac group and 65 in IR-Tac group). The time to therapeutic tacrolimus level was similar between formulations (7.2 days with LCP-Tac compared to 6.7 days with IR-Tac, P = .63). The time within therapeutic range during the first 3 months post-transplant, via modified Rosendaal, was similar with LCP-Tac and IR-Tac (56.1% vs 64.8%, respectively). Rates of biopsy-proven acute rejection at 12 months were similar (7/63 (11.1%) compared to 4/65 (6.2%)). There was no difference in patient/graft survival between groups. Conclusions: The time to therapeutic tacrolimus levels did not differ based on tacrolimus formulation and was not correlated with clinical outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Solid organ transplantation has progressed rapidly over the decades from the first experimental procedures to its role in the modern era as an established treatment for end-stage organ disease. Solid organ transplantation including liver, kidney, pancreas, heart, and lung transplantation, is the definitive option for many patients, but despite the advances that have been made, there are still significant challenges in meeting the demand for viable donor grafts. Furthermore, post-operatively, the recipient faces several hurdles, including poor early outcomes like primary graft dysfunction and acute and chronic forms of graft rejection. In an effort to address these issues, innovations in organ engineering and treatment have been developed. This review covers efforts made to expand the donor pool including bioengineering techniques and the use of ex vivo graft perfusion. It also covers modifications and treatments that have been trialed, in addition to research efforts in both abdominal organs and thoracic organs. Overall, this article discusses recent innovations in machine perfusion and organ bioengineering with the aim of improving and increasing the quality of donor organs., 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 Niroomand, Nita and Lindstedt.)

Non-adherence to immunosuppressive medication among transplant patients is associated with poor clinical outcomes and higher economic costs. Barriers to immunosuppressives are a proximal determinant of non-adherence. So far, international variability of barriers to adherence in transplantation has not been studied. As part of the cross-sectional multi-country and multi-center BRIGHT study, barriers to adherence were measured in 1,382 adult heart transplant recipients of 11 countries using the 28-item self-report questionnaire "Identifying Medication Adherence Barriers" (IMAB). Barriers were ranked by their frequency of occurrence for the total sample and by country. Countries were also ranked the by recipients' total number of barriers. Intra-class correlations were calculated at country and center level. The five most frequently mentioned barriers were sleepiness (27.1%), being away from home (25.2%), forgetfulness (24.5%), interruptions to daily routine (23.6%) and being busy (22.8%), fairly consistently across countries. The participants reported on average three barriers, ranging from zero up to 22 barriers. The majority of the variability among reported barriers frequency was situated at the recipient level (94.8%). We found limited international variability in primarily person-level barriers in our study. Understanding of barriers in variable contexts guides intervention development to support adherence to the immunosuppressive regimen in real-world settings., 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 Denhaerynck, Berger Wermuth, Dobbels, Berben, Russell and De Geest.)