There is no consensus on the strategy for therapeutic drug monitoring of the immunosuppressive drug mycophenolic acid (MPA) in organ transplant recipients. The present study proposes the utilization of ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for determining the concentrations of MPA and its metabolites: 7-O-mycophenolic acid glucuronide (MPAG) and acyl mycophenolic acid glucoside (AcMPAG) in peripheral blood mononuclear cells (PBMCs). We aimed to assess the potential application of monitoring MPA and its metabolite concentrations in PBMCs in the infection after transplantation in Chinese kidney transplant recipients (KTRs). The UPLC-MS/MS method we developed demonstrated good linearity in the quantitative ranges of 0.05-50.00 ng/mL for MPA, 0.50-50.00 ng/mL for MPAG, and 0.10-20.00 ng/mL for AcMPAG. AcMPAG in PBMCs was unstable, degrading significantly after 48 h of storage at -80°C or after 3 freeze-thaw cycles. MPA and MPAG concentrations in KTRs' PBMCs exhibited high inter-individual variability, and the MPA concentration in PBMCs was poorly correlated with that in plasma (rs = 0.206, p = 0.117). Compared with the stable group, the infected group had significantly higher MPA concentration in PBMCs at 2 and 4 h post-dosing and in plasma at 4 h post-dosing (p < 0.05). The receiver operating characteristic (ROC) analysis for post-transplantation infection revealed that PBMCs MPA-C4 and PBMCs-MPA-C2 possessed much better diagnostic efficiency than Plasma-MPA-C4. This method is easy-to-use and reliable, making it a promising clinical quantitative tool for MPA, MPAG, and AcMPAG in PBMCs. PBMC-MPA monitoring may be a potential biomarker for infection monitoring for KTRs.

Lung transplantation is a common treatment for end-stage lung disease (ESLD). Patients present to lung transplantation evaluation on various medications that could impact their candidacy and posttransplant course. In this review, we will discuss pretransplant optimization of pharmacotherapy to minimize complications while waiting for transplant and increase posttransplant success. We will also discuss important considerations for posttransplant immunosuppression, antimicrobial prophylaxis, and complex drug interactions.

Prior to lung transplantation, several medications should be optimized to promote posttransplant success including minimization of corticosteroids, opioids, and benzodiazepines. Lung transplantation candidates should be up to date on vaccinations. Most medications for ESLD are well tolerated to continue up until the point of transplant including antifibrotics, CFTR modulators, and pulmonary vasodilators. Mammalian target of rapamycin inhibitors and other immunosuppressants may need to be stopped or minimized before lung transplantation to minimize posttransplant infection and would healing complications. Medications that increase risk of posttransplant bleeding, thrombosis, or aspiration should be stopped prior to listing.

In this article, we discuss management of pharmacotherapy for lung transplantation candidates to minimize posttransplant complications. Changes in medications for ESLD should be done cautiously to prevent worsening of native disease while waiting for lung transplantation.

Kidney transplantation is the preferred therapy for many patients with kidney failure. Delayed graft function (DGF) is more common in donors after cardiac death (DCD), especially those with older age, longer cold ischemia time, or higher creatinine levels. Currently, there is no agreement on the optimal immunosuppressive approach for patients at increased risk of DGF. Strategies include delaying the introduction of calcineurin inhibitors (CNI) or using an initial low dose of CNI.

To evaluate the benefits and harms of delayed initiation of CNI or reduced CNI dose as initial immunosuppression therapy for kidney transplant recipients at high risk of DGF.

The Cochrane Kidney and Transplant Register of Studies was searched up to 11 December 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.

All randomised controlled trials (RCTs) and quasi-RCTs evaluating delayed versus early initiation of CNI or reduced versus standard initial dose of CNI in kidney transplant recipients at high risk of DGF.

Three authors independently assessed study eligibility, and two assessed the risk of bias, certainty of evidence, extracted the data, and performed the analysis. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and as mean difference (MD) with 95% CI for continuous outcomes. Statistical analysis was performed using the random-effects model. Risk of bias was assessed with the Cochrane risk of bias assessment tool 1.0, and the certainty of the evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methods, which are presented in the summary of findings tables.

We included 12 studies (2230 randomised participants). All studies were performed in Europe. Around 60% of the participants were males, reflecting the expected proportion in the population on kidney replacement therapy in Europe. Most studies had insufficient information to judge adequate random sequence generation and, or allocation concealment. All studies were unblinded, and judged as high risk of bias for DGF if the definition was based on need for dialysis, and for acute rejection if the diagnosis did not require a biopsy. Overall, the level of certainty was low, and reasons to downgrade were mainly due to risk of bias and imprecision. Delayed versus early initiation of CNI There may be little or no difference in DGF between the groups (6 studies, 905 recipients: RR 0.92, 95% CI 0.76 to 1.12; low certainty evidence) or in acute rejection (8 studies, 1295 recipients: RR 1.02, 95% CI 0.75 to 1.40; low certainty evidence). Delaying the initiation of CNI probably makes little or no difference to eGFR (6 studies, 851 recipients: MD -0.81 mL/min, 95% CI -3.33 to 1.72; moderate certainty evidence). Delaying the initiation of CNI may make little or no difference to graft loss censored for death (8 studies, 1295 recipients: RR 1.58, 95% CI 0.68 to 3.65; very low certainty evidence) or to all-cause death (8 studies, 907 recipients: RR 1.08, 95% CI 0.54 to 2.14; very low certainty evidence) although the evidence is very uncertain. There is probably little or no difference in all infections between the groups (6 studies, 1226 recipients: RR 1.10, 95% CI 0.97 to 1.25; moderate certainty evidence). Low versus standard initial dose of CNI There may be little or no difference to DGF between the groups (5 studies, 983 recipients: RR 1.16, 95% CI 0.90 to 1.50; low certainty evidence) or in acute rejection (5 studies, 947 recipients: RR 0.83, 95% CI 0.52 to 1.30; low certainty evidence). Starting CNI at a lower dose may make little or no difference to eGFR (5 studies, 935 recipients: MD 4.06 mL/min, 95% CI -1.36 to 9.48, low certainty evidence). Starting CNI at a lower dose may make little or no difference to graft loss censored for death, although the evidence is very uncertain (5 studies, 983 recipients: RR 1.05, 95% CI 0.64 to 1.71; very low certainty evidence), or to all-cause death (4 studies, 521 recipients: RR 1.01, 95% CI 0.41 to 2.47; low certainty evidence). There is probably little or no difference in all infections between the groups (4 studies, 828 recipients: RR 0.87, 95% CI 0.71 to 1.07; moderate certainty evidence).

There may be little or no difference in DGF or acute rejection when delaying the start of CNI or when starting it at a lower dose in kidney transplant recipients at high risk of DGF. The available data are of low certainty.

Renal transplant recipients (RTRs) use a combination of immunosuppressive agents: a corticosteroid; a calcineurin inhibitor (cyclosporine or tacrolimus) and an antimetabolic agent (azathioprine [AZA] or a mycophenolic acid precursor [MPA] ‒ Mycophenolate mofetil or sodium) or an mTOR inhibitor (mTORi) ‒ sirolimus or everolimus. These treatments increase the incidence of various neoplasms, especially non-melanoma skin cancers (NMSCs).

To evaluate the histopathological alterations in the skin of the RTRs under three different immunosuppressive regimens: one mTORi (sirolimus or everolimus); or one antimetabolic agent (MPA or AZA), comparing them by groups and with healthy controls.

This was an observational, cross-sectional, comparative study of 30 patients selected from the Renal Transplant Service and divided into three groups: mTORi (n = 10), MPA (n = 10), and AZA (n = 10). The control group consisted of 10 immunocompetent non-transplanted volunteers. All RTRs were using tacrolimus and prednisone. Each participant underwent two biopsies of intact skin: one in a sun-protected and another in a sun-exposed area. The specimens were analyzed without previous information on which group they belonged to.

The most significant histopathological change was thinning of the epidermis in the mTORi group, both in photoexposed and photoprotected skin.

The study was conducted on a limited number of patients, which may influence the representativeness of the results.

Only RTRs treated with mTORi presented interruption of epidermal proliferation. These findings help to understand the influence of these different types of immunosuppressive regimens and their subsequent potential effects on carcinogenesis.

Calcineurin inhibitors (CNIs) are central to immunosuppression in kidney transplantation (KT), improving short-term outcomes but falling short in enhancing long-term outcomes due to cardiovascular, metabolic, and renal complications. Belatacept, an FDA-approved costimulation blocker, offers a less toxic alternative to CNIs but is limited by its intravenous administration and reduced efficacy in high-immunological-risk patients.

Emerging therapies target more specific pathways to improve efficacy and accessibility. Abatacept, a first-generation cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immunoglobulin, has shown favorable outcomes in small studies. VEL-101 and Lulizumab selectively block CD28 while preserving CTLA-4 signaling, showing promise in early trials. In the CD40/CD40L pathway, results have been mixed. Iscalimab (CD40 antibody) was inferior to tacrolimus in Phase 2 trials, and Bleselumab (CD40 antibody) showed variable rejection rates despite being noninferior to tacrolimus. CD40L-targeting agents such as TNX-1500, Tegoprubart, and Dazodalibep have demonstrated promising efficacy and safety in rejection prophylaxis.

The focus in transplantation is shifting toward safer, long-term therapies with greater accessibility. Investigational agents with subcutaneous delivery methods could overcome logistical challenges, improve adherence, and redefine posttransplant care. These advancements in costimulation blockade may enhance long-term graft survival and transform the management of KT recipients.

Breastfeeding after kidney transplantation remains a complex and underexplored topic, primarily due to concerns regarding the safety of immunosuppressive therapies during lactation. Individuals who have received kidney transplants face a higher likelihood of delivering preterm infants and giving birth to babies with a low birth weight when compared with the general population. In this context, breastfeeding is increasingly important because of its advantages for preterm infants. Despite the well-established benefits of breastfeeding for both the mother and infant, the traditional recommendation has been to avoid nursing due to potential drug transmission through breast milk. However, emerging evidence suggests that certain immunosuppressants may be compatible with breastfeeding, challenging long-standing clinical guidelines. In this review, we examine the current literature on the pharmacokinetics, safety profiles, and clinical outcomes associated with key immunosuppressive agents, including cyclosporine, tacrolimus, everolimus, azathioprine, corticosteroids, and belatacept. Our work highlights that all published reports to date on the studied treatments indicate that the amount of the drug reaching breast milk is considered safe for the child's health. These conclusions, however, are derived from very short-term measurements and small numbers of patients. Therefore, we emphasize the need to design structured prospective studies to assess safety in the medium and long term. Our review aims to equip clinicians with the most up-to-date evidence on this topic, enabling them to make informed decisions regarding the compatibility of post-kidney transplant treatments with breastfeeding.

Kidney transplantation is the preferred treatment for patients with advanced chronic kidney disease and end-stage kidney disease, offering superior quality of life and survival compared to dialysis. This manuscript provides an updated overview of post-transplant care, highlighting recent advancements and current practices to assist generalists in managing these patients. It covers key areas such as immunosuppression strategies, drug interactions, and the management of transplant-specific acute kidney injury. The focus includes the use of sodium-glucose cotransporter-2 inhibitors and cell-free DNA monitoring for evaluating allograft health and immune-mediated injury. The manuscript reviews the fundamentals of immunosuppression, including both induction and maintenance therapies, and underscores the importance of monitoring kidney function, as well as addressing hypertension, diabetes, and infections. It also provides recommendations for vaccinations and cancer screening tailored to kidney transplant recipients and emphasizes lifestyle management strategies, such as exercise and sodium intake, to reduce post-transplant complications.

Vascularized composite allografts (VCA) encompass the face, upper limb, trachea, penis, abdominal wall, and, more recently, uterus transplants. They offer unique reconstructive possibilities to overcome the limitations of traditional reconstructive techniques. Unlike solid organ transplants (heart, liver, kidney, lung, etc.), VCA is not generally performed in a life-threatening situation but aims to improve quality of life, at the cost of a major constraint to its expansion: the need for lifelong immunosuppressive treatment. Nevertheless, VCA is considered one of the five most important innovations of the modern era of the discipline, and a worldwide survey of plastic surgeons has confirmed that significant changes in reconstructive surgery will be related to VCA in the future. France pioneered this type of transplantation by successfully performing the first VCA (unilateral hand transplant), the first double hand transplant, the first face transplant, the first face retransplant, and the first bilateral shoulder and arm transplant, and continues to demonstrate unprecedented surgical prowess. This activity continues to expand across the country, with active VCA programs notably in the upper limb, face, uterus and penis. This article aims to provide an update on the clinical advances made in France in the field of composite tissue allografts.

Tacrolimus, a calcineurin inhibitor widely used in transplant immunosuppression, requires careful monitoring due to its narrow therapeutic index and metabolism by cytochrome P450 CYP3A4. We present a case of a 72-year-old kidney transplant recipient who developed acute tacrolimus toxicity following treatment with nirmatrelvir/ritonavir (Paxlovid) for COVID-19. The patient presented with altered mental status, acute kidney injury, and supratherapeutic tacrolimus levels (>90 ng/mL). Given persistent toxicity, tacrolimus was held, and intravenous phenytoin was initiated to enhance clearance through CYP3A4 induction. The patient demonstrated improvement in renal function and tacrolimus levels, allowing for cautious reinitiation of immunosuppression. This case highlights the critical need for vigilant monitoring of drug-drug interactions in transplant recipients and the potential role of phenytoin as an effective therapeutic strategy in managing tacrolimus toxicity induced by CYP3A4 inhibitors as well as the urgent need for developing COVID-19 outpatient treatments with minimal interaction with tacrolimus.

Pre-transplantation red blood cell transfusion (RBCT) is a well-recognized cause of allosensitization. However, the effects of RBCT after kidney transplantation remain controversial. This study evaluates the impacts of RBCT within the first 30 days post-transplantation (early RBCT) with regard to long-term patient and graft outcomes. We retrospectively analyzed 785 patients who underwent HLA- and ABO-compatible kidney transplantation between 2014 and 2020. Patients were categorized based on whether they received early RBCT. Overall, 18.9% of patients received early RBCT. On multivariable analysis, early RBCT was independently associated with increased risks of all-cause mortality (hazard ratio, 2.264; 95% CI 1.186-4.324; P = 0.013) and death-censored graft loss (hazard ratio, 1.995; 95% CI 1.045-3.810; P = 0.036). Cumulative incidence of antibody-mediated rejection was significantly higher in the early RBCT group (P = 0.024). In the sensitivity analysis, the early RBCT significantly increased the risk of patient mortality (P = 0.017), death-censored graft loss (P = 0.018) and antibody-mediated rejection (P = 0.05), regardless of the donor profile. Early post-transplantation RBCT was associated with increased risks of all-cause mortality, graft loss, and antibody-mediated rejection, highlighting the need for reconsideration of transfusion practices following kidney transplantation.

To date, no drugs are approved for BK polyomavirus (BKPyV) reactivation, a major cause of nephropathy after kidney transplantation. Recently, tumor necrosis factor-α (TNF-α) blockade has been proposed as a promising therapy, however, the effect of TNF-α on the clinically most common archetype (ww) BKPyV remained unclear. Assays in primary renal proximal tubule epithelial cells (RPTEC) allowed efficient replication only of BKPyV strains with rearranged (rr) non-coding control regions (NCCR), which may develop at later disease stages, but not of ww-BKPyV. Here, we optimized culture conditions allowing robust replication of patient-derived ww-BKPyV, while efficiently preserving their ww-NCCR. TNF-α promoted rr-BKPyV replication, while the TH1 cytokine IFN-γ suppressed it, also in the presence of TNF-α. Surprisingly, TNF-α alone was sufficient to suppress all ww-BKPyV strains tested. Comprehensive analysis using siRNAs, and chimeric or mutated BKPyV-strains revealed that the response to TNF-α depends on the NCCR type, and that the NF-κB p65 pathway but not the conserved NF-κB binding site is essential for the TNF-α-induced enhancement of rr-BKPyV replication. Our data suggest that in immunosuppressed patients with archetype-dominated infections, TNF-α blockade could interfere with natural TNF-α-mediated anti-BKPyviral control, and this could be detrimental when IFN-γ-driven TH1 responses are impaired. Ongoing inflammation, however, could lead to the selection of rearrangements responding to NCCR-activating pathways downstream of NF-κB p65 signaling, that may overcome the initial TNF-α-mediated suppression. Our findings also highlight the importance of using clinically relevant BKPyV isolates for drug testing and discovery, for which this new assay paves the way.

The 1- and 5-year patient and graft survival rates of pediatric kidney transplant recipients have improved considerably in recent years. Regardless of early success, kidney transplantation is challenged by suboptimal long-term allograft and patient survival. Many kidney transplants are lost due to immune (rejection) and nonimmune allograft injuries, and patient survival is limited from cardiovascular disease, infection, and malignancy. Many of these co-morbidities are due to side effects of the currently available immunosuppressive drugs, especially calcineurin inhibitors and glucocorticoids, which are associated with long-term toxicity. Hence, there is an urgent need to develop new, more specific and less toxic immunosuppressive drugs. Unfortunately, there have also been no new drug approvals for adult kidney transplant recipients since belatacept in 2012, leaving the immunosuppressive drug armamentarium unchanged for more than 20 years. As a consequence of the lack of innovation in adult kidney transplant recipients, the pipeline of novel immunosuppressive agents for pediatric solid organ transplant recipients is also limited. The most promising agent in the near future, at least for adolescent patients, appears to be belatacept, despite its many limitations. In this review article, we report on three areas that appear to be the most relevant topics at this time: (i) extended-release tacrolimus, (ii) costimulation blockade with belatacept, and (iii) treatment of antibody-mediated rejection. Improved synergies between the pharmaceutical industry and the transplant community are needed to achieve the ultimate goal of improving long-term outcomes in pediatric kidney transplantation.

Cyclosporine is used as an immunosuppressive drug to improve graft survival rates in the field of organ transplantation. Therapeutic drug monitoring [TDM] of cyclosporine in transplant patients is crucial for optimizing drug dosage and minimizing the risks. Diarrhea is a common gastrointestinal condition, resulting in pharmacokinetic, malabsorption, and clinical consequences for people who rely on cyclosporine medication.

The case series discusses three pediatric patients who underwent therapeutic drug monitoring of cyclosporine to guide their treatment. The first two cases involved post-renal transplant patients with glomerulonephritis, while the third case involved a patient with tubulointerstitial kidney disease. TDM was employed to guide dose adjustments. The first patient initially received 15 mg/kg but showed high trough concentration. The dosage was gradually reduced, while diarrhea was managed. The second and third patients exhibited a similar trend which also necessitated dose adjustments.

Diarrhea was identified as a factor impacting cyclosporine levels. This case series evaluated the impact of diarrhea on cyclosporine therapeutic levels in three pediatric renal transplant patients. TDM in cyclosporine therapy is significant due to its narrow therapeutic index and variable pharmacokinetics. Elevated trough concentrations led to a gradual dose reduction to achieve the target levels.

This case series highlights the importance of TDM-guided dosing of cyclosporine, particularly in patients with diarrhea, to maintain target trough concentrations.

Acute kidney injury (AKI) in paediatric kidney transplant recipients is common. Infection including urinary tract infection (UTI) and rejection are the most common causes in children. Surgical complications often cause AKI early post-transplant, whereas BK polyomavirus nephropathy rarely occurs in the first month post-transplant. Understanding kidney physiology helps to appreciate the sensitivity of the allograft to AKI, more so than native kidneys. Although the cause of AKI is often multi-factorial, there may be an underlying process that is treatable. Eliciting the aetiology, in this regard, is of paramount importance. Pre-renal and post-renal causes of allograft dysfunction are important to distinguish from intrinsic kidney disease. Clinical information and examination of fluid balance, urine dipstick testing, blood tests, bladder and kidney transplant ultrasound, and kidney transplant biopsy remain vital assessment tools in narrowing the differential diagnosis. A careful prescribed and recreational drug history is always warranted as many drugs including supplements are nephrotoxic. Additional causes such as allograft rejection, recurrent disease, and calcineurin inhibitor toxicity need to be considered in cases of allograft dysfunction, which would not affect the native kidneys. Early detection and assessment of AKI is crucial in promoting recovery. Significant progress has been made in specific pathologies over the last 20 years, which has improved kidney allograft survival rates considerably. Research into identifying AKI biomarkers to assist early diagnosis, before the serum creatinine rises, is ongoing.

Gut microbiota affect transplantation outcomes; however, the influence of immunosuppression and cell therapy on the gut microbiota in cardiovascular care remains unexplored. We investigated gut microbiota dynamics in a nonhuman primate (NHP) cardiac ischemia/reperfusion model while under immunosuppression and receiving cell therapy with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (EC) and cardiomyocytes (CM). Both immunosuppression and EC/CM co-treatment increased gut microbiota alpha diversity. Immunosuppression promoted anaerobes, such as Faecalibacterium, Streptococcus, Anaerovibrio and Dialister, and altered amino acid metabolism and nucleosides/nucleotides biosynthesis in host plasma. EC + CM cotreatment favors Phascolarctobacterium, Fusicatenibacter, Erysipelotrichaceae UCG-006, Veillonella and Mailhella. Remarkably, gut microbiota of the EC/CM co-treatment group resembled that of the pre-injury group, and the NHPs exhibited a metabolic shift towards amino acid and fatty acid/lipid biosynthesis in plasma following cell therapy. The interplay between shift in microbial community and host homeostasis during treatment suggests gut microbiome modulation could improve cell therapy outcomes.

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.

Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.

Exercise has the potential to reduce the susceptibility to comorbidity and cardiovascular disease in kidney transplant recipients. However, kidney transplant recipients report lower levels of exercise compared to the general population, prompting an investigation into the barriers and enablers to exercise in this transplant cohort.

This systematic review aimed to explore and map the barriers and enablers to exercise in kidney transplant recipients.

Seven electronic databases were systematically searched. Themes were synthesised and then deductively categorised using the Theoretical Domains Framework.

Eleven studies were included in the review. Commonly reported barriers to exercise were lack of exercise guidance (n = 9 studies), physical limitations (n = 5 studies) and a fear of harming the kidney (n = 7 studies). Enablers were a desire to return to normality (n = 5 studies), physical and mental benefits (n = 3 studies), goal setting and tracking improvements (n = 3 studies). At the local level, barriers identified by kidney transplant recipients were a lack of knowledge, fear of injuring the kidney, bad weather and physical limitations. Perceived enablers were already living an active lifestyle, mental benefits, exercise preferences and social support.

Key findings of this research were an increased demand for specific/explicit exercise information regarding type and intensity, and personalised guidance and support for kidney transplant recipients after transplantation. These findings can be used to inform the development of exercise resources and interventions for kidney transplant recipients and their health care professionals within the local community and at a greater level.

Torque teno virus load (TTVL) is gaining importance as a surrogate parameter to assess immunocompetence in kidney transplant recipients. Although the dynamics of TTVL have been investigated before, the impact of different induction agents and variations in immunosuppressive maintenance therapies on TTVL remain unknown.

In this retrospective study, TTVL was quantified in 537 plasma or serum samples from 134 patients transplanted between 2018 and 2021. TTVL was examined pre-transplantation and 30-, 90-, 180-, and 360-days post-transplant. To assess the influence of induction therapy on TTVL, 67 patients receiving anti-thymocyte globulin (ATG) induction were matched with 67 patients receiving an interleukin-2 receptor antagonist (IL2-RA) induction in terms of age, sex, and donor modality.

Following transplantation, there was a steep increase in TTVL post-transplant for all patients with peak viral loads at 90 days post-transplant (median TTVL [IQR] 7.97×106, [4.50×105-1.12×108]) followed by subsequently declining viral loads. Compared to patients receiving IL2-RA as induction therapy, patients receiving ATG had significantly higher peak viral loads 3 months post-transplant (median TTVL [IQR] 2.82×107 [3.93×106-1.30×108] vs. median TTVL [IQR] 2.40×106 [5.73×104-2.60×107]; P<0.001). Throughout all post-transplant time points, patients receiving additional rituximab for induction along with higher tacrolimus target levels exhibited the highest TTVL.Patients whose TTVL 3-months post-transplant exceeded the currently proposed cutoff to predict infections within the first year post-transplant [6.2 log10] showed a trend towards a higher risk of being hospitalized with an infection in the following 9 months, albeit without being statistically significant (HR=1.642, P=0.07).

Higher TTVL reflects the greater immunosuppressive burden in immunological high-risk patients receiving intensive immunosuppression. The choice of induction agent and intensified immunosuppressive maintenance therapy notably affects TTVL at 3 months post-transplant and beyond, necessitating careful consideration when interpreting and applying TTVL cutoffs to monitor immunocompetence post-transplant.

Kidney transplant recipients (KTRs) are highly vulnerable to COVID-19. An intensified scheme of vaccination offers short-term protection to the 50%-75% of KTRs able to develop a germinal center reaction, required for the generation of neutralizing titers of antibodies (NAbs). However, the duration of this vaccinal protection is unknown. In-depth longitudinal analysis of the immune response to vaccination of 33 KTRs demonstrates that the low peak of IgGs, the progressive decline in antibody titers, and the emergence of a variant of concerns (VOC) of SARS-CoV2, synergize to let 2/3 of responders to vaccine without NAbs after only a few months. Yet, a retrospective study of an independent cohort of 274 KTRs, revealed that the risk of severe COVID-19 in the latter was low, similar to that of patients with serum neutralizing capacity against VOC. Our work links this late vaccine protection with the presence of memory B cells, which are generated during the initial vaccine-induced germinal center reaction, have a wide repertoire directed against conserved spike epitopes, and rapidly differentiate into IgG-producing plasma cells upon antigenic rechallenge. We conclude that in contrast with a serological layer that goes fading rapidly, the cellular layer of humoral memory provides an efficient long-term protection against VOC to KTRs. This illustration of the complementary roles of the two layers of the humoral memory has implications in immunopathology beyond the COVID-19 in KTRs.

Background and Objectives: Inherited metabolic disorders (IMDs), primarily cystinosis, Fabry disease, and methylmalonic acidemia (MMA), are genetic conditions that typically result in multi-organ disease manifestations. Kidney function progressively deteriorates in many cases, with patients eventually reaching end-stage kidney disease (ESKD) and requiring renal replacement therapy. Kidney transplantation has been deemed the optimal renal replacement therapy option to achieve long-term survival in patients with IMD. Whilst improved long-term survival is expected, the patterns of clinical evolution for IMD after transplantation remain largely unknown. Methods: Our group conducted a retrospective observational study that included 37 adult patients with IMD (11 with cystinosis, 20 with Fabry disease, and 6 with MMA). The study evaluated the clinical status and progression of these patients following kidney transplantation between January 2010 and December 2023. Results: This generally resulted in good graft outcomes for patients with IMD. Standard immunosuppression regimes included tacrolimus, mycophenolate mofetil, and prednisolone. The mean graft survival duration was noted to be 12 years in patients with cystinosis, 11 years in patients with Fabry disease, and 7 years in patients with MMA. Suboptimal outcomes were noted with grafts of cadaveric origin and poor adherence to the prescribed post-transplant immunosuppression regime. A greater extra-renal morbidity burden was associated with a reduced duration of graft function and increased mortality in patients with IMD. Conclusions: Our findings emphasise the need for a multi-disciplinary approach in the care of IMD patients following kidney transplantation.

Solid organ transplant (SOT) recipients display weak seroconversion and neutralizing antibody (NAb) responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and remain at risk of severe coronavirus disease 2019 (COVID-19). While B-cell memory is the hallmark of serological immunity, its role in driving successful vaccine responses and providing immune protection in SOT patients remains unclear.

We investigated the function and interplay of SARS-CoV-2-specific memory B cells (mBc), different cytokineproducing T cells, and cross-reactive NAb in driving seroconversion and protection against COVID-19 in two cohorts. First, we studied a large cohort of 148 SOT recipients and 32 immunocompetent individuals who underwent several vaccinations. Subsequently, we assessed 25 SOT patients participating in a randomized controlled trial to compare two different immunosuppressive strategies for allowing successful seroconversion and memory-cell responses after booster vaccination.

We corroborate previous findings that B- and T-cell memory responses are weaker and more delayed in SOT patients than in immunocompetent (IC) individuals; however, within the SOT cohort, we found that these responses are relatively stronger and more robust in patients not receiving mycophenolate mofetil (MMF)-based therapies. Anti- spike IgG titers strongly correlated with RBD-specific IgG-producing mBc, with both displaying broad viral cross reactivity. Prebooster SARS-CoV-2-specific mBc and IL-2- producing T cells accurately predicted Nab seroconversion (AUC, 0.828) and protection against severe COVID-19. While switching unresponsive SOT patients from calcineurin inhibitors (CNI)/MMF to a low-exposure CNI/mTOR-i regimen favored wider SARS-CoV-2-specific immune responses after a fourth booster vaccination, preformed RBD-specific mBc predicted NAb seroconversion.

Our study adds new insights into the pathobiology of immune memory and highlights the pivotal role of SARS-CoV-2-specific mBc in promoting immune protection inSOT patients.

Background: Type 1 diabetes (T1D) is an autoimmune disorder characterised by the destruction of insulin-producing beta cells in the pancreatic islets, resulting from a breakdown in immunological tolerance. Currently, T1D treatment primarily relies on insulin replacement or immunosuppressive therapies. However, these approaches often have significant drawbacks, including adverse effects, high costs, and limited long-term efficacy. Consequently, there is a pressing need for innovative immunotherapeutic strategies capable of inducing antigen-specific tolerance and protecting beta cells from autoimmune destruction. Among the various antigens, β-cell antigens like 65 kDa glutamic acid decarboxylase (GAD65) have been explored as vaccine candidates for T1D. Despite their potential, their effectiveness in humans remains modest, necessitating the use of appropriate adjuvants to enhance the vaccine's protective effects. Methods: In this study, we evaluated the therapeutic potential of kynurenine (KYN), dexamethasone (DXMS), tacrolimus (FK506), and aluminium hydroxide (Alum) in combination with the GAD65 phage vaccine as adjuvants. Results: Our findings demonstrate that KYN, when used in conjunction with the GAD65 vaccine, significantly enhances the vaccine's immunosuppressive effects. Compared to dexamethasone, FK506, and Alum adjuvants, KYN more effectively reduced the incidence and delayed the onset of T1D, preserved β-cell function, and promoted the induction of regulatory T cells and antigen-specific tolerance. These results suggest that KYN combined with vaccines could offer superior preventive and therapeutic benefits for T1D compared to existing treatments. Additionally, we investigated the dose-dependent effects of the GAD65 vaccine by including a low-dose group in our study. The results indicated that reducing the vaccine dose below 1010 plaque-forming units (pfu) did not confer any protective advantage or therapeutic benefit in combination with KYN. This finding underscores that 1010 pfu is the minimum effective dose for the GAD65 vaccine in achieving a protective response. In conclusion, KYN shows considerable promise as an adjuvant for the GAD65 vaccine in T1D therapy, potentially offering a more effective and durable treatment option than current immunosuppressive strategies.

Tailored exercise prescription is a crucial intervention for kidney transplant recipients (KTRs). This longitudinal study investigates the impact on long-term effectiveness of exercise prescriptions over one year follow-up, implementing telehealth tools for exercise administration and adherence monitoring.

KTRs were evaluated with clinical assessments including body composition, blood and urinary parameters, physical performance and quality of life at baseline (T0), after six (T6) and twelve (T12) months. The adherence to prescribed exercise training was monitored via video call interviews until T6 when the sample was divided into a group monitored via wearables (WG) and a group continuing video calls (VG) until T12.

Twenty-six KTRs completed the study. No changes in body composition and kidney function were reported. KTRs showed an improvement in lipid profile, systolic blood pressure, cardiorespiratory fitness and quality of life. WG showed no clinical differences compared to VG except for reported higher quality of life.

A good adherence to the exercise prescription was obtained with both monitoring methods (232 vs 253 min/week). This study reinforces the inclusion exercise training for KTRs to enhance physical fitness and reduce cardiovascular risk factors. These results emphasize the role of telehealth monitoring methods as motivators for adherence to long-term exercise prescriptions.

Severity of deceased donor kidney fibrosis impacts graft survival in deceased-donor kidney transplantation. Our aim was to identify potential miRNA biomarkers in urinary exosomes that mirror interstitial fibrosis and tubular atrophy (IFTA) severity. Among 109 urine samples from deceased donors, 34 displayed no IFTA in the zero-day biopsy (No IFTA group), while the remaining 75 deceased donor kidneys exhibited an IFTA score ≥ 1 (IFTA group). After analyzing previous reports and electronic databases, six miRNAs (miR-19, miR-21, miR-29c, miR-150, miR-200b, and miR-205) were selected as potential IFTA biomarker candidates. MiR-21, miR-29c, miR-150, and miR-205 levels were significantly higher, while miR-19 expression was significantly lower in the IFTA group. MiR-21 (AUC = 0.762; P < 0.001) and miR-29c (AUC = 0.795; P < 0.001) showed good predictive accuracy for IFTA. In the No IFTA group, the eGFR level at 1 week after transplantation was significantly higher compared to the IFTA group (41.34 mL/min/1.73m2 vs. 28.65 mL/min/1.73m2, P = 0.012). These findings signify the potential of urinary exosomal miRNAs as valuable biomarker candidates for evaluating the severity of IFTA in deceased donor kidneys before they undergo recovery.

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.

In a kidney transplant tertiary referral center; we compared 3 operating team configurations of different surgical specialties to highlight the effect of the operating surgeon's specialty on various operative details and procedural outcome.

A total of 50 cases of living donor transplantations were divided into 3 main groups according to the operating surgeons' specialty, the first group (A) includes 12 patients exclusively operated on by urologists with advanced training in transplantation, the second group (B) includes 35 patients operated by combined surgical specialties; a urologist and a vascular surgeon both with advanced transplantation training, and a third group (C) includes 3 cases where the transplant operation commenced with operating urologists as in group (A) but required intraoperative urgent notification of a vascular surgeon to manage unexpected intraoperative technical difficulties or major complications. Cases were studied according to operative details, anastomosis techniques, ischemia times, total procedure time, recovery of urinary output, intensive care unit (ICU) stay, postoperative surgical complications and serum creatinine level for up to 3 years of follow-up.

Study of operative details revealed that total duration of graft ischemia was significantly shorter in group (B) and significantly longer in group (C) (P value 0.001), Total procedural duration also varied significantly between the 3 groups, group (B) being the shortest while group (C) was the longest (P value less than 0.001). Technically; group (A) used only end to end arterial anastomosis as a standard technique, while group (B) used both end-to-end and end-to-side anastomoses as required per each case. End to side anastomosis in group (B) yielded better immediate graft response in the form of change in color, texture, earlier and more profuse postoperative urine volumes (P value 0.025). Furthermore, anastomosis to common and external iliac arteries (group B) yielded earlier and higher urine volumes than the internal iliac artery (P values 0.024 and 0.031 respectively). Group (B) recorded significantly less postoperative perigraft hematomas and lymphoceles compared to the other 2 groups. Equal rates of urine leaks, ICU stay, creatinine levels, patient and grafts survival rates among groups (A) and (B), while postoperative recovery and ICU stay duration were more lengthy in the complicated group (C).

A vascular surgeon operating in a transplantation team would deal comfortably and efficiently with various vascular related challenges and complications, thus avoiding unnecessary time waste, complications and costs.

Existing literature on best practices to reduce the risk of infectious complications associated with ureteral stent removal in kidney transplant recipients is limited. Prior to 2021, a formal process surrounding stent removal was not in place at our institution. In June 2021, a stent removal protocol was established. This protocol included the following: obtaining a preprocedure urine culture, prescribing universal culture-directed antimicrobial prophylaxis, earlier stent removal posttransplant, and patient education. We performed a retrospective quasi-experimental study of kidney transplant recipients who had their stents removed between July 2020 and June 2022. The primary outcome was the incidence of infectious complications within 30 days. Infectious complications were defined as urinary tract infection and bacteremia due to urinary source, as well as hospitalization, emergency department visit, or outpatient encounter for possible urinary tract infection. Secondary objectives included infectious and immunologic complications within 30 days to 1 year from transplant. During this study period, 239 adult kidney transplant recipients were included: 88 in the preprotocol group and 151 in the protocol group. The median time to stent removal was shorter in the protocol group (25 vs 36 days, P < .001). More patients in the protocol group received preprocedure antibiotics (99% vs 36%, P < .001). Infectious complications were higher in the preprotocol group (9% vs 3%, P = .035). Overall, the stent removal protocol was associated with fewer infectious complications (odds ratio, 0.18; 95% CI, 0.05-0.73). Further investigation is necessary to determine which individual interventions, if any, drive this benefit.

Posttransplantation complications pose a major challenge to the long-term survival and quality of life of organ transplant recipients. These complications encompass immune-mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft-versus-host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients.

End stage renal disease (ESRD) occurs when the kidneys are unable to filter the waste products and excessive fluids from the blood that results into the accumulation of toxins and fluid in the body. Tacrolimus is commonly used immunosuppressant while sirolimus and cyclosporin are rarely used drugs to stop solid organ transplant rejection. The host's immunological response following transplantation produces interleukin-10 (IL-10), which influences the varied CYP3A-dependent drug disposition of tacrolimus. The aim of this study was to determine the genetic polymorphisms of IL-10 (rs1800871, rs1800872 and rs1800896) gene associated with tacrolimus metabolism in kidney transplant patients from Lahore Punjab, Pakistan.

The study collected blood samples of 103 healthy individuals and 137 kidney transplant patients as control and treatment groups, respectively. We employed Tetra ARMS PCR for the genotype analysis of extracted DNA. The alleles were called on 2% agarose gel. Moreover, the study utilized SPSS software to analyze statistical significance of polymorphism.

It was found that genotypic frequencies of IL-10 (rs1800871), IL-10 (rs1800872), and IL-10 (rs1800896) were (TT: 66.4%; TC: 31.4%; CC: 2.2%), (AA: 27.7%; AC: 54%; CC: 18.2%), (AA: 64.2%; GA: 17.5%; GG: 18.3%), respectively among kidney transplant patients. All parameters show significant association at different points after transplantation. Genetic analysis showed that TC and CC genotypes in rs1800871 (OR (95%CI) = 5.721 (3.231-10.131), P < 0.001; OR (95%CI) = 3.370 (0.642-17.672), P = 0.150), AC and CC genotypes in rs1800872 (OR (95%CI) = 1.294 (0.695-2.410), P = 0.415; OR (95%CI) = 1.453 (0.671-3.147), P = 0.342), GA and GG genotypes in rs1800896 (OR (95%CI) = 42.952 (17.566-105.021), P = 0.001; OR (95%CI) = 7.040 (2.563-19.333), P = 0.342) was associated with risk of renal rejection in kidney transplant patients. Besides, genetic models showed that TT in rs1800871, AA genotypes in rs1800872 and rs1800892 were associated with risk of renal rejection under dominant model when compared to controls (OR (95%CI) = 5.721 (3.231-10.131), P < 0.001; OR (95%CI) = 1.335 (0.735-9.290), P < 0.341; OR (95%CI) = 24.629 (10.599-57.230), P < 0.001), respectively.

From the results, it is concluded that genetic polymorphism of IL-10 (rs1800871, rs1800872 and rs1800896) has a highly significant association with risk of renal rejection in Pakistani kidney transplant patients.