Risk Of Graft Rejection Research Articles

New Scenarios in Liver Transplantation for Hepatocellular Carcinoma.

Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct-acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash-out period before LT and post-LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non-hepatic complications must be understood to prevent them from becoming obstacles to long-term OS. In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system.

Risk of cellular or antibody-mediated rejection in pediatric kidney transplant recipients with BK polyomavirus replication-an international CERTAIN registry study.

In kidney transplant recipients (KTR), BK polyomavirus-associated nephropathy (BKPyVAN) is a major cause of graft loss. To facilitate the clearance of BKPyV-DNAemia, reduction of immunosuppression is currently the treatment of choice but may increase the risk of graft rejection. This international CERTAIN study was designed to determine the risk of alloimmune response and graft dysfunction associated with immunosuppression reduction for BKPyV treatment in 195 pediatric KTR. BKPyV-DNAemia was associated with a more than twofold increased risk of late T cell-mediated rejection (TCMR) (HR 2.22, p = 0.024), of de novo donor-specific HLA antibodies (dnDSA) and/or antibody-mediated rejection (ABMR) (HR 2.64, p = 0.002), and of graft function deterioration (HR 2.73, p = 0.001). Additional independent risk factors for dnDSA/ABMR development were a higher HLA mismatch (HR 2.72, p = 0.006) and re-transplantation (HR 6.40, p = 0.000). Other independent predictors of graft function deterioration were TCMR (HR 3.98, p = 0.003), higher donor age (HR 1.03, p = 0.020), and re-transplantation (HR 3.56, p = 0.013). These data indicate that reduction of immunosuppression for BKPyV-DNAemia management is associated with increased alloimmune response in pediatric KTR. Therefore, regular dnDSA screening and close monitoring of graft function in case of BKPyV-DNAemia followed by subsequent reduction of immunosuppressive therapy are recommended.

Autologous Contralateral and Ipsilateral Rotational Penetrating Keratoplasty - A Case Series and Mini-Review.

Corneal stromal opacities can severely impact visual acuity if they are located in the visual axis. Homologous penetrating keratoplasty (HPK) is usually the preferred surgical option in such clinical circumstances. However, autologous penetrating keratoplasty (APK) could be an immunologically safer alternative. The purpose of this study was to report the surgical technique, indications, and (dis)advantages of ipsilateral rotational and contralateral APK, as well as pre- and postoperative clinical findings of four patients who underwent contralateral APK. In ipsilateral rotational APK, eccentric trephination places the central corneal opacity at the excision edge, whereafter the corneal button is rotated to clear the visual axis. Contralateral APK is suitable for more specific clinical situations with corneal opacity in a functionally much better eye. Clear cornea of the (almost) blind eye suffering from a noncorneal pathology is transplanted to the potentially better seeing eye suffering from a corneal pathology, followed by HPK in the (almost) blind donor eye. After 18 months, potentially better-seeing eyes improved from logMAR 1.3 to 0.6 in visual acuity, with most HPK-treated weaker eyes matching preoperative levels. Considering ipsilateral rotational and contralateral APK before moving on straight towards HPK is crucial in select cases. Autologous contralateral keratoplasty should be preferred for patients with (1) corneal scars in a potentially better seeing eye and (2) a clear cornea in an (almost) blind eye, especially in cases of high risk for graft rejection.

B-297 Tacrolimus Concentrations in Envarsus vs Prograf Patients: An Evaluation of the Clinical Impact of LC-MS/MS and Immunoassay Methods on Tacrolimus measurement

Abstract Background Tacrolimus is a calcineurin inhibitor used as part of an immunosuppressive regimen in kidney and liver transplant patients to prevent graft-versus-host disease (GvHD) and requires therapeutic drug monitoring due to its narrow therapeutic index. Tacrolimus levels are commonly measured using two different methodologies - immunoassay and liquid chromatography tandem mass spectrometry (LC-MS/MS). A global proficiency study to assess and compare the measurement of trough levels by these two methodologies noted a positive bias with the ARCHITECT immunoassay which is likely due to the presence of tacrolimus metabolites. The aim of our study is to assess the impact of two different formulations of tacrolimus on the accuracy of its analytical measurement. While differences between immunoassay and LC-MS/MS results have been evaluated for immediate-release tacrolimus (Prograf), it has yet to be characterized for extended-release formulations such as Envarsus. The discrepancy between immunoassay and LC-MS/MS has clinical implications, as dosage modifications are based on measured concentrations, analytical variation may cause intervals of subtherapeutic or supratherapeutic exposure, increasing the risk of graft rejection or toxicity. Methods Development of an LC-MS/MS method for the simultaneous quantification of tacrolimus and its major metabolite, desmethyl tacrolimus, was performed in whole blood. Traceable calibrators and quality control material for tacrolimus and specimens supplemented with desmethyl tacrolimus were used to determine accuracy and precision. Tacrolimus concentrations were measured by LC-MS/MS and ARCHITECT immunoassay methods in excess whole blood specimens from patients treated with either Prograf or Envarsus. Measurement biases between LC-MS/MS and immunoassay methodologies were determined for both formulations of tacrolimus. Results External calibration curves for both tacrolimus and desmethyl tacrolimus were linear (R2>0.995), and the analytical measurement range (AMR) for tacrolimus spanned from 1.1 - 31.6 ng/ml. Calibrator and Quality control (QC) biases were within 15% of their target values throughout the AMR and within-run imprecision was less than 10% (n=25) for all calibrators and QCs. Between-run imprecision for Low, Mid, and High QC levels over a period of 2 weeks (n=5 days) was less than 10%. Comparative bias of tacrolimus concentrations between immunoassay and LC-MS/MS was significantly lower (P value=0.0074) for Envarsus (n=20 specimens) relative to Prograf (n=32 specimens). Conclusions The differential bias between immunoassay and LC-MS/MS in the measurement of tacrolimus in patients dosed with immediate-release versus extended-release formulations suggests that their distinct pharmacokinetic profile may impact the accuracy of the measurement. Therefore, applying observed measurement biases from different assays derived from Prograf patients to Envarsus patients and vice versa may result in erroneous estimation of tacrolimus concentrations.

Cancer Screening and Cancer Treatment in Kidney Transplant Recipients.

As the population ages and post-transplant survival improves, pretransplant and post-transplant malignancy are becoming increasingly common. In addition, rapid advances in cancer therapies and improving outcomes prompt us to rethink pretransplant cancer-free wait time and screening strategies. Although kidney transplant recipients (KTRs) are at higher risk of developing cancer, epidemiological data on how to best screen and treat cancers in KTRs are incomplete. Thus, current recommendations are still largely on the basis of studies in the general population, and their validity in KTRs is uncertain. Kidney transplant candidates without prior cancer should be evaluated for latent malignancies even in the absence of symptoms. Conversely, individuals with a history of malignancy require thorough monitoring to detect potential recurrences or de novo malignancies. When treating KTRs with cancer, reducing immunosuppression can enhance antitumor immunity, yet this also increases the risk of graft rejection. Optimal treatment and immunosuppression management remains undefined. As the emergence of novel cancer therapies adds complexity to this challenge, individualized risk-benefit assessment is crucial. In this review, we discuss up-to-date data on pretransplant screening and cancer-free wait time, as well as post-transplant cancer screening, prevention strategies, and treatment, including novel therapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies.

Comparison of Autologous and Allogeneic Adipose-Derived Stem Cells in Kidney Transplantation: Immunological Considerations and Therapeutic Efficacy.

Regenerative medicine shows significant potential in treating kidney diseases through the application of various types of stem and progenitor cells, including mesenchymal stem cells (MSCs), renal stem/progenitor cells, embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Stem cells possess the unique ability to repair injured organs and improve impaired functions, making them a key element in the research of therapies for kidney tissue repair and organ regeneration. In kidney transplantation, reperfusion injury can cause tissue destruction, leading to an initially low glomerular filtration rate and long-term impact on function by creating irreversible interstitial fibrosis. MSCs have proven useful in repairing early tissue injury in animal models of kidney, lung, heart, and intestine transplantation. The use of stem cell therapies in solid organ transplantation raises the question of whether autologous or allogeneic cells should be preferred. Adipose-derived stem cells (ASCs), characterized by the lack of HLA Class II molecules and low expression of HLA Class I and co-stimulatory signals, are considered immune-privileged. However, the actual risk of graft rejection associated with allogeneic ASCs remains unclear. It has been demonstrated that donor-derived ASCs can promote the development of Treg cells in vitro, and some degree of tolerance induction has been observed in vivo. Nevertheless, a study comparing the efficacy of autologous and allogeneic ASCs in a rat model with a total MHC mismatch for kidney transplantation showed that donor-derived administration of ASCs did not improve the grafts' survival and was associated with increased mortality through an immunologically mediated mechanism. Given the lack of data, autologous ASCs appear to be a safer option in this research context. The aim of this review was to examine the differences between autologous and allogeneic ASCs in the context of their application in kidney transplantation therapies, considering potential immune reactions and therapeutic efficacy. Some have argued that ASCs harvested from end-stage renal disease (ESRD) patients may have lower regenerative potential due to the toxic effects of uremia, potentially limiting their use in transplantation settings. However, evidence suggests that the beneficial properties of ASCs are not affected by uremia or dialysis. Indeed, some investigators have demonstrated that ASCs harvested from chronic kidney disease (CKD) patients exhibit normal characteristics and function, maintaining consistent proliferative capacity and genetic stability over time, even after prolonged exposure to uremic serum Furthermore, no differences were observed in the response of ASCs to immune activation or their inhibitory effect on the proliferation of alloantigen-activated peripheral blood mononuclear cells between patients with normal or impaired renal function. This review presents the current achievements in stem cell research aimed at treating kidney diseases, highlighting significant progress and ongoing efforts in the development of stem cell-based therapies. Despite the encouraging results, further research is needed to overcome the current limitations and fully realize the potential of these innovative treatments. Advances in this field are crucial for developing effective therapies that can address the complex challenges associated with kidney damage and failure.

Improved Outcomes in Myelofibrosis after Allogeneic Stem-Cell Transplantation in the Era of Ruxolitinib Pretreatment and Intensified Conditioning Regimen—Single-Center Analysis

(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. (2) Methods: In this retrospective, single-center study, we compared allo-HSCT outcomes in 36 adult patients with MF transplanted at two-time intervals (2001–2015 versus 2016–2021). (3) Results: The estimated median overall survival was 48.9 months (95%CI 0.00–98.2) in the cohort transplanted before 2016 and not reached in the more recent years (p = 0.04) due to markedly lower non-relapse mortality (p = 0.02). The 3-year relapse incidence was low in both cohorts (11.1% and 12.5%, p > 0.99). When comparing only subgroups within the more recent cohort based on the presence or absence of total body irradiation (TBI) or the use of sequential regimens, OS and PFS were comparable. (4) Conclusion: Pretreatment with ruxolitinib, intensified conditioning, and the preferential use of haploidentical related instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allo-HCT in MF in recent years.

Torque Teno Virus Loads as a Marker of Immunosuppression in Pediatric Kidney Transplant Recipients.

Long-term renal function and survival after kidney transplantation rely on appropriate immunosuppressive treatment to prevent the risk of rejection. New biomarkers are needed to accurately assess the degree of immunosuppression in renal transplant recipients in order to avoid organ rejection and the development of opportunistic infections. Highly prevalent in humans, torque teno virus (TTV), which belongs to the family Anelloviridae, is a small, nonenveloped, single-stranded DNA virus which has not been linked with any specific human illness, but which constitutes a major component of the human virome. Host antiviral responses allow TTV levels to be controlled; however, viral persistence remains, explaining the high prevalence in human populations, including healthy individuals. Important confounders of TTV load include time since transplantation, age, gender, obesity, and smoking status. TTV-based guidance of immunosuppressive drug dosing could help with risk stratification, reducing the risk of infection, graft rejection and oncologic disease on an individual level, enabling long-term patient and graft survival. Original studies were accessed by a systematic search from electronic databases including PubMed, ScienceDirect and Wiley Online Library. The presented data mainly derive from adult transplant recipients showing an association between TTV plasma levels and the immune status of the host: High-TTV load and high immunosuppression are associated with a risk of infection, and low-TTV load and low immunosuppression indicate a risk of rejection. However, there is minimal information on pediatric transplant recipients with further research required in this cohort. To date, it has been demonstrated that longer posttransplant times are significantly associated with lower TTV levels in children with renal transplant. Meanwhile, an association between lower TTV loads and increased risk of graft reject during the first year of transplantation was also reported. More recently, Eibensteiner etal. revealed a robust, independent association between TTV plasma load and the onset of Cytomegalovirus and BK virus infections. Data from randomized controlled trials are still missing, even in adults, but a multicenter randomized controlled trial for TTV-guided immunosuppression in adult kidney recipients (TTVguideIT) began in 2022. There is, therefore, great promise for TTV levels to be used as a biomarker that could potentially improve both graft and patient survival in transplantation.

Mechanism, Potential, and Concerns of Immunotherapy for Hepatocellular Carcinoma and Liver Transplantation.

In the last decade, immunotherapy (IT) has revolutionized oncology and found indications in many cancers, including hepatocellular carcinoma (HCC). In HCC, IT has become the leading systemic therapy for advanced diseases. At the same time, it carries the promise of being a valuable therapy in other settings, including intermediate-stage and unresectable disease, as a downstaging or conversion modality. More controversial is the role of IT in relationship to liver transplantation (LT): on one side, it could be a helpful tool to control or downstage HCC before LT or to treat tumor recurrence after LT, while on the other, it carries the risk of graft rejection and graft loss. This review aims to cover these concerns in depth and unravel the current literature.

Effect of CYP3A5*3, ABCC2 C-24T, and ABCC2 C3972T Genetic Polymorphisms on Direct Cost of Kidney Transplant Recipients.

Introduction Genetic variations can influence how kidney transplant recipients (KTRs) respond to immunosuppressive drugs. However, limited resources necessitate a cost-benefit analysis of pharmacogenetic testing to determine its role in routine practice. This study investigated the cost-effectiveness of three genetic polymorphisms (CYP3A5*3, ABCC2 -24C>T,andABCC2 3972C>T) in KTRs. Methods This was a multicenter, prospective observational cohort study that included patients on tacrolimus-mycophenolate-prednisolone treatment. Ethnically diverse adult KTRs who had undergone kidney transplantation between 2020 and 2021 and consented were enrolled in the study. Deoxyribonucleic acid(DNA) was extracted from the collected blood samples using a commercially available kit.CYP3A5*3,ABCC2 -24C>T,andABCC2 3972C>Tsingle nucleotide polymorphisms (SNPs) were determined by polymerase chain reaction (PCR). Results Data was analyzed from 39 KTRs with an average age of 32.2 ± 7.0 years. The median annual healthcare cost per patient was MYR 52,700 (laboratory tests and immunosuppressants being the highest expenses). Notably, the annual cost was significantly higher in patients with theCYP3A5*3variant compared to the wildtype (p < 0.001). Furthermore, an incremental cost-effectiveness analysis revealed that carriers of theCYP3A5*1wildtype allele, theABCC2 -24C>T Tvariant allele, and theABCC2 3972C>T Tvariant allele were associated with a more cost-effective approach to kidney transplantation management, potentially reducing the risk of graft rejection and acute tubular necrosis (ATN). Conclusion While these findings suggest potential cost benefits for specific genotypes, further research with larger and more diverse patient populations is necessary to definitively establish the role of pharmacogenetic testing in optimizing cost-effectiveness for KTRs.

Molecular screening of transitional B cells as a prognostic marker of improved graft outcome and reduced rejection risk in kidney transplant.

Understanding immune cell dynamics in kidney transplantation may provide insight into the mechanisms of rejection and improve patient management. B cells have gained interest with a special relevance of the "regulatory" subsets and their graft outcome prognostic value. In this study, we aimed to prove that the direct immunophenotyping and target gene expression analysis of kidney transplant patients' fresh whole blood will help to identify graft rejection risk and assist in the monitoring of kidney transplanted patients. We employed flow cytometry and qPCR techniques to characterize B and T cell subsets within fresh whole blood samples, with particular emphasis on transitional B cells (TrB) identified as CD19+CD24hiCD38hi. TrB are a relevant population in the context of kidney transplantation and are closely associated with regulatory B cells (Bregs) in humans. Patients were monitored, tracking pertinent clinical parameters and kidney-related events, including alterations in graft function and episodes of biopsy proven rejection. Higher percentages of TrB cells at 3 months after transplantation were positively associated with better graft outcomes and lower biopsy-proven acute rejection risk. Furthermore, a novel panel of B cell regulatory associated genes was validated at 3 months post-transplantation by qPCR analysis of peripheral blood mononuclear cell (PBMC) mRNA, showing high predictive power of graft events and prognostic value. These findings suggest that monitoring TrB may provide interesting patient management information, improve transplant outcomes, and allow for personalized drug regimens to minimize clinical complications.

Adverse Pregnancy Outcomes in Solid Organ Transplant Recipients

Transplant recipients experience high rates of adverse pregnancy outcomes; however, contemporary estimates of the association between solid organ transplantation and adverse pregnancy outcomes are lacking. To evaluate the association between solid organ transplantation and adverse pregnancy outcomes and to quantify the incidence of allograft rejection and allograft loss during pregnancy. PubMed/MEDLINE, EMBASE and Scopus databases were searched from January 1, 2000, to June 20, 2024, and reference lists were manually reviewed. Cohort and case-control studies that reported at least 1 adverse pregnancy outcome in pregnant women with solid organ transplantation vs without solid organ transplant or studies that reported allograft outcomes in pregnant women with solid organ transplantation were included following independent dual review of abstracts and full-text articles. Two investigators abstracted data and independently appraised risk of bias using the Newcastle Ottawa Scale. A random-effects model was used to calculate overall pooled estimates using the DerSimonian-Laird estimator. Reporting followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Primary pregnancy outcomes were preeclampsia, preterm birth (<37 weeks), and low birth weight (<2500 g). Secondary pregnancy outcomes were live birth rate, gestation, very preterm birth (<32 weeks), very low birth weight (<1500 g), and cesarean delivery. Allograft outcomes were allograft loss and rejection during pregnancy. Data from 22 studies and 93 565 343 pregnancies (4786 pregnancies in solid organ transplant recipients) were included; 14 studies reported adverse pregnancy outcomes, and 13 studies provided data for allograft outcomes. Pregnancies in organ transplant recipients were associated with significantly increased risk of preeclampsia (adjusted odds ratio [aOR], 5.83 [95% CI, 3.45-9.87]; I2 = 77.4%), preterm birth (aOR, 6.65 [95% CI, 4.09-12.83]; I2 = 81.8%), and low birth weight (aOR, 6.51 [95% CI, 2.85-14.88]; I2 = 90.6%). The incidence of acute allograft rejection was 2.39% (95% CI, 1.20%-3.96%; I2 = 68.5%), and the incidence of allograft loss during pregnancy was 1.55% (95% CI, 0.05%-4.44%; I2 = 69.2%). In this systematic review and meta-analysis, pregnancies in recipients of a solid organ transplant were associated with a 4 to 6 times increased risk of preeclampsia, preterm birth, and low birth weight during pregnancy. There was a low overall risk of graft rejection or loss during pregnancy.

Recent advances in fecal microbiota transplantation for Clostridium difficile infection-associated diarrhea after kidney transplantation

Kidney transplantation is considered to be the best treatment for end-stage renal disease. To reduce the incidence of rejection and improve the survival of recipients and kidney grafts, kidney transplant recipients must take immunosuppressive agents, and some patients require them for the rest of their lifetime. These treatment regimens can result in susceptibility to opportunistic infections and disrupt the intestinal microbiota, thereby leading to diarrhea, which causes water and electrolyte metabolism disorder, nutrient malabsorption, and instability in the blood concentrations of the immunosuppressive agents. Fluctuating blood concentration levels of these agents necessitate frequent laboratory monitoring and dose adjustments to avoid poor adherence and increase the risk of graft rejection. Furthermore, severe diarrhea can cause kidney transplant failure or death. Clostridium difficile infection (CDI) is the leading cause of diarrhea after renal transplantation. Traditional antibiotics can kill C. difficile; however, spores can remain in the gut. Disruption of the intestinal flora caused by antibiotherapy increases the risk of developing recurrent CDI (rCDI). Fecal microbiota transplantation (FMT) has been proven to be a safe and effective treatment for CDI and is recommended for rCDI owing to its convenient material acquisition method, high efficacy, and low incidence of adverse reactions. This review summarizes the recent progress in FMT for CDI-associated diarrhea after renal transplantation.

Safe immunosuppression. New tool for personalized immunosuppressant treatment in renal transplantation. A case report

Background: The adjustment of immunosuppressive therapy after kidney transplantation (KT) to avoid graft rejection remains an important challenge for clinicians. It is difficult to achieve a good balance between under-immunosuppression (with an increased risk of graft rejection) and over-immunosuppression (with an increased risk of side effects) by only relying on the available information about immunosuppressive drugs (IMS). Immunobiogram® (IMBG) is a novel in vitro diagnostic test that provides clinicians with information about the patient’s sensitivity to individual IMS. Objective: To present a case report of a patient with renal transplant in the maintenance phase who presented several complications probably related to the immunosuppression during the follow-up, where the use of IMBG as complementary information helped clinicians to guide the therapeutical decision. Methods: IMBG is a first-in-class in vitro immunoassay that involves the culture of the patient peripheral blood mononuclear cells (PBMCs) in a semi-solid 3D matrix, then submitted to immune stimulation. It reveals the capacity of an IMS over a gradient to inhibit the activation of immune cells. The read-out allows the building of a dose-response curve per IMS tested, which is mathematically analyzed by a software using the key curve parameters and finally to be translated into a sensitivity map to IMS. Findings: We present a case report of a 72-year-old patient with a cadaveric donor kidney transplant receiving standard immunosuppressive treatment with mycophenolate, tacrolimus, and corticosteroids. The patient presented several episodes of infections during the follow-up (SARS-CoV2, Cytomegalovirus, spondylodisquitis by Staphylococcus aureus, and emphysematous cystitis) which were managed with different treatment adjustments such as de-escalation of mycophenolate and switching to mTOR. The information provided by the IMBG showed a lack of sensitivity to mTOR which allowed to confirm the final adjustment to a treatment with tacrolimus and corticosteroids, remaining the patient stable since then. Discussion: Despite various adjustments to the immunosuppressive therapy during the follow-up, the patient continued experiencing adverse effects that could be related to an over-immunosuppression state. The IMBG provided pharmacodynamic information that complemented the clinical and pharmacokinetic data available, facilitating the individualization of the treatment. Conclusion: The case highlights the potential of the IMBG as a complementary clinical tool for personalized treatment of kidney transplant patient management.

HLA Genotype Imputation Results in Largely Accurate Epitope Mismatch Risk Categorization Across Racial Groups.

Biomarkers that predict posttransplant alloimmunity could lead to improved long-term graft survival. Evaluation of the number of mismatched epitopes between donor and recipient HLA proteins, termed molecular mismatch analysis, has emerged as an approach to classify transplant recipients as having high, intermediate, or low risk of graft rejection. When high-resolution genotypes are unavailable, molecular mismatch analysis requires algorithmic assignment, or imputation, of a high-resolution genotyping. Although imputation introduces inaccuracies in molecular mismatch analyses, it is unclear whether these inaccuracies would impact the clinical risk assessment for graft rejection. Using renal transplant patients and donors from our center, we constructed cohorts of surrogate donor-recipient pairs with high-resolution and low-resolution HLA genotyping that were racially concordant or discordant. We systemically assessed the impact of imputation on molecular mismatch analysis for cohorts of 180-200 donor-recipient pairs for each of 4 major racial groups. We also evaluated the effect of imputation for a racially diverse validation cohort of 35 real-world renal transplant pairs. In the surrogate donor-recipient cohorts, imputation preserved the molecular mismatch risk category for 90.5%-99.6% of racially concordant donor-recipient pairs and 92.5%-100% of racially discordant pairs. In the validation cohort, which comprised 72% racially discordant pairs, we found that imputation preserved the molecular mismatch risk category for 97.1% of pairs. Overall, these data demonstrate that imputation preserves the molecular mismatch risk assessment in the vast majority of cases and provides evidence supporting imputation in the performance of molecular mismatch analysis for clinical assessment.

Neoadjuvant and adjuvant systemic therapy in HCC: Current status and the future.

Surgical therapies in patients with early-stage HCC can afford long-term survival but are often limited by the continued risk of recurrence, underscoring an interest in (neo)adjuvant strategies. Prior attempts at adjuvant therapy using tyrosine kinase inhibitors failed to yield significant improvements in recurrence-free survival or overall survival. Advances in the efficacy of systemic therapy options, including the introduction of immune checkpoint inhibitors, have fueled renewed interest in this area. Indeed, the IMBrave050 trial recently demonstrated significant improvements in recurrence-free survival with 1 year of adjuvant atezolizumab plus bevacizumab in high-risk patients undergoing surgical resection or ablation, with several other ongoing trials in this space. There is a strong rationale for consideration of the administration of these therapies in the neoadjuvant setting, supported by early clinical data demonstrating high rates of objective responses, although larger trials examining downstream outcomes are necessary, particularly considering the possible risks of this strategy. In parallel, there has been increased interest in using systemic therapies as a bridging or downstaging strategy for liver transplantation. Current data suggest the short-term safety of this approach, with acceptable rates of rejection, so immunotherapy is not considered a contraindication to transplant; however, larger studies are needed to evaluate the incremental value of this approach over locoregional therapy. Conversely, the use of immunotherapy is currently discouraged after liver transplantation, given the high risk of graft rejection and death. The increasing complexity of HCC management and increased consideration of (neo)adjuvant strategies highlight the critical role of multidisciplinary care when making these decisions.

Case Report ‘Layer of Hope’: Managing Large Surface Wounds on Frontal Bare Bone in a Challenging Patient

This was a case of an elderly gentleman with large bleeding basal cell carcinoma occupying almost three quarter of the forehead managed with adjunct usage of integra acellular dermal regeneration template after lesion’s wide local excision despite challenged with patient’s newly diagnosed bicytopenia to rule out haematological malignancy. Standard management of tissue reconstruction with purely living tissue (split skin grafting) has higher risk of graft rejection due to bare bone as wound bed. This limits the neo-graft ability to achieve optimal potential of imbibition and inosculation. Thus, dermal matrix usage makes split skin grafting difficult wound bed has higher chance of surviving and hence shortens healing time and reduces hospital stay.

#1985 Tocilizumab in chronic active antibody-mediated rejection: a randomized controlled open-label multi-center trial (INTERCEPT study)

Abstract Background and Aims Chronic active antibody mediated graft rejection (caAMR) caused by immune-mediated injury is the leading cause of long-term graft loss in kidney transplant recipients. Nevertheless, no effective treatment exists for caAMR to date, highlighting a great unmet need for evaluation of novel treatment options. Recently, tocilizumab (TCZ), a monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, by antagonizing IL-6-triggered inflammation and B cell/plasma cell-driven immune activation, has shown promise in the treatment of caAMR. However, TCZ has not been assessed systematically in a randomized study. The INTERCEPT study aims to evaluate the efficacy of addition of TCZ to standard of treatment (SOC) as compared to SOC alone in reducing the decline of graft function from baseline at 24 months after start of treatment as assessed by estimated glomerular filtration rate (eGFR) in kidney transplant recipients with caAMR. Method This ongoing randomized controlled open-label multi-center investigator-initiated trial plans to include a total of 50 adult kidney transplant recipients with biopsy-proven caAMR using Banff 2019 criteria at least 12 months after transplantation and eGFR ≥20 ml/min/1.73 m2. Any subject who underwent kidney transplantation in Sweden or is currently living in Sweden and being followed up at any of the Swedish transplant centers or their affiliated regional centers can be considered for participation. Participants are randomized to receive either TCZ (n=25) added to our standard of care (SOC) maintenance treatment or SOC alone (n=25) for a period of 24 months and followed for additional 12 months after cessation of the study medication. After the inclusion transplant biopsy at baseline, protocol biopsies are performed at 12 and 24 months. The study design flow-chart is shown in the Figure. The primary endpoint is the slope of eGFR at 24 months after start of treatment. The eGFR is assessed using Modification of Diet in Renal Disease (MDRD) formula. The secondary endpoints include assessment of the following at 12, 24 and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection. Results We expect that addition of TCZ to SOC will slow down the decline of graft function in kidney transplant recipients with caAMR. Conclusion Currently there is no effective treatment for caAMR. Based on the hypothesis that inhibition of IL-6 by TCZ will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR. If TCZ is found to be effective, our study has the potential to improve long-term graft survival and quality of life, reduce morbidity and mortality in kidney transplant patients as well as lower the health care costs.

The Predictors and Risk Factors of 2-Year Rejection in Renal Transplant Patients: A Multicenter Case-Control Study

Introduction: Kidney transplantation is a definitive treatment for end-stage renal disease. It is associated with improved life expectancy and quality of life. One of the most common complications following kidney transplantation is graft rejection. To our knowledge, no previous study has identified rejection risk factors in kidney transplant recipients in Saudi Arabia. Therefore, this study aimed to determine the specific risk factors of graft rejection. Methods: A multicenter case-control study was conducted at four transplant centers in Saudi Arabia. All adult patients who underwent a renal transplant between January 1, 2015 and December 31, 2021 were screened for eligibility. Included patients were categorized into two groups (cases and control) based on the occurrence of biopsy-proven rejection within 2 years. The primary outcome was to determine the risk factors for rejection within the 2 years of transplant. Exact matching was utilized using a 1:4 ratio based on patients’ age, gender, and transplant year. Results: Out of 1,320 screened renal transplant recipients, 816 patients were included. The overall prevalence of 2-year rejection was 13.9%. In bivariate analysis, deceased donor status, the presence of donor-specific antibody (DSA), intraoperative hypotension, Pseudomonas aeruginosa, Candida, and any infection within 2 years were linked with an increased risk of 2-year rejection. However, in the logistic regression analysis, the presence of DSA was identified as a significant risk for 2-year rejection (adjusted OR: 2.68; 95% CI: 1.10, 6.49, p = 0.03). Furthermore, blood infection, infected with Pseudomonas aeruginosa or BK virus within 2 years of transplant, were associated with higher odds of 2-year rejection (adjusted OR: 3.10; 95% CI: 1.48, 6.48, p = 0.003, adjusted OR: 3.23; 95% CI: 0.87, 11.97, p = 0.08 and adjusted OR: 2.76; 95% CI: 0.89, 8.48, p = 0.07, respectively). Conclusion: Our findings emphasize the need for appropriate prevention and management of infections following kidney transplantation to avoid more serious problems, such as rejection, which could significantly raise the likelihood of allograft failure and probably death. Further studies with larger sample sizes are needed to investigate the impact of serum chloride levels prior to transplant and intraoperative hypotension on the risk of graft rejection and failure.

Does Donor Age Have Effects on Senescence Biomarkers in Kidney-Transplanted Patients?

Renal transplantation is an effective treatment for severe chronic kidney diseases. However, young patients often face a scarcity of kidneys from donors of similar age, resulting in the transplantation of older organs, which increase the risk of graft rejection and several complications compared with older individuals who receive kidneys from donors of similar age or younger. This article focuses on studying different senescence biomarkers in donors and patients who received kidneys from various age ranges complying with the STROBE requirements. We studied 61 patients subjected to renal transplant isolating blood samples 24 h before, and 24 h, 3 days, 7 days, 3 months, and 6 months after transplant. The patients were divided into three groups: older donor than the patient (Old Donor), younger donor than the patient (Young Donor), and similar age (Matched). We studied different senescence markers such as p16, p21, interleukin 6 (IL-6), and senescence-associated secretory phenotype (SASP) release. Young patients who receive older organs showed increased mRNA and protein expression of the senescence makers. Hence, increased SASP release was also observed in patients from older donor. In contrast, older patients who receive younger organs showed a slow but consistent improvement in their initial senescent phenotype. In addition, macrophage cell model treated with blood-derived serum from patients 6 months after the transplant showed a pro-senescence environment in macrophages proposed by the SASP from the patients. These results lead the hypothesis that senolytics could reduce the presence of senescent cells and mitigate the complications associated with the transplantation of older organs in young patients.