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Background: Troponin I is a blood biomarker of cardiac injury and levels measured using a high‐sensitivity assay after pediatric heart transplantation (HT) have not been described. We sought to assess the association between high‐sensitivity troponin I (hsTnI) and N‐terminal pro‐B‐type natriuretic peptide (NTproBNP) with treated acute rejection (AR) and graft loss in pediatric heart transplant (HT) recipients. Methods: Serum was collected and banked from pediatric HT recipients prior to cardiac catheterization. Patients with samples drawn within 365 days post‐HT were included and followed for up to 5 years. Generalized linear mixed‐effect models examined the association between hsTnI and treated AR using a random intercept per patient. Cox proportional hazards models tested the association between maximal hsTnI and NT‐proBNP and death/graft loss. Results: HsTnI and NTproBNP values decline in the weeks following HT, after which these biomarkers stabilize. HsTnI was higher in AR versus no AR (6.2 vs. 3.5 ng/L, p < 0.001); doubling of hsTnI increased the odds of AR by 33% (p = 0.004). HsTnI showed moderate discrimination for AR with an AUC of 0.811 (95% CI 0.76, 0.87) and a NPV of 96.4% (95% CI 93.0, 98.1). Elevation in NT‐proBNP was not associated with AR. In multivariable Cox modeling, a doubling of maximal NT‐proBNP was associated with graft loss (HR 8.96, p = 0.014). Conclusions: In this pediatric HT cohort, HsTnI was moderately discriminative for AR and higher maximal NT‐proBNP was associated with graft loss. HsTnI may add value in pediatric HT non‐invasive AR surveillance, and elevated NTproBNP could suggest an increased risk of graft loss. [ABSTRACT FROM AUTHOR]

Background: Induction therapy with basiliximab is recommended in kidney transplant (KT) recipients with a low immunological risk (LIR) profile. Whether basiliximab is associated with a decreased risk of acute rejection (AR) and graft loss is controversial. Methods: In our institution, LIR patients (absence of anti-HLA antibodies before KT) are inducted with basiliximab in case of living-donor KT, while deceased-donor KT recipients receive no induction. Maintenance immunosuppression is similar, including a combination of tacrolimus (Tac), mycophenolate (MPA) and steroids. In this single-center retrospective study, we included all adult LIR patients who underwent KT between 1 January 2015 and 31 December 2022. Results: Of the 471 patients included, 354 received no induction and 117 received basiliximab. The median (IQR) number of HLA A-B-DR mismatches was 3 (2–3) and 2 (2–4) in the no induction group and the basiliximab group, respectively. The cumulative incidences in the no induction group vs. the basiliximab group of acute rejection and graft loss over 5 years post-KT were similar at 8.9% vs. 7.8% (p = 0.8) and 8.5% vs. 4.2% (p = 0.063), respectively. In multivariable Cox regression analysis, delayed graft function emerged as an independent risk factor for acute rejection (hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.23–6.13, p = 0.014) and graft loss (HR 9.32, CI 4.10–21.1, p < 0.001). Conclusions: Basiliximab did not provide any advantage in terms of rate of acute rejection and graft survival within 5 years post KT compared with a strategy without induction therapy in patients with a low immunological risk profile receiving triple maintenance immunosuppression Tac/MPA/steroids. [ABSTRACT FROM AUTHOR]

Background: Recipient's VEGF‐A polymorphisms have been reported to be associated with the risk of acute allograft rejection. However, an association of the donor's VEGF‐A gene polymorphism with rejection remained unelucidated till now. Methods: In this study, VEGF‐A gene SNPs at nine loci were analyzed in 160 kidney donors and recipients with rejection (rejectors, n = 80) and without rejection (non‐rejectors, n = 80). Blood VEGF‐A mRNA, plasma VEGF level, and intragraft VEGF expression were also analyzed by RT‐PCR, ELISA, and immunohistochemistry, respectively. Results: On comparing between the donor and rejectors, the polymorphic genotypes of VEGF –634 C>G [GG genotype, p < 0.0001; OR (95% CI) = 17.74 (5.16–60.96)]; VEGF –1154 G>A [AG genotype, p < 0.0001, OR (95% CI) = 16.07 (3.68–70.15)]; VEGF +936 C>T [CT genotype, p < 0.0001, OR (95% CI) = 178.64 (23.28–1370.9), and TT genotype, p < 0.0001; OR (95% CI) = 3149 (278.91–35 553)]; VEGF –1455 T>C [CC genotype, p value = 0.0464, OR (95% CI) = 3.13 (1.07–9.10)]; VEGF –2578 C>A [CA genotype, p = 0.0426, OR (95% CI) = 4.62 (1.03–20.59), and AA genotype, p value < 0.0001, OR (95% CI) = 21.89 (4.94–97.04)]; VEGF –2549 18 bp Insertion/Deletion [ID genotype, p value < 0.0001, OR (95% CI) = 27.27 (3.61–205.73) and DD genotype, p value < 0.0001, OR (95% CI) = 25.18 (3.30–191.89) were significantly associated with acute rejection risk. On comparing rejectors versus non‐rejectors, GA genotype of VEGF –1190 G>A and TC genotype of VEGF –1455 T>C were associated with the risk of rejection. On comparing donor VEGF between rejectors and non‐rejectors, CG genotype of VEGF –634 C>G, AG of VEGF –1154 G>A; GA of VEGF –1190 G>A were associated with rejection. The blood VEGF‐A mRNA and plasma VEGF levels were higher in the rejectors group compared to non‐rejectors. Conclusions: Besides the recipient's VEGF SNPS, the donor's VEGF SNPs are also associated with the risk of acute rejection and may be closely monitored in evaluation to determine the risk of rejection. [ABSTRACT FROM AUTHOR]

Prior studies have shown reduced development of cardiac allograft vasculopathy (CAV) in multiorgan transplant recipients. The aim of this study was to compare the incidence of CAV between isolated heart transplants and simultaneous multiorgan heart transplants in the contemporary era. We utilized the Scientific Registry of Transplant Recipients to perform a retrospective analysis of first-time adult heart transplant recipients between January 1, 2010 and December 31, 2019 in the United States. The primary end-point was the development of angiographic CAV within 5 years of follow-up. Among 20,591 patients included in the analysis, 1,279 (6%) underwent multiorgan heart transplantation (70% heart-kidney, 16% heart-liver, 13% heart-lung, and 1% triple-organ), and 19,312 (94%) were isolated heart transplant recipients. The average age was 53 years, and 74% were male. There were no significant between-group differences in cold ischemic time. The incidence of acute rejection during the first year after transplant was significantly lower in the multiorgan group (18% vs 33%, p < 0.01). The 5-year incidence of CAV was 33% in the isolated heart group and 27% in the multiorgan group (p < 0.0001); differences in CAV incidence were seen as early as 1 year after transplant and persisted over time. In multivariable analysis, multiorgan heart transplant recipients had a significantly lower likelihood of CAV at 5 years (hazard ratio = 0.76, 95% confidence interval: 0.66-0.88, p < 0.01). Simultaneous multiorgan heart transplantation is associated with a significantly lower long-term risk of angiographic CAV compared with isolated heart transplantation in the contemporary era. [ABSTRACT FROM AUTHOR]

Postoperative JC viruria is common in kidney transplant recipients, however there remains a dearth of research on perioperative JCV infection in this population. The clinical significance of JCV monitoring in kidney transplant recipients remains unclear. Based on JCV urine monitoring during the perioperative phase, renal transplant recipients who underwent perioperative and postoperative monitoring at our center were categorized into two groups: the perioperative JC virus infection group and the control group consisting of recipients without detectable JCV DNA in plasma or urine during the two-year follow-up period. A comparative analysis of baseline data was initially performed, followed by a 1:1 propensity score matching of 80 cases from each group. Within the first month after transplantation, the JC viruria group exhibited a significant decrease in the incidence of delayed graft function compared to the control group (P = 0.031).Over the two-year postoperative period, the JC viruria group displayed a significantly lower rate of acute rejection (P = 0.027). Notably, the JC viruria group demonstrated higher estimated glomerular filtration rate levels compared to the control group, particularly within the first year post-transplantation. Moreover, recipient and transplant kidney survival rates did not significantly differ between the two groups (P = 0.642). Perioperative JC viruria in kidney transplant recipients may persist beyond the initial two postoperative years. The presence of JCV is associated with lower rates of DGF and acute rejection, indicating a favorable post-transplant recovery. These findings provide novel insights into the importance of postoperative JCV monitoring. [ABSTRACT FROM AUTHOR]

Objective To investigate the antigen presentation characteristics of dendritic cells (DC) and B cells in cardiac grafts. Methods The heart of BALB/c mice was transplanted into the abdominal cavity of C57BL/6J mice. CD45+ cells in the heart graft were extracted and sorted by flow cytometry at postoperative 5 d, and single cell RNA sequencing was performed. Taking DC and B cell subsets in cardiac grafts as the main study cells, the changing trend, antigen presenting ability and intercellular communication with T cells after heart transplantation were analyzed by bioinformatics analysis and flow cytometry. Gene ontology (GO) function enrichment difference analysis was adopted to prove the specific function and the reliability annotation of cell subsets. Results Germinal center-like B cell (GC-L B) was the B cell subset with the largest increase in quantity during the acute rejection phase, accounting for 87%. Classical DC (cDC) 2 was the only DC subset with a significant increase in quantity during acute rejection of heart transplantation, accounting for 44% of DC subset, and it occupied the highest communication intensity with T cells after heart transplantation. Mononucleated DC (moDC) and memory B cell (MBC) were the main transmitters of T cell input signals in nontransplanted hearts, whereas transformed into cDC2 and GC-L B during the acute rejection phase. Among them, MBC and GC-L B were the main sources of T cell input signals in non-transplanted hearts and heart grafts. Conclusions Compared with DC, B cells occupy a higher number and weight in the intercellular communication with T cells in non-transplanted hearts and heart grafts, prompting that the antigen presenting activity of B cells is more active and stronger than DC in the early stage of acute rejection of heart transplantation. [ABSTRACT FROM AUTHOR]

Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of chronic lung allograft dysfunction (CLAD) or death. This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated with these conditions. EMI developed in 16% of patients at a median 343.5 (IQR: 177.3–535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.78, 95% CI: 1.26–6.22, p = 0.012). The risk remained consistent for the Primary EMI subgroup (HR: 2.34, 95% CI 1.18–4.85, p = 0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC = 0.856, 95% CI = 0.805–0.908, p < 0.001). Episodes of EMI in lung transplant recipients are often isolated and may not be detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications. [ABSTRACT FROM AUTHOR]

Abstract Postoperative JC viruria is common in kidney transplant recipients, however there remains a dearth of research on perioperative JCV infection in this population. The clinical significance of JCV monitoring in kidney transplant recipients remains unclear. Based on JCV urine monitoring during the perioperative phase, renal transplant recipients who underwent perioperative and postoperative monitoring at our center were categorized into two groups: the perioperative JC virus infection group and the control group consisting of recipients without detectable JCV DNA in plasma or urine during the two-year follow-up period. A comparative analysis of baseline data was initially performed, followed by a 1:1 propensity score matching of 80 cases from each group. Within the first month after transplantation, the JC viruria group exhibited a significant decrease in the incidence of delayed graft function compared to the control group (P = 0.031).Over the two-year postoperative period, the JC viruria group displayed a significantly lower rate of acute rejection (P = 0.027). Notably, the JC viruria group demonstrated higher estimated glomerular filtration rate levels compared to the control group, particularly within the first year post-transplantation. Moreover, recipient and transplant kidney survival rates did not significantly differ between the two groups (P = 0.642). Perioperative JC viruria in kidney transplant recipients may persist beyond the initial two postoperative years. The presence of JCV is associated with lower rates of DGF and acute rejection, indicating a favorable post-transplant recovery. These findings provide novel insights into the importance of postoperative JCV monitoring.

Kidney transplantation is the treatment of choice in patients with an end-stage kidney disease (ESKD). Before kidney transplantation, it is important to assess the patient's immunological risk, which has an impact on graft survival after kidney transplantation. Human leukocyte antigens (HLA), also known as major histocompatibility complex (MHC) are responsible for the rejection of genetically different tissue by recognizing and distinguishing foreign proteins from self-proteins. HLA-typing and anti-HLA antibody screening are crucial to determine the donor/recipient mismatching. Diagnostic methods used for anti-HLA antibody detection and immunological risk assessment are complement-dependent cytotoxicity (CDC), flow cytometry crossmatch (FCXM), bead-based assays (Luminex technology), calculated panel-reactive antibody (cPRA), and algorithm “predicted Indirectly Recognizable HLA Epitopes“ (PIRCHE). The aim of these diagnostic tests is to minimize HLA mismatch between the donor and the recipient and prevent an early graft failure by the presence of HLA donor-specific antibodies (DSA).

Objective To investigate the clinical efficacy of preoperative therapeutic plasma exchange(TPE) in preventing acute rejection after ABO incompatible kidney transplantation(ABOi-KT). Methods Nine patients with ABOi-KT who were admitted to the renal transplant department of our hospital from April 2022 to April 2024 were retrospectively analyzed. They received a total of 28 TPEs before kidney transplantation, and the treatment plan was summarized as follows: The proportion of the substitute fluid, as well as the frequency and volume of TPE were determined based on the patient′s ABO blood group system antibody titer, gender, height, weight, hematocrit and other indicators upon admission. The patient′s relevant laboratory indicators, including hemoglobin, platelets, leukocytes, coagulation function, total protein, albumin, globulin, A/G, creatinine and urea nitrogen upon admission and after TPE were monitored and statistically analyzed. After transplantation, changes in renal function indicators such as ABO blood group system antibody titers, creatinine and urinary excretion were observed, and clinical symptoms of acute rejection, such as swelling, pain and edema in the transplanted kidney area were observed. Results Nine ABOi-KT patients had an average of about 3 TPEs before transplantation surgery, with an average total volume of approximately 2 500 mL to 3 500 mL per TPE, or approximately about 1.01 to 1.16 plasma volume (PV). After multiple TPEs, pre-transplantation antibody titers decreased by an average of 3 times compared to before TPE. There were no statistically significant differences in Hb, PLT, PT, PTA, INR, TBil, ALB, Cr and BUN (P>0.05), while statistically significant differences were found in WBC, APTT, Fbg, TP, GLB and A/G (P

Introduction: Outcomes of deceased donor kidney transplant (DDKT) recipients from the same donor with donor–recipient sex discordance have been studied with inconsistent results. Methods: Adult DDKT where both kidneys from the same donor occurred at our center in two different recipients of different sexes were included. Outcomes were analyzed separately for male and female donors, based on the concordance or discordance between donor–recipient sex: Male‐male (M‐m) versus Male to female (M‐f) or vice versa, F‐f versus F‐m. Acute rejection (AR) and uncensored graft failure were primary outcomes of interest. The univariate and multivariate risks for AR and graft failure were conducted using the Cox proportional hazards model and log‐rank tests. Results: A total of 130 donors, 84 male and 46 female fulfilled our selection criteria and were transplanted in 260 recipients. With respect to the concordant groups (M‐m or F‐f), sex discordance was not significantly associated with the risk of rejection in multivariate analysis (M‐f vs. M‐m HR 1.15 [0.53–2.53, P = 0.72]; F‐m vs. F‐f HR 1.77 [0.71–4.39, P = 0.23]). Sex discordance was also not significantly associated with graft failure in multivariate analysis. Interestingly, risk factors for AR differed among male donors and female donors. The higher calculated panel reactive antibodies (cPRA) and nonwhite recipients were at increased risk for AR in F‐m, but not in M‐f. Conclusions: Donor–recipient sex discordance was not significantly associated with AR or graft failure. Risk factors for AR may differ across male and female donors. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) have witnessed significant success in systemic therapy of hepatocellular carcinoma, stimulating the transplant community to consider their use in the liver transplantation (LT) setting. This review provides an updated overview of the current evidence on ICI therapy before and after LT, discussing the associated pitfalls and remaining challenges. A particular focus is placed on the interactions between ICIs and immunosuppressive drugs, in order to identify predictive factors of good response, as well as critical aspects that should guide future research on the topic. Hepatocellular carcinoma (HCC) remains the leading oncological indication for liver transplantation (LT), with evolving and broadened inclusion criteria. Immune checkpoint inhibitors (ICIs) gained a central role in systemic HCC treatment and showed potential in the peri-transplant setting as downstaging/bridging therapy before LT or as a treatment for HCC recurrence following LT. However, the antagonistic mechanisms of action between ICIs and immunosuppressive drugs pose significant challenges, particularly regarding the risk of acute rejection (AR). This review analyzes the main signaling pathways targeted by ICI therapies and summarizes current studies on ICI therapy before and after LT. The literature on this topic is limited and highly heterogeneous, precluding definitive evidence-based conclusions. The use of ICIs before LT appears promising, provided that a sufficient wash-out period is implemented. In contrast, the results of post-LT ICI therapy do not support its wide clinical application due to high AR rates and overall poor response to treatment. In the future, modern graft preservation techniques might support the selection of good ICI responders, but data from high-level studies are urgently needed. [ABSTRACT FROM AUTHOR]

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Introduction: Kidney transplantation significantly improves the lives of those with end-stage kidney disease, offering best alternative to dialysis. However, transplant success is threatened by the acute and chronic rejection mechanisms due to complex immune responses against the new organ. Areas covered: The ongoing research into biomarkers holds promise for revolutionizing the early detection and monitoring of the graft health. Liquid biopsy techniques offer a new avenue, with several diagnostic, predictive, and prognostic biomarkers showing promise in detecting and monitoring kidney diseases and an early and chronic allograft rejection. Expert opinion: Evaluating the protein composition related to kidney transplant results could lead to identifying biomarkers that provide insights into the graft functionality. Non-invasive proteomic biomarkers can drastically enhance clinical outcomes and change the way how kidney transplants are evaluated for patients and physicians if they succeed in this transition. Hence, the advancement in proteomic technologies, leads toward a significant improvement in understanding of the protein markers and molecular mechanisms linked to the outcomes of kidney transplants. However, the road from discovery to the use of such proteins in clinical practice is long, with a need for continuous validation and beyond the singular research team with comprehensive infrastructure and across research groups collaboration. [ABSTRACT FROM AUTHOR]

Background: We hypothesized that alemtuzumab use is safe in pediatric kidney transplant recipients (KTRs) with equivalent long‐term outcomes compared to other induction agents. Methods: Using pediatric kidney transplant recipient data in the UNOS database between January 1, 2000, and June 30, 2022, multivariate logistic regression, multivariable Cox regression, and survival analyses were utilized to estimate the likelihoods of 1st‐year and all‐time hospitalizations, acute rejection, CMV infection, delayed graft function (DGF), graft loss, and patient mortality among recipients of three common induction regimens (ATG, alemtuzumab, and basiliximab). Results: There were no differences in acute rejection or graft failure among induction or maintenance regimens. Basiliximab was associated with lower odds of DGF in deceased donor recipients (OR 0.77 [0.60–0.99], p =.04). Mortality was increased in patients treated with steroid‐containing maintenance (HR 1.3 [1.005–1.7] p =.045). Alemtuzumab induction correlated with less risk of CMV infection than ATG (OR 0.76 [0.59–0.99], p =.039). Steroid‐containing maintenance conferred lower rate of PTLD compared to steroid‐free maintenance (HR 0.59 [0.4–0.8] p =.001). Alemtuzumab was associated with less risk of hospitalization within 1 year (OR 0.79 [0.67–0.95] p =.012) and 5 years (HR 0.54 [0.46–0.65] p <.001) of transplantation. Steroid maintenance also decreased 5 years hospitalization risk (HR 0.78 [0.69–0.89] p <.001). Conclusions: Pediatric KTRs may be safely treated with alemtuzumab induction without increased risk of acute rejection, DGF, graft loss, or patient mortality. The decreased risk of CMV infections and lower hospitalization rates compared to other agents make alemtuzumab an attractive choice for induction in pediatric KTRs, especially in those who cannot tolerate ATG. [ABSTRACT FROM AUTHOR]

Vascularized Composite Allografts (VCA) are usually performed in a full major histocompatibility complex mismatch setting, with a risk of acute rejection depending on factors such as the type of immunosuppression therapy and the quality of graft preservation. In this systematic review, we present the different immunosuppression protocols used in VCA and point out relationships between acute rejection rates and possible factors that might influence it. This systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. We systematically searched Medline (PubMed), Embase, and The Cochrane Library between November 2022 and February 2023, using following Mesh Terms: Transplant, Transplantation, Hand, Face, Uterus, Penis, Abdominal Wall, Larynx, and Composite Tissue Allografts. All VCA case reports and reviews describing multiple case reports were included. We discovered 211 VCA cases reported. The preferred treatment was a combination of antithymocyte globulins, mycophenolate mofetil (MMF), tacrolimus, and steroids; and a combination of MMF, tacrolimus, and steroids for induction and maintenance treatment, respectively. Burn patients showed a higher acute rejection rate (P = 0.073) and were administered higher MMF doses (P = 0.020). In contrast to previous statements, the field of VCA is not rapidly evolving, as it has encountered challenges in addressing immune-related concerns. This is highlighted by the absence of a standardized immunosuppression regimen. Consequently, more substantial data are required to draw more conclusive results regarding the immunogenicity of VCAs and the potential superiority of one immunosuppressive treatment over another. Future efforts should be made to report the VCA surgeries comprehensively, and muti-institutional long-term prospective follow-up studies should be performed to compare the number of acute rejections with influencing factors. [ABSTRACT FROM AUTHOR]

Background: Identifying the cause of renal allograft dysfunction is important for the clinical management of kidney transplant recipients. Purpose: To evaluate the diagnostic efficiency of diffusion tensor imaging (DTI) for identifying allografts with acute rejection (AR) and chronic allograft nephropathy (CAN). Study Type: Prospective. Subjects: Seventy‐seven renal transplant patients (aged 42.5 ± 9.5 years), including 29 patients with well‐functioning stable allografts (Control group), 25 patients diagnosed with acute rejection (AR group), and 23 patients diagnosed with chronic allograft nephropathy (CAN group). Field Strength/Sequence: 1.5 T/T2‐weighted imaging and DTI. Assessment: The serum creatinine, proteinuria, pathologic results, and fractional anisotropy (FA) values were obtained and compared among the three groups. Statistical Test: One‐way analysis of variance; correlation analysis; independent‐sample t‐test; intraclass correlation coefficients and receiver operating characteristic curves. Statistical significance was set to a P‐value <0.05. Results: The AR and CAN groups presented with significantly elevated serum creatinine as compared with the Control group (191.8 ± 181.0 and 163.1 ± 115.8 μmol/L vs. 82.3 ± 20.9 μmol/L). FA decreased in AR group (cortical/medullary: 0.13 ± 0.02/0.31 ± 0.07) and CAN group (cortical/medullary: 0.11 ± 0.02/0.27 ± 0.06), compared with the Control group (cortical/medullary: 0.15 ± 0.02/0.35 ± 0.05). Cortical FA in the AR group was higher than in the CAN group. The area under the curve (AUC) for identifying AR from normal allografts was 0.756 and 0.744 by cortical FA and medullary FA, respectively. The AUC of cortical FA and medullary FA for differentiating CAN from normal allografts was 0.907 and 0.830, respectively. The AUC of cortical FA and medullary FA for distinguishing AR and CAN from normal allografts was 0.828 and 0.785, respectively. Cortical FA was able to distinguish between AR and CAN with an AUC of 0.728. Data Conclusion: DTI was able to detect patients with dysfunctional allografts. Cortical FA can further distinguish between AR and CAN. Evidence Level: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

BackgroundDonor-derived cell-free DNA (dd-cfDNA) testing is an emerging screening modality for noninvasive detection of acute rejection (AR). This study compared the testing accuracy for AR of two commercially available dd-cfDNA and gene-expression profiling (GEP) testing in heart transplant (HTx) recipients.MethodsThis is a retrospective, observational study of HTx only patients who underwent standard and expanded single nucleotide polymorphism (SNP) dd-cfDNA between October 2020 to January 2022. Comparison with GEP was also performed. Assays were compared for correlation, accurate classification, and prediction for AR.ResultsA total of 428 samples from 112 unique HTx patients were used for the study. A positive standard SNP correlated with the expanded SNP assay (p

Acute rejection is an important factor affecting the survival of recipients after liver transplantation. Salidroside has various properties, including anti-inflammatory, antioxidant, and hepatoprotective properties. This study aims to investigate whether salidroside can prevent acute rejection after liver transplantation and to examine the underlying mechanisms involved. An in vivo acute rejection model is established in rats that are pretreated with tacrolimus (1 mg/kg/d) or salidroside (10 or 20 mg/kg/d) for seven days after liver transplantation. In addition, an in vitro experiment is performed using neutrophils incubated with salidroside (1, 10, 50 or 100 μM). Hematoxylin-eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, immunosorbent assays, immunofluorescence analysis, Evans blue staining, and western blot analysis are performed to examine the impact of salidroside on NET formation and acute rejection in vitro and in vivo. We find that Salidroside treatment reduces pathological liver damage, serum aminotransferase level, and serum levels of IL-1β, IL-6, and TNF-α in vivo. The expressions of proteins associated with the HMGB1/TLR-4/MAPK signaling pathway (HMGB1, TLR-4, p-ERK1/2, p-JNK, p-P38, cleaved caspase-3, cleaved caspase-9, Bcl-2, Bax, IL-1β, TNF-α, and IL-6) are also decreased after salidroside treatment. In vitro experiments show that the release of HMGB1/TLR-4/MAPK signaling pathway-associated proteins from neutrophils treated with lipopolysaccharide is decreased by salidroside. Moreover, salidroside inhibits NETosis and protects against acute rejection by regulating the HMGB1/TLR-4/MAPK signaling pathway. Furthermore, salidroside combined with tacrolimus has a better effect than either of the other treatments alone. In summary, salidroside can prevent acute liver rejection after liver transplantation by reducing neutrophil extracellular trap development through the HMGB1/TLR-4/MAPK signaling pathway.

IntroductionDonation after circulatory death (DCD) liver transplantation (LT) makes up well less than 1% of all LTs with a Model for End-Stage Liver Disease (MELD)≥35 in the United States. We hypothesized DCD-LT yields acceptable ischemia-reperfusion and reasonable outcomes for recipients with MELD≥35.MethodsWe analyzed recipients with lab-MELD≥35 at transplant within the UCSF (n=41) and the UNOS (n=375) cohorts using multivariate Cox regression and propensity score matching.ResultsIn the UCSF cohort, five-year patient survival was 85% for DCD-LTs and 86% for matched-Donation after Brain Death donors-(DBD) LTs (p=0.843). Multivariate analyses showed that younger donor/recipient age and more recent transplants (2011-2021 versus 1999-2010) were associated with better survival. DCD vs. DBD graft use did not significantly impact survival (HR: 1.2, 95%CI 0.6-2.7). The transaminase peak was approximately doubled, indicating suggesting an increased ischemia-reperfusion hit. DCD-LTs had a median post-LT length of stay of 11 days, and 34% (14/41) were on dialysis at discharge versus 12 days and 22% (9/41) for DBD-LTs. 27% (11/41) DCD-LTs versus 12% (5/41) DBD-LTs developed a biliary complication (p=0.095). UNOS cohort analysis confirmed patient survival predictors, but DCD graft emerged as a risk factor (HR: 1.5, 95%CI 1.3-1.9) with five-year patient survival of 65% versus 75% for DBD-LTs (p=0.016). This difference became non-significant in a sub-analysis focusing on MELD 35-36 recipients. Analysis of MELD≥35 DCD recipients showed that donor age of

In pediatric heart transplant (PHT), cardiac catheterization with endomyocardial biopsy (EMB) is standard for diagnosing acute rejection (AR) and cardiac allograft vasculopathy (CAV) but is costly and invasive. To evaluate the ability of cardiac magnetic resonance (CMR) to noninvasively identify differences in PHT patients with AR and CAV. Patients were enrolled at three children's hospitals. Data were collected from surveillance EMB or EMB for-cause AR. Patients were excluded if they had concurrent diagnoses of AR and CAV, CMR obtained >7 days from AR diagnosis, they had EMB negative AR, or could not undergo contrasted, unsedated CMR. Kruskal-Wallis test was used to compare groups: (1) No AR or CAV (Healthy), (2) AR, (3) CAV. Wilcoxon rank-sum test was used for pairwise comparisons. Fifty-nine patients met inclusion criteria (median age 17 years [IQR 15-19]) 10 (17%) with AR, and 11 (19%) with CAV. AR subjects had worse left ventricular ejection fraction compared to Healthy patients (p = 0.001). Global circumferential strain (GCS) was worse in AR (p = 0.054) and CAV (p = 0.019), compared to Healthy patients. ECV, native T1, and T2 z-scores were elevated in patients with AR. CMR was able to identify differences between CAV and AR. CAV subjects had normal global function but abnormal GCS which may suggest subclinical dysfunction. AR patients have abnormal function and tissue characteristics consistent with edema (elevated ECV, native T1 and T2 z-scores). Characterization of CMR patterns is critical for the development of noninvasive biomarkers for PHT and may decrease dependence on EMB. [ABSTRACT FROM AUTHOR]

Background: The aims of the study were to assess the performance of a clinically available cell‐free DNA (cfDNA) assay in a large cohort of pediatric and adult heart transplant recipients and to evaluate performance at specific cut points in detection of rejection. Methods: Observational, non‐interventional, prospective study enrolled pediatric and adult heart transplant recipients from seven centers. Biopsy‐associated plasma samples were used for cfDNA measurements. Pre‐determined cut points were tested for analytic performance. Results: A total of 487 samples from 160 subjects were used for the analysis. There were significant differences for df‐cfDNA values between rejection [0.21% (IQR 0.12–0.69)] and healthy samples [0.05% (IQR 0.01–0.14), p <.0001]. The pediatric rejection group had a median df‐cfDNA value of 0.93% (IQR 0.28–2.84) compared to 0.09% (IQR 0.04–0.23) for healthy samples, p =.005. Overall negative predictive value was 0.94 while it was 0.99 for pediatric patients. Cut points of 0.13% and 0.15% were tested for various types of rejection profiles and were appropriate to rule out rejection. Conclusion: The study suggests that pediatric patients with rejection show higher levels of circulating df‐cfDNA compared to adults and supports the specific cut points for clinical use in pediatric and adult patients with overall acceptable performance. [ABSTRACT FROM AUTHOR]

Background: Blood oxygen level dependent-magnetic resonance imaging (BOLD-MRI) is a non-invasive functional imaging technique that can be used to assess renal allograft dysfunction. Purpose: To evaluate the diagnostic performance of BOLD-MRI using a 3-T scanner in discriminating causes of renal allograft dysfunction in the post-transplant period. Material and Methods: This prospective study was conducted on 112 live donor-renal allograft recipients: 53 with normal graft function, as controls; 18 with biopsy-proven acute rejection (AR); and 41 with biopsy-proven acute tubular necrosis (ATN). Multiple fast-field echo sequences were performed to obtain T2*-weighted images. Cortical R2* (CR2*) level, medullary R2* (MR2*) level, and medullary over cortical R2* ratio (MCR) were measured in all participants. Results: The mean MR2* level was significantly lower in the AR group (20.8 ± 2.8/s) compared to the normal group (24 ± 2.4/s, P <0.001) and ATN group (27.4 ± 1.7/s, P <0.001). The MCR was higher in ATN group (1.47 ± 0.18) compared to the AR group (1.18 ± 0.17) and normal functioning group (1.34 ± 0.2). Both MR2* (area under the curve [AUC] = 0.837, P <0.001) and MCR (AUC = 0.727, P = 0.003) can accurately discriminate ATN from AR, however CR2* (AUC = 0.590, P = 0.237) showed no significant difference between both groups. Conclusion: In early post-transplant renal dysfunction, BOLD-MRI is a valuable non-invasive diagnostic technique that can differentiate between AR and ATN by measuring changes in intra-renal tissue oxygenation. [ABSTRACT FROM AUTHOR]

Introduction. Tacrolimus is the mainstem of immunosuppressive therapy in kidney transplant patients. It has high intrapatient variability (Tac-IPV), which has been reported to affect graft function by predisposing patients to rejection or nephrotoxicity. We conducted this study with the aim of assessing the influence of Tac-IPV on 2-year graft function, biopsy-proven rejection, and infections in compliant renal recipients. Methods. In this single-center retrospective analytic cross-sectional study, 250 patients who underwent transplantation from March 21, 2018, to March 20, 2020 and had at least three outpatient tacrolimus trough levels on the same daily dose 6 to 12 months after transplantation were recruited. Tac-IPV was defined as a coefficient variation of > 15%. Graft function, biopsy-proven rejection, cytomegalovirus (CMV) and BK virus viremia, and calcineurin inhibitor (CNI) toxicity were evaluated. Results. Of 202 transplant recipients, 128 were included with a mean age of 45.48 ± 13.14 years. The median Tac-IPV was 13.28% with 43.75% of patients with Tac-IPV > 15%. There were no significant differences in graft function, rejection, CNI toxicity, and CMV viremia among the groups during the 24-month study (P > .05). However, BK viremia was significantly higher among patients with Tac-IPV > 15% (13 vs. 2.9%, P = .042). The risk of antibody-mediated rejection alone (22.7 vs. 2.9%) or any kind of rejection (22.7 vs. 11.8%) was significantly higher in patients with higher Tac-IPV, and in those who had mean trough levels below 7 ng/ mL (P = .015, .032; respectively). Conclusion. Tac-IPV is low in adherent patients (with the median of 13.28%) and maintaining tacrolimus trough level above 7 ng/mL can overcome the adverse graft outcome of Tac-IPV in compliant kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Background: Acute rejection (AR) is the predominant form of rejection observed in liver transplantation and plays a crucial role in transplant immunology. This study aims to utilize bibliometric analysis to understand the status quo, hotspots, and future trends of research on AR after liver transplantation. Methods: We searched the Web of Science Core Collection (WoSCC) for studies on AR after liver transplantation published from 1988 to 2022. The Bibliometric Online Analysis Platform, VOSviewer, and CiteSpace were used for analysis of all extracted publications. Results: This study included 2,398 articles published in 456 journals by 12,568 authors from 1,965 institutions in 55 countries/regions. The United States and its affiliated institution, the University of Pittsburgh, were the most productive contributors. Transplantation (n = 12,435) was the most frequently cited journal. Neuhaus P (n = 38) was the highest output author, and Demetris AJ (n = 670) was the most co-cited author. The research hotspots of AR after liver transplantation include pathogenesis, immunosuppressive therapy, and prognosis. Emerging research directions include regulatory T cells, immunosuppression minimization, intra-patient variability (IPV) of tacrolimus, and novel non-invasive diagnostic markers. Conclusion: Our study utilized bibliometric methods to analyze the study of AR after liver transplantation over the past 35 years. With the prolonged survival of liver transplant recipients, the most active areas currently focus on individualized treatment and improving patient prognosis. Minimizing adverse reactions to immunosuppressive therapy while simultaneously avoiding an increase in the risk of AR remains a future research focus. [ABSTRACT FROM AUTHOR]

Vascularized composite allografts (VCA) face ischemic challenges due to their limited availability. Reperfusion following ischemia triggers oxidative stress and immune reactions, and scavenger molecules could mitigate ischemia–reperfusion injuries and, therefore, immune rejection. We compared two scavengers in a myocutaneous flap VCA model. In total, 18 myocutaneous flap transplants were performed in Major histocompatibility complex (MHC)-defined miniature swine. In the MATCH group (n = 9), donors and recipients had minor antigen mismatch, while the animals were fully mismatched in the MISMATCH group (n = 9). Grafts were pretreated with saline, sodium iodide (NaI), or hydrogen sulfide (H2S), stored at 4 °C for 3 h, and then transplanted. Flaps were monitored until clinical rejection without immunosuppression. In the MATCH group, flap survival did not significantly differ between the saline and hydrogen sulfide treatments (p = 0.483) but was reduced with the sodium iodide treatment (p = 0.007). In the MISMATCH group, survival was similar between the saline and hydrogen sulfide treatments (p = 0.483) but decreased with the sodium iodide treatment (p = 0.007). Rhabdomyolysis markers showed lower but non-significant levels in the experimental subgroups for both the MATCH and MISMATCH animals. This study provides insightful data for the field of antioxidant-based approaches in VCA and transplantation. [ABSTRACT FROM AUTHOR]

The association between organizing pneumonia (OP) after lung transplantation with the development of acute rejection (AR) remains undefined. In addition, molecular allograft injury, as measured by donor-derived cell-free DNA (dd-cfDNA), during episodes of OP and its relationship to episodes of AR, chronic lung allograft dysfunction (CLAD), or death is unknown. This multicenter, prospective cohort study collected serial plasma samples from 188 lung transplant recipients for dd-cfDNA at the time of bronchoscopy with biopsy. Multivariable Cox regression was used to analyze the association between OP with the development of AR (antibody-mediated rejection (AMR) and acute cellular rejection (ACR)), CLAD, and death. Multivariable models were performed to test the association of dd-cfDNA at OP with the risk of AR, CLAD, or death. In multivariable analysis, OP was associated with increased risk of AMR (hazard ratio (HR) = 2.26, 95% confidence interval (CI) 1.04-4.92, p = 0.040) but not ACR (HR = 1.29, 95% CI: 0.66-2.5, p = 0.45) or the composite outcome of CLAD or death (HR = 0.88, 95% CI, 0.47-1.65, p = 0.69). Median levels of dd-cfDNA were higher in OP compared to stable controls (1.33% vs 0.43%, p = 0.0006). Multivariable analysis demonstrated that levels of dd-cfDNA at diagnosis of OP were associated with increased risk of both AMR (HR = 1.29, 95% CI 1.03-1.62, p = 0.030) and death (HR = 1.16, 95% CI, 1.02-1.31, p = 0.026). OP is independently associated with an increased risk of AMR but not CLAD or death. The degree of molecular allograft injury at the diagnosis of OP may further predict the risk of AMR and death. [ABSTRACT FROM AUTHOR]

Background: Acute rejection (AR) after liver transplantation (LT) remains an important factor affecting the prognosis of patients. CD8+ T cells are considered to be important regulatory T lymphocytes involved in AR after LT. Our previous study confirmed that autophagy mediated AR by promoting activation and proliferation of CD8+ T cells. However, the underlying mechanisms regulating autophagy in CD8+ T cells during AR remain unclear. Methods: Human liver biopsy specimens of AR after orthotopic LT were collected to assess the relationship between JNK and CD8+ T cells autophagy. The effect of JNK inhibition on CD8+ T cells autophagy and its role in AR were further examined in rats. Besides, the underlying mechanisms how JNK regulated the autophagy of CD8+ T cells were further explored. Results: The expression of JNK is positive correlated with the autophagy level of CD8+ T cells in AR patients. And similar findings were obtained in rats after LT. Further, JNK inhibitor remarkably inhibited the autophagy of CD8+ T cells in rat LT recipients. In addition, administration of JNK inhibitor significantly attenuated AR injury by promoting the apoptosis and downregulating the function of CD8+ T cells. Mechanistically, JNK may activate the autophagy of CD8+ T cells through upregulating BECN1 by inhibiting the formation of Bcl-2/BECN1 complex. Conclusion: JNK signaling promoted CD8+ T cells autophagy to mediate AR after LT, providing a theoretical basis for finding new drug targets for the prevention and treatment of AR after LT. [ABSTRACT FROM AUTHOR]

Objective To analyze the influencing factors of survival of patients with airway stenosis requiring clinical interventions after lung transplantation. Methods Clinical data of 66 patients with airway stenosis requiring clinical interventions after lung transplantation were retrospectively analyzed. Univariate and multivariate Cox’s regression models were adopted to analyze the influencing factors of survival of all patients with airway stenosis and those with early airway stenosis. Kaplan-Meier method was used to calculate the overall survival and delineate the survival curve. Results For 66 patients with airway stenosis, the median airway stenosis-free time was 72 (52,102) d, 27% (18/66) for central airway stenosis and 73% (48/66) for distal airway stenosis. Postoperative mechanical ventilation time [hazard ratio (HR) 1.037, 95% confidence interval (CI) 1.005-1.070, P=0.024] and type of surgery (HR 0.400, 95%CI 0.177-0.903, P=0.027) were correlated with the survival of patients with airway stenosis after lung transplantation. The longer the postoperative mechanical ventilation time, the higher the risk of mortality of the recipients. The overall survival of airway stenosis recipients undergoing bilateral lung transplantation was better than that of their counterparts after single lung transplantation. Subgroup analysis showed that grade 3 primary graft dysfunction (PGD) (HR 4.577, 95%CI 1.439-14.555, P=0.010) and immunosuppressive drugs (HR 0.079, 95%CI 0.022-0.287, P<0.001) were associated with the survival of patients with early airway stenosis after lung transplantation. The overall survival of patients with early airway stenosis after lung transplantation without grade 3 PGD was better compared with that of those with grade 3 PGD. The overall survival of patients with early airway stenosis after lung transplantation treated with tacrolimus was superior to that of their counterparts treated with cyclosporine. Conclusions Long postoperative mechanical ventilation time, single lung transplantation, grade 3 PGD and use of cyclosporine may affect the survival of patients with airway stenosis after lung transplantation. [ABSTRACT FROM AUTHOR]

ObjectiveUtilize VUEBOX quantitative analysis software to perform quantitative analysis dynamic ultrasound contrast images of post-transplant renal patients were assessed quantitatively five parameters of ultrasonic contrast and two-dimensional ultrasound are examined to explore their six value in Diagnosing Renal Graft Dysfunction.MethodsA retrospective analysis was conducted on 73 post-transplant renal patients who underwent ultrasound contrast examinations at Yiyang Central Hospital from July 2022 to December 2023, They were diagnosed clinically and pathologically. Based on pathological and clinical diagnostic results, the patients were divided into three groups: 47 cases in the stable renal function group, 18 cases in the acute rejection (AR) group, and 8 cases in the delayed graft function (DGF) group. All patients underwent routine ultrasound and ultrasound contrast examinations post-transplantation. By comprehensively assessing renal function test results, clinical course, and pathological findings, differences in ultrasonic contrast quantitative parameters were analyzed. Additionally, ROC curves were constructed to evaluate the diagnostic efficacy of ultrasound contrast in discriminating between transplant renal rejection reactions and delayed renal function recovery.ResultsStatistically significant differences in characteristics, such as renal segmental artery resistance index, were observed among the stable renal function group, AR group, and DGF group (all P < 0.05), while peak systolic velocity showed no statistical significance (P > 0.05). Differences in cortical time to peak (TTP), medullary time to peak(TTP), main renal artery rise time (RT), main renal artery(TTP), and main renal artery fall time (FT) were statistically significant among the stable renal function group, AR group, and DGF group (P < 0.05). ROC curve analysis demonstrated that the accuracy of quantitative parameters for the DGF group and AR group was as follows: Renal artery TTP = Renal artery RT > Renal artery FT > Medulla TTP > Cortex TTP (with respective area under the curve values of 0.828, 0.828, 0.758, 0.742, 0.719). Among these, Renal artery TTP and Renal artery RT exhibited larger AUC values, with sensitivities of 87.5% each and specificities of 81.2 and 87.5%, respectively.ConclusionThere are discernible differences in VUEBOX quantitative parameters between post-transplant AR and DGF cases, thereby providing imaging references for diagnosing of acute rejection and functional impairment following renal transplantation.

Background: Acute rejection (AR) is a leading cause of early morbidity and mortality in heart transplant (HTx) recipients. There is limited data on donation after circulatory death (DCD) HTx recipients where ischemia reperfusion injury may contribute to the development of AR and may be detected early with noninvasive biomarkers, such as donor-derived cell-free DNA (dd-cfDNA) and gene expression profile (GEP). The goal of this study is to compare dd-cfDNA, GEP, and rejection outcomes in DCD and donation after brain death (DBD) HTx recipients. Methods: This single-center, retrospective study included DCD and DBD HTx recipients from January 2020 to September 2022. Patients were excluded from the study if dd-cfDNA and GEP were not available. The CareDx HeartCare platform was used to obtain dd-cfDNA (AlloSure-Heart) and GEP (AlloMap) with the highest values for each patient recorded at 6 and 12 months. The mean values for these noninvasive markers were compared between DCD and DBD groups. Patients were followed for clinical outcomes, including treated AR, cardiac allograft vasculopathy (CAV), and death, through September 2023. Results: A total of 156 HTx patients were included with 50 DCD and 106 DBD recipients. Baseline characteristics were similar between DCD and DBD recipients including mean age (58.5 vs 56.9 years, p = 0.48), male sex (82% vs 76%, p = 0.56), and Caucasian race (46% vs 43%, p = 0.78). There were no significant differences in mean AlloSure-Heart at 6 and 12 months between DCD and DBD recipients. AlloMap was significantly lower at 6 months (p = 0.04), but not at 12 months between DCD and DBD recipients. With respect to clinical outcomes at 1 year, there were no significant differences in treated AR (22% vs 14%, p = 0.32), International society of heart and lung transplant grade ≥2 CAV (0% vs 4%, p = 0.44), or mortality (2% vs 0%, p = 0.69) between DCD and DBD recipients. Conclusions: In this single-center study, there were no significant differences in mean dd-cfDNA and treated AR at 1 year between DCD and DBD HTx recipients. There was a significant increase in mean GEP at 6 months, but not at 12 months in the DBD cohort. Overall, there does not appear to be clinically significant cardiac allograft injury related to DCD as measured by noninvasive markers. Further work is needed to confirm these findings.

Our case illustrates the possible explanation of renal allograft rejection in a patient who had recovered from Covid-19 infection in the post-transplant period, which ultimately led to the death of the patient. A 27-year-old male patient received renal allograft from his mother, with an uneventful post-transplant period. Three years after the transplantation he contracted Covid-19 infection. The patient recovered from Covid-19 infection after being treated according to the treatment protocol. Subsequently, in the next 2 weeks, he presented with heavy proteinuria and a rise in serum creatinine level. Renal biopsy examination showed features of acute T-cell mediated rejection (TCMR) without any evidence of antibody-mediated rejection. He was given all due care but he deteriorated quickly leading to his death. This case highlights the inter-relation between Covid-19 infection and acute TCMR of the renal allograft, where renal biopsy serves as an indispensable tool in understanding its pathophysiology.

Background : Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are G1 cell arrest biomarkers that have demonstrated accuracy and validity in predicting and diagnosing acute kidney injury (AKI). This study aimed to evaluate the validity of [TIMP-2]×[IGFBP7] in diagnosing acute allograft dysfunction and its utility in distinguishing acute rejection (AR) from nonrejection causes in kidney transplantation. Methods : This study included 48 adult living donor kidney transplant recipients (KTRs; 18 with AR, 15 with nonrejection causes of AKI, and 15 with stable grafts). Urinary TIMP-2 and IGFBP7 were measured, and [TIMP-2]×[IGFBP7] was calculated in all subjects. Results : IGFBP7, TIMP-2, and [TIMP-2]×[IGFBP7] were statistically significantly higher in KTRs with acute allograft dysfunction than in those with stable grafts. [TIMP-2]×[IGFBP7] was statistically significantly higher in KTRs with AR than in those with nonrejection AKI. [TIMP-2]×[IGFBP7] at a cutoff level of 0.278 (ng/mL)2/1,000 had an area under the curve (AUC) of 0.99 with a sensitivity of 100% and a specificity of 93.3% in diagnosing acute allograft dysfunction, while at a cutoff level of 0.803 (ng/mL)2/1,000 had an AUC of 0.939 with a sensitivity of 94.4% and a specificity of 83.3% in diagnosing AR. Conclusions: Besides its role in the early detection of acute allograft dysfunction, [TIMP-2]×[IGFBP7] may help to differentiate between AR and nonrejection causes in KTRs. However, whether and how urinary [TIMP-2]×[IGFBP7] can be used in clinical diagnosis still requires further research.

BackgroundEndomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adult HTx recipients.MethodsPlasma samples with contemporaneous EMBs were obtained from HTx recipients. A clinically available SNP-based massively multiplexed-PCR dd-cfDNA assay was used to measure dd-cfDNA fraction. dd-cfDNA fractions were compared with EMB-defined rejection status and test performance was assessed by constructing ROC curves and calculating accuracy measures.ResultsA total of 811 samples from 223 patients with dd-cfDNA testing and contemporaneous EMB were eligible for the study. dd-cfDNA fraction was significantly higher in AR (median 0.58%, IQR, 0.13%-1.68%) compared to non-AR (median 0.04%, IQR, 0.01%-0.11%, pc < 0.001). ROC analysis produced an area under the curve (AUC-ROC) of 0.86 (95% CI, 0.77-0.96). Defining samples with dd-cfDNA fraction ≥0.15% as AR yielded 78.5% sensitivity (95% CI, 60.7%-96.3%) and 76.9% specificity (95% CI, 71.1%-82.7%). Positive and negative predictive values were 25.1% (95% CI, 18.8%-31.5%) and 97.3% (95% CI, 95.1%-99.5%) respectively, calculated using the cohort AR prevalence of 9.0% (95% CI, 5.3%-12.8%) with adjustment for repeat samples.ConclusionsThis novel dd-cfDNA test detects AR in HTx recipients with good accuracy and holds promise as a noninvasive test for AR in HTx recipients.

Background: The association between cannabis use and access to waitlisting, transplantation, and post‐transplant outcomes remains uncertain. Methods: Patients referred for kidney transplant (KT) to the University Health Network from January 1, 2003, to June 30, 2020, and followed until December 31, 2020, were included. Predictors of reported cannabis use were examined using a logistic regression model. The association between cannabis use and time to clearance for KT, undergoing KT, and post‐transplant outcomes was evaluated using Cox proportional hazards models. Results: Among 3734 patients, the prevalence of reported cannabis use was 11.8%. Cannabis use was associated with a lower likelihood of KT clearance (adjusted hazard ratio [aHR].82 [95% confidence interval (CI):.72,.94]). Once cleared for KT, cannabis use did not predict the subsequent receipt of KT (aHR.92, [95% CI:.79, 1.08]). Among 2091 KT recipients, cannabis use was associated with a higher likelihood of biopsy‐proven acute rejection (aHR 1.55, [95% CI: 1.06, 2.27]). The relative hazard of death‐censored graft failure was similarly elevated (aHR 1.60 [95% CI:.95, 2.72]). Cannabis use did not predict total graft failure (aHR 1.33 [95% CI:.90, 1.96]), death with graft function (aHR 1.06 [95% CI:.59, 1.89]), or hospital readmission in the first‐year post‐transplant (aHR 1.26 [95% CI:.95, 1.68]). Conclusions: Cannabis users have less access to transplantation and an increased risk of acute rejection, possibly leading to more graft loss. Further studies are warranted to understand possible mechanisms for the increased risk of allograft immune injury among cannabis users. [ABSTRACT FROM AUTHOR]

High donor‐derived cell‐free DNA (dd‐cfDNA) levels indicate transplant allograft injury and can identify graft rejection in kidney transplant recipients. Here, we evaluated the use of dd‐cfDNA in pediatric kidney transplant rejection monitoring and treatment. Methods: Forty‐two pediatric kidney transplant patients were enrolled between February 2020 and August 2021. Dd‐cfDNA was tested before and after biopsy/rejection treatment. There was a total of 61 allograft biopsies (44 for‐cause, 17 surveillance). Results: Graft rejection was found in 35/61 biopsies. Rejection was more common in basiliximab induction compared to rATG (77.1% vs. 22.9%, p =.0121). Median dd‐cfDNA was higher in those with rejection (1.2% [0.34–3.12] vs. 0.24% [0.08–0.78], p <.0001). Dd‐cfDNA was highest in biopsies with AMR and mixed AMR/TCMR. In addition, dd‐cfDNA in basiliximab induction was higher compared to rATG (0.92% [0.27–1.8] vs. 0.26% [0.08–2], p =.0437). Median change in dd‐cfDNA after rejection treatment was −0.57% (−1.67 to 0.05). Median time to dd‐cfDNA <1% post‐rejection treatment was 8.5 days (3.0–19.5). Dd‐cfDNA in AMR was higher compared to TCMR or mixed rejection, and levels remained higher in AMR after treatment. In surveillance biopsies, 4/17 had rejection. Median dd‐cfDNA was not different in those with versus without rejection (0.48% vs. 0.28%, p =.2342). Those without rejection all had dd‐cfDNA <1%. In those with rejection, only one patient had dd‐cfDNA >1%, and all had TCMR. Conclusions: Our findings support dd‐cfDNA as a useful indicator of graft rejection and response to treatment. Additional studies are needed to determine the role of dd‐cfDNA in graft health surveillance. [ABSTRACT FROM AUTHOR]

Background and Aims: The importance of human leukocyte antigen (HLA) matching between liver transplant donors and recipients on graft survival remains unclear and is not a clinical consideration in liver transplantation. This study aimed to determine the relationship between HLA matching and liver graft survival using a large-scale multi-centre database (UNOS/OPTN) and multivariate logistic analysis. The secondary aim was to determine whether this relationship was influenced by transplant indication and donor status. Methods: This retrospective observational analysis was performed using 22 702 liver transplant recipients from the UNOS/OPTN database. Patients were divided into two groups based on number of HLA mismatches (0--3 mismatches vs. 4--6 mismatches) and then subcategorized by indication and donor status. Risk-adjusted outcomes were assessed by multivariate Cox analysis adjusting for donor and recipient characteristics and visualized using Kaplan--Meier survival curves. Results: Allograft survival and risk of acute rejection were associated with degree of HLA mismatch. This association between HLA mismatch and graft survival persisted in individuals who underwent transplant for hepatitis, metabolic, drug toxicity, and congenital indications. Donor status also influenced the relationship between HLA mismatch and graft survival. Graft survival in DBD recipients was longer than in DCD in the 4--6 HLA mismatch group, whereas no significant difference was found in the 0--3 HLA mismatch group. Conclusion: HLA mismatch significantly reduced graft survival and increased risk of acute rejection. This association was noted only in specific indications. These findings are of potential clinical relevance to organ allocation, allograft matching algorithms, immunosuppression protocols, and transplant surveillance. [ABSTRACT FROM AUTHOR]

Donation after circulatory death (DCD) heart transplantation has promising early survival, but the effects on rejection remain unclear. The United Network for Organ Sharing database was queried for adult heart transplants from December 1, 2019, to December 31, 2021. Multiorgan transplants and loss to follow-up were excluded. The primary outcome was acute rejection, comparing DCD and donation after brain death (DBD) transplants. A total of 292 DCD and 5,582 DBD transplants met study criteria. Most DCD transplants were transplanted at status 3-4 (61.0%) compared to 58.6% of DBD recipients at status 1-2. DCD recipients were less likely to be hospitalized at transplant (26.7% vs 58.3%, p < 0.001) and to require intra-aortic balloon pumping (IABP; 9.6% vs 28.9%, p < 0.001), extracorporeal membrane oxygenation (ECMO; 0.3% vs 5.9%, p < 0.001) or temporary left ventricular assist device (LVAD; 1.0% vs 2.7%, p < 0.001). DCD recipients were more likely to have acute rejection prior to discharge (23.3% vs 18.4%, p = 0.044) and to be hospitalized for rejection (23.4% vs 11.4%, p = 0.003) at a median follow-up of 15 months; the latter remained significant after propensity matching. On multivariable logistic regression, DCD donation was an independent predictor of acute rejection (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.00-2.15, p = 0.048) and hospitalization for rejection (OR 2.03, 95% CI 1.06-3.70, p = 0.026). On center-specific subgroup analysis, DCD recipients continued to have higher rates of hospitalization for rejection (23.4% vs 13.8%, p = 0.043). DCD recipients are more likely to experience acute rejection. Early survival is similar between DCD and DBD recipients, but long-term implications of increased early rejection in DCD recipients require further investigation. [ABSTRACT FROM AUTHOR]

Background: Outcomes of intestinal transplantation with colon allograft (ICTx) remain controversial. We aimed to assess the outcomes of ICTx in comparison to intestinal transplantation without colon (ITx) using the UNOS/OPTN registry database. Methods: We retrospectively reviewed 2612 patients who received primary intestinal transplants from 1998 to 2020. The rates of acute rejection (AR) within 6 months after transplant were compared between ICTx and ITx. Risk factors of 6‐month AR were examined using logistic regression model by era. Furthermore, conditional graft survival was analyzed to determine long‐term outcomes of ICTx. Results: Of 2612 recipients, 506 (19.4%) received ICTx. Graft and patient survival in ICTx recipients were comparable to those in ITx recipients. White ICTx recipients had a higher incidence of AR within 6 months compared to ITx during the entire study period (p =.002), colonic inclusion did not increase the risk of 6‐month AR in the past decade. ICTx recipients who experienced 6‐month AR had worse graft and patient survival compared to those who did not (p <.001 and p =.004, respectively). Among patients who did not develop 6‐month AR, Cox proportional hazard model analysis revealed that colonic inclusion was independently associated with improved conditional graft survival. Conclusions: In the recent transplant era, colonic inclusion is no longer associated with a heightened risk of 6‐month AR and may provide better long‐term survival compared to ITx when AR is absent. Risk adjustment for rejection and proper immunosuppressive therapy are crucial to maximize the benefits of colonic inclusion. [ABSTRACT FROM AUTHOR]

Objective: Kidney transplantation is the most suitable kidney replacement therapy for patients with end-stage kidney disease. The relationship between the pretransplant antibodies detected by Luminex Single Antigen Bead test and the clinical outcome is still unclear. In this study, we aimed to examine the effects of pretransplant anti-human leukocyte antigen antibody status on graft functions, posttransplant complications, graft, and patient survival in kidney transplantation recipients. Methods: Two hundred eleven patients who underwent kidney transplantation between January 2015 and July 2020 were included in the study. Detailed immunological assessment, donor and recipient characteristics, posttransplant immunological and non-immunological complications, graft loss, and death were analyzed. Results: Thirty-three (15.6%) patients were donor-specific antibody positive, 58 (27.5%) patients were non-donor-specific antibody positive, and 120 (56.9%) patients were anti-human leukocyte antigen antibody negative. There was no significant difference between these groups in terms of acute rejection, opportunistic infections, urinary tract infections, malignancy, graft, and patient survival. The rate of desensitization therapy and antithymocyte globulin induction were higher in donor-specific antibody-positive group (P < .001 and < .001, respectively). Increased recipient and donor age and BK virus infection significantly decreased graft and patient survival in multivariate analyses. Conclusion: Pretansplant donor-specific antibody and non-donor-specific antibody should not be a barrier for kidney transplantation. With the guidance of immunosuppression with advanced immunological risk assessment methods, kidney transplantation can be performed successfully in patients with high immunological risk. [ABSTRACT FROM AUTHOR]

Background De novo donor-specific antibodies (dnDSAs) may cause antibody-mediated rejection and graft dysfunction. Little is known about the clinical course after first detection of dnDSAs during screening in asymptomatic patients. We aimed to assess the value of estimated glomerular filtration rate (eGFR) and proteinuria to predict graft failure in patients with dnDSAs and their potential utility as surrogate endpoints. Methods All 400 kidney transplant recipients with dnDSAs at our centre (1 March 2000–31 May 2021) were included in this retrospective study. The dates of graft loss, rejection, doubling of creatinine, ≥30% eGFR decline, proteinuria ≥500 mg/g and ≥1000 mg/g were registered from the first dnDSA appearance. Results During 8.3 years of follow-up, graft failure occurred in 33.3% of patients. Baseline eGFR and proteinuria correlated with 5-year graft loss (area under the receiver operating characteristics curve 0.75 and 0.80, P  < .001). Creatinine doubled after a median of 2.8 years [interquartile range (IQR) 1.5–5.0] from dnDSA and the time from doubling creatinine to graft failure was 1.0 year (IQR 0.4–2.9). Analysing eGFR reduction ≥30% as a surrogate endpoint (148/400), the time from dnDSA to this event was 2.0 years (IQR 0.6–4.2), with a positive predictive value (PPV) of 45.9% to predict graft loss, which occurred after 2.0 years (IQR 0.8–3.2). The median time from proteinuria ≥500 mg/g and ≥1000 mg/g to graft failure was identical, 1.8 years, with a PPV of 43.8% and 49.0%, respectively. Composite endpoints did not improve PPV. Multivariable analysis showed that rejection was the most important independent risk factor for all renal endpoints and graft loss. Conclusions Renal function, proteinuria and rejection are strongly associated with graft failure in patients with dnDSA and may serve as surrogate endpoints. [ABSTRACT FROM AUTHOR]

Kidney transplantation is a crucial treatment for end-stage kidney disease, with immunosuppressive drugs helping to reduce acute rejection rates. However, kidney graft longevity remains a concern. This study explores the role of indoleamine 2,3-dioxygenase 1 (IDO1) in kidney transplant immunology. IDO1 breaks down tryptophan, affecting immune cell behavior, primarily T-cells. The research focuses on both cellular and antibody-mediated immune responses, often causing graft damage. The study assessed IDO1 expression in renal transplant biopsies from patients with graft function decline, examining its connection to clinical parameters. A total of 121 biopsy samples were evaluated for IDO1 expression using immunohistochemistry. Patients were categorized as IDO1(+) positive or IDO1(−) negative based on immunoreactivity in tubular epithelium. Results showed a significant link between IDO1 expression and rejection incidence. IDO1(+) positive patients had lower rejection rates (32.9%) compared to IDO1(−) negative ones (62.2%) [p = 0.0017], with substantial differences in antibody-mediated rejection (AMR) (5.2% vs. 20%) [p = 0.0085] and T-cell mediated rejection (TCMR) (31.6% vs. 57.8%). These associations suggest that IDO1 may play a protective role in kidney transplant rejection. IDO1 modulation could offer novel therapeutic avenues to enhance graft survival. The study underscores IDO1 as a potential marker for rejection risk assessment, with its potential applications in personalized interventions and improved patient outcomes. Further research is needed to fully comprehend the mechanisms behind IDO1's immunomodulatory functions and its potential clinical translation. [ABSTRACT FROM AUTHOR]

Background: De novo donor-specific antibody (dnDSA) generation and acute rejection (AR) are the main factors affecting long-term graft survival. This study aims to investigate human leukocyte antigen (HLA) eplet mismatching (MM), delayed graft function (DGF), and tacrolimus (TAC) trough levels on the occurrence of dnDSA and AR in the early stages after kidney transplantation (KT). Methods: This retrospective study included 526 cases of deceased donation KT. The effects of DGF, HLA eplet MM, and TAC trough levels on dnDSA and AR occurrence were analyzed with logistic regression analysis. Results: Multivariate logistic regression analysis showed the independent risk factor of dnDSA generation was HLA B eplet MM (OR: 1.201. 95% CI: 1.007-1.431, P 0.041). The independent risk factors of AR occurrence include DGF (OR: 4.045, 95% CI: 1.047-15.626, P 0.043), HLA B eplet MM (OR: 1.090, 95% CI: 1.000-1.187, P = 0.050), and TAC trough levels at 12 months (OR: 0.750, 95% CI: 565-0.997, P - 0.048). HLA B eplet MM combined with DGF and TAC trough levels at 12 months increased the predictive value of dnDSA (AUC 0.735) and AR (AUC 0.730) occurrence. HLA B eplet MM > 9 and TAC trough levels below 5.95 ng/mL at 12 months could increase the risk of early AR occurrence. Conclusions: HLA B eplet MM, DGF, and TAC trough levels at 12 months after KT could affect the occurrence of dnDSA and AR in the early stage of KT. [ABSTRACT FROM AUTHOR]

Background: Antibody mediated rejection (ABMR) of kidney transplants has been shown to occur in the absence of a known donor specific antibody to human leucocyte antigen (HLA). Antibodies to the human neutrophil antigen (HNA) system have been detected in kidney transplant recipients and linked to ABMR in the absence of an HLA donor specific antibody (DSA), but there remains limited literature regarding this. Methods: Case series analysis was carried out examining three cases of HNA-3a antibody positive flow cytometry cross match (FC-XM) from two transplant centres in Scotland. Results: All patients included were female and had been sensitised as a result of pregnancy. One live donor recipient with HNA-3a antibodies identified prior to transplant received ATG induction and has had a good outcome. The remaining two patients received deceased donor transplants. HNA-3a antibodies were indicated following a retrospective flow cytometry crossmatch. Both patients received Basiliximab induction and both have experienced ABMR requiring supplementary immunosuppression. Conclusions: The predicted rate of HNA-3a antibodies amongst patients awaiting kidney transplant in the UK is <1%. However, with increasing evidence to support a role for HNA-3a antibodies in the development of ABMR there may be value in screening at risk groups to allow for augmented immunosuppression to be considered at the time of kidney transplant. [ABSTRACT FROM AUTHOR]

Purpose: Acute rejection is a frequent complication among lung transplant recipients and poses substantial therapeutic challenges. 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme responsible for the inactivation of prostaglandin E2 (PGE2), has recently been implicated in inflammatory lung diseases. However, the role of 15-PGDH in lung transplantation rejection remains elusive. The present study was undertaken to examine the expression of 15-PGDH in rejected lung allografts and whether inhibition of 15-PGDH ameliorates acute lung allograft rejection. Methods: Orthotopic mouse lung transplantations were performed between donor and recipient mice of the same strain or allogeneic mismatched pairs. The expression of 15-PGDH in mouse lung grafts was measured. The efficacy of a selective 15-PGDH inhibitor (SW033291) in ameliorating acute rejection was assessed through histopathological examination, micro-CT imaging, and pulmonary function tests. Additionally, the mechanism underlying the effects of SW033291 treatment was explored using CD8+ T cells isolated from mouse lung allografts. Results: Increased 15-PGDH expression was observed in rejected allografts and allogeneic CD8+ T cells. Treatment with SW033291 led to an accumulation of PGE2, modulation of CD8+ T-cell responses and mitochondrial activity, and improved allograft function and survival. Conclusion: Our study provides new insights into the role of 15-PGDH in acute lung rejection and highlights the therapeutic potential of inhibiting 15-PGDH for enhancing graft survival. The accumulation of PGE2 and modulation of CD8+ T-cell responses represent potential mechanisms underlying the benefits of 15-PGDH inhibition in this model. Our findings provide impetus for further exploring 15-PGDH as a target for improving lung transplantation outcomes. [ABSTRACT FROM AUTHOR]

BackgroundAcute rejection (AR) after liver transplantation (LT) remains an important factor affecting the prognosis of patients. CD8+ T cells are considered to be important regulatory T lymphocytes involved in AR after LT. Our previous study confirmed that autophagy mediated AR by promoting activation and proliferation of CD8+ T cells. However, the underlying mechanisms regulating autophagy in CD8+ T cells during AR remain unclear.MethodsHuman liver biopsy specimens of AR after orthotopic LT were collected to assess the relationship between JNK and CD8+ T cells autophagy. The effect of JNK inhibition on CD8+ T cells autophagy and its role in AR were further examined in rats. Besides, the underlying mechanisms how JNK regulated the autophagy of CD8+ T cells were further explored.ResultsThe expression of JNK is positive correlated with the autophagy level of CD8+ T cells in AR patients. And similar findings were obtained in rats after LT. Further, JNK inhibitor remarkably inhibited the autophagy of CD8+ T cells in rat LT recipients. In addition, administration of JNK inhibitor significantly attenuated AR injury by promoting the apoptosis and downregulating the function of CD8+ T cells. Mechanistically, JNK may activate the autophagy of CD8+ T cells through upregulating BECN1 by inhibiting the formation of Bcl-2/BECN1 complex.ConclusionJNK signaling promoted CD8+ T cells autophagy to mediate AR after LT, providing a theoretical basis for finding new drug targets for the prevention and treatment of AR after LT.

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.