Acute Cellular Rejection Research Articles

Genetically engineered pig heart transplantation in non-human primates

BackgroundImprovement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients.MethodsBased on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (n = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients.Results10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (n = 1), chronic vasculopathy (n = 1), micro and macro thrombosis, and acute cellular rejection (n = 1).ConclusionsThese data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.

Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation.

Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver transplantation. We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted meta-analysis. During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99; 95% CI: 1.39-20.08; p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54; 95% CI 1.95-28.79; p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ACR. Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findings using a genotyped HLA cohort.

Predicting graft survival in paediatric kidney transplant recipients using machine learning.

Identification of factors that affect graft survival in kidney transplantation can increase graft survival and reduce mortality. Artificial intelligence modelling enables impartial evaluation of clinician bias. This study aimed to examine factors that affect the survival of grafts in paediatric kidney transplantation through the use of machine learning. A retrospective review was conducted on records of paediatric patients who underwent kidney transplantation between 1994 and 2021 and had post-transplant follow-up > 12months. The nearest neighbour method was used to impute missing fields from a total of 48 variables in the dataset. Models including Naive Bayes, logistic regression, support vector machine (SVM), multi-layer perceptron, and XGBoost were trained to predict graft survival. The study used 80% of the patients for training and the remaining 20% for testing. Modelling success was evaluated based on accuracy and F1 score metrics. The study analysed 465 kidney transplant recipients. Of these, 56.7% were male. The mean age at transplantation was 12.08 ± 5.01years. Of the kidney transplants, 73.1% (n = 339) were from living donors, 34.5% (n = 160) were pre-emptive transplants, and 2.2% (n = 10) were second-time transplants. The machine learning model identified several features associated with graft survival, including antibody-mediated rejection (+ 0.7), acute cellular rejection (+ 0.66), eGFR at 3years (+ 0.43), eGFR at 5years (+ 0.34), pre-transplant peritoneal dialysis (+ 0.2), and cadaveric donor (+ 0.2). The successes of the logistic regression and SVM models were similar. The F1 score was 91.9%, and accuracy was 96.5%. Machine learning can be used to identify factors that affect graft survival in kidney transplant recipients. By expanding similar studies, risk maps can be created prior to transplantation.

Long Term Renal Allograft Function After Thymoglobulin Treated Acute Cellular Rejection in a Single Center

Long Term Renal Allograft Function After Thymoglobulin Treated Acute Cellular Rejection in a Single Center

Proteomics in Acute Heart Transplant Rejection, On Behalf of the GRAfT Investigators.

Proteomic phenotyping can provide insights into rejection pathophysiology, novel biomarkers, and therapeutic targets. Within the prospective, multicenter Genomic Research Alliance for Transplantation study, 181 proteins were evaluated from blood drawn at the time of endomyocardial biopsy; protein fold change, logistic regression, and pathway analyses were conducted, with protein discovery adjusted for a 5% false discovery rate. Among 104 adult heart transplant patients (31% female sex, 53% Black race, median age 52 y), 74 had no rejection, 18 developed acute cellular rejection (ACR), and 12 developed antibody-mediated rejection (AMR). Differential expression was found in 2 proteins during ACR (inflammatory proteins CXCL10 and CD5) and 73 proteins during AMR. The most abundant AMR proteins were the heart failure biomarkers N-terminal pro-B-type natriuretic peptide and suppression of tumorigenicity 2. In univariate logistic regression, odds of identifying ACR on endomyocardial biopsy increased with doubling of CXCL10 (odds ratio [OR] 2.2 [95% confidence interval (CI), 1.3-3.6]) and CD5 (OR 4.7 [95% CI, 1.7-12.9]) concentrations, and odds of AMR increased with doubling of N-terminal pro-B-type natriuretic peptide (OR 13.0 [95% CI, 2.7-62.7) and suppression of tumorigenicity 2 (OR 4.8 [95% CI, 2.1-10.7]) concentrations. After multivariable analysis with clinical covariates, these proteins showed similar odds of ACR or AMR on biopsy. Pathway analysis identified T cell-receptor signaling and cell differentiation as key pathways in ACR and cardiovascular disease and cell turnover in AMR. Proteomic analysis reveals unique biomarkers and biological pathway expression in ACR and AMR. Cardiac injury-associated biomarkers were more pronounced in AMR, whereas inflammatory biomarkers were more pronounced in ACR. Proteomic analysis may provide insights into rejection pathophysiology, detection, and therapy.

Speckle-tracking echocardiography of left and right ventricle and acute cellular rejection in orthotropic heart transplantation: a systematic review and meta-analysis.

After a cardiac transplantation, the steering of immunosuppression requires an active search for acute cellular rejection (ACR). Surveillance with endomyocardial biopsy (EMB) is the gold standard. Given the costs and potential complications, there is growing interest in the use of non-invasive screening methods. Thus, we have conducted a systematic review and meta-analysis to evaluate the role of speckle-tracking echocardiography as a screening method for ACR. We searched PubMed (CENTRAL) and gray literature for studies presenting data on speckle tracking echocardiography in heart-transplant patients experiencing acute cellular rejection. The primary outcomes of the meta-analysis were left and right ventricular global longitudinal strain. We used random effects models for all our calculations. We pre-registered our meta-analysis with PROSPERO (CRD42024508654). By incorporating data from over 2000 biopsies included in 18 studies, we found that both left (LVGLS, MD -1.96, 95% CI -2.85 to -1.07, p < 0.0001), and right (RVGLS, MD -2.90, 95% CI -4.03 to -1.76, p < 0.00001) ventricular longitudinal strain were lower among patients without ACR. The change of LVGLS from baseline over time was also greater among patients experiencing ACR (MD -2.43, 95% CI -4.82 to -0.05, p = 0.045). Current data suggest that myocardial strain measured by speckle tracking echocardiography is affected in ACR and could potentially be used for early rejection detection as a rule-out strategy, leading to reduction of routine EMB in heart transplant follow-up.

Extracorporeal Photopheresis for the prevention of rejection after lung transplantation - a prospective randomized controlled trial.

Lung transplant recipients have the worst long-term outcomes of all solid organs due to acute rejection and chronic lung allograft dysfunction (CLAD). To investigate the efficacy of ECP as a prophylactic treatment to prevent acute cellular rejection (ACR), CMV infections and reduce the risk of CLAD. Single-center prospective randomized controlled trial conducted at Medical University of Vienna between 2018 and 2020. It included 31 COPD recipients per group. Treatment group underwent extracorporeal photopheresis in addition to standard triple-drug immunosuppression protocol after lung transplantation. Control group received standard triple-drug immunosuppressive therapy. The primary outcome was a composite outcome defined as incidence of high-grade ACR, CMV infection or CLAD within 24 months after lung transplantation. In the control group, 19 patients (61.3%) achieved the primary combined endpoint, compared with only 6 patients (19.4%) in the treatment group (p<0.001). Freedom from high-grade ACR was significantly greater in the ECP group (p=0.045). Cumulative A scores were significantly lower in the ECP group than in the control group at 3 months (0.18±0.44 versus 0.56±0.94, p<0.05) and at 12 months (0.25±0.48 versus 1.0±1.45, p=0.002). The rate of infections was lower in the ECP group with 5 cases and 67 cumulative hospital days compared to 22 cases and 309 days in the control group (p=0.002). Freedom from CLAD at three years was significantly greater in the ECP group (p=0.015). Adding ECP to standard triple immunosuppression resulted in a significant reduction of the number of ACR episodes and significantly lower incidence of CLAD.

Emerging role of circulating piRNAs in the diagnosis of heart transplant rejection.

Liquid biopsy offers a potential alternative to decrease or eliminate endomyocardial biopsy (EMB) for diagnosing allograft rejection. piRNAs are novel and promising disease biomarkers for their intrinsic characteristics such as stability in body fluids; however, their role in allograft rejection remains unexplored. A training set based on small RNA sequencing technology was performed to identify piRNAs in endomyocardial tissue (n=8) and serum samples (n=40) from patients following heart transplantation. A validation set of the potential piRNAs identified in the training study was conducted in an independent larger cohort for the detection of acute cellular rejection (ACR, n=105) and antibody-mediated rejection (AMR, n=61). We identified 20292 piRNAs in endomyocardial tissue and 24602 piRNAs in serum samples from patients following heart transplantation. We identified seven piRNAs with a coincident expression profile in both types of samples and potential capacity for the non-invasive detection of cardiac rejection. Validation in a large independent cohort demonstrated that a panel of these piRNAs showed excellent performance for detecting grade ≥2R ACR (AUC=0.819; p<0.0001) and grade 1R ACR (AUC=0.721; p=0.001). Furthermore, our piRNA panel showed a potential discrimination ability of pAMR2 (AUC=0.967; p<0.0001). To the best of knowledge, this study is the first to report the presence of piRNAs in both endomyocardial tissue and serum samples of patients after heart transplant, including their association with allograft rejection events. We propose a novel piRNA panel for the detection of cardiac allograft rejection.

Prevalence and Impact of Cytomegalovirus Primary Infection and Reactivation on Graft Function in Post-Renal Transplant Recipients.

Introduction Cytomegalovirus (CMV) is often associated with mortality and significant morbidity following renal transplantation leading to graft rejection or dysfunction. Primary CMV infection refers to the first detection of the virus in a person who has no prior evidence of CMV exposure before transplantation.CMVhas a unique property called latency. After the initial infection, CMV can enter a dormant state within the body, residing in myeloid cells without causing active disease. CMV reactivation is likely when a latent CMV infection switches to a lytic phase of replication, which can bedetected using IgG avidity ELISA. Aims and objectives This study aims to assess the prevalence of primary CMV infection and reactivation in renal transplant recipients, evaluate the impact of CMV infection on graft function following transplantation, andidentify the risk factors and comorbidities associated with CMV-related graft rejection. Methodology During the study period from March 2020 to November 2021, blood samples were collected from 46 CMV-positive (by PCR) renal transplant recipients, and serum was separated and stored. IgG avidity ELISA test was performed, which served as a valuable tool to differentiate primary infection from reactivation due to difference in binding strength where low binding strength (low avidity<30%) indicated primary infection and high binding strength (high avidity>40%) indicated reactivation. All these patients were followed up to study the impact of CMV on graft functions. Results The age-wise distribution of patients shows a maximum number of cases under 40 years. The gender distribution of cases shows a higher preponderance of males (76%) compared to females (24%). The clinical presentation showed CMV syndrome as the most common (50%), followed by CMV colitis (37%), CMV nephritis (9%), CMV pneumonitis, CMV esophagitis, and CMV duodenitis, each comprising 2%. After performing the IgG avidity test, CMV infection with maximum cases of reactivation (87%) followed by primary infection (13%) was observed. The investigations related to renal dysfunction such as serum creatinine showed >3 mg/dL (85% of cases), 2.1-3 mg/dL (4.33% of cases), 1.6-2 mg/dL (2% of cases), 1-1.5 mg/dL (4.33% of cases) in decreasing order. Normal urea values are seen in 9% of cases followed by the range between 24 and 55 mg/dL in 67% and >100% in 24% of cases. The graft rejection based on the biopsy report showed that acute cellular rejection (ACR) (72%) was higher followed by antibody-mediated rejection (ABMR) with 15% and then ACR+ ABMRwith 4%. No rejection was found in 9% of cases. Renal dysfunction showed a higher preponderance to chronic graft dysfunction (67%) followed by acute graft dysfunction (24%) and stable graft function among 9% of cases. A comparison of graft dysfunction in primary infection/reactivation was assessed, and it was found that acute graft dysfunction was more common in primary infection. In the case of reactivation, chronic graft dysfunction was more common. Conclusion This study focuses on the microbiological dimensions and the critical role of CMV antibody screening. It underscores the necessity of vigilant monitoring and prophylactic antiviral therapy to reduce CMV infection risks and enhance patient outcomes. It also highlights the use of IgG avidity testing to differentiate between primary infection and reactivation, facilitating timely and effective interventions to prevent graft dysfunction and rejection.

Arbovirus in Solid Organ Transplants: A Narrative Review of the Literature.

The incidence of arbovirus infections has increased in recent decades. Other than dengue, chikungunya, and West Nile viruses, the data on arbovirus in solid organ transplant (SOT) are limited to case reports, and infections in renal transplant recipients account for most of the reported cases. Dengue and West Nile infections seem to be more severe with higher mortality in SOT patients than in the general population. Acute kidney injury is more frequent in patients with dengue and chikungunya although persistent arthralgia with the latter is less frequent. There is no clear relationship between arboviral infection and acute cellular rejection. Pre-transplant screening of donors should be implemented during increased arboviral activity but, despite donor screening and negative donor nucleic acid amplification test (NAT), donor derived infection can occur. NAT may be transiently positive. IgM tests lack specificity, and neutralizing antibody assays are more specific but not readily available. Other tests, such as immunohistochemistry, antigen tests, PCR, metagenomic assays, and viral culture, can also be performed. There are a few vaccines available against some arboviruses, but live vaccines should be avoided. Treatment is largely supportive. More data on arboviral infection in SOT are needed to understand its epidemiology and clinical course.

Transition from Transbronchial Forceps to Cryobiopsy After Lung Transplantation: A Single-Centre Experience.

The gold standard for histological acute cellular rejection diagnosis is transbronchial forceps biopsy (FB), but in recent years, transbronchial cryobiopsy (CB) has been increasingly used. This study aims to compare the diagnostic rate and safety of FBs and CBs performed in two different periods. We retrospectively reviewed our case history for the two biopsy procedures: 251 FBs (223 for surveillance purposes and 28 for clinical indication) and 218 consecutive CBs (159 for surveillance purposes and 59 for clinical indication). All biopsies were scored according to the ISHLT criteria. Diagnostic yield was higher in the CB group for all the parameters considered: a grade of acute rejection (AR) was detected in 95.0% vs. 84.5% in the CB vs. FB groups (p < 0.001). The diagnostic rate of airway inflammation was 65.1% vs. 51.8% (p = 0.005), and 89.0% vs. 64.9% (p < 0.001) for chronic rejection. Pneumothorax requiring chest drainage occurred in 4% of the CB group and 3% of the FB group. Moderate and severe bleeding complicated CB and FB procedures in seven (3%) and three cases (1%), respectively. Transbronchial cryobiopsies improved the diagnostic yield in the monitoring of the lung allograft. The complication rate did not increase significantly in CBs vs. FBs.

Abstract 4136036: Five-year Outcomes of Heart-Kidney Transplant Recipients Bridged with Durable Mechanical Circulatory Support: Less AMR Better Survival?

Introduction: Despite the increased risk of sensitization in patients receiving pre-transplant durable mechanical circulatory support (D-MCS), it has been suggested that removing D-MCS at the time of transplant may lead to a drop in HLA-antibody levels. Whether this may reduce rejection rates and improve long-term outcomes in patients undergoing heart-kidney transplantation (HKTx) has not been widely investigated. Therefore, we aim to investigate the impact of pre-transplant D-MCS on 5-year clinical outcomes of patients undergoing HKTx. Methods: We included 98 patients undergoing HKTx between 2010 and 2018 at a single center. Recipient pre-transplant characteristics and clinical outcomes were compared between patients receiving D-MCS (n=24) versus non-D-MCS patients (n=74). The D-MCS cohort included those who received total artificial heart (n=13), left ventricular assist device (n=8), and biventricular assist devices (n=3). Endpoints included 1- and 5-year survival, 1-year-freedom from acute cellular rejection (defined as grade 2R or 3R), 1-year-freedom from antibody-mediated rejection (AMR, defined as pathologic AMR of grade ≥1), 5-year freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30% by angiography), 5-year freedom from non-fatal major adverse cardiac events (NF-MACE including myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and 5-year freedom from left ventricular dysfunction (LVEF ≤40). Results: At 1 year, freedom for AMR was numerically higher in the D-MCS group (100 vs. 90.2%, P=0.12). Additionally, the 5-year post-transplant survival rate was higher in the D-MCS group (95.8% vs. 80.8%), but it did not reach statistical significance (P=0.091). Comparable outcomes were noted for other outcomes, including 5-year freedom from CAV, NF-MACE, or LVD (Table 1 ). Conclusion: The current study hints at better 5-year survival in HTKx recipients receiving pre-transplant D-MCS, which could be attributed to lower rates of AMR in this population. Future larger studies are warranted to further validate these findings.

The Pre-/Post-Transplant Hepatitis C Antibody Associated with the IL-28B RS8099917 TT Genotype and miRNA-122 Expression May Protect Acute Cellular Rejection After LDLT.

This study aimed to investigate the relationship between the IL-28B SNP rs8099917 genotype, miRNA-122 expression, and the immune mechanism of ACR after LT using anti-HCV antibody calibration. A total of 45 patients with HCV received LT. IL-28B SNP rs8099917 genotyping was used to divide patients into TT and GT groups. The relative expression levels of miRNA-122 were calculated by quantitative PCR. Anti-HCV titers before and after LT were tracked to observe the relationship with ACR. The ACR rates were 27.6% for genotype TT and 62.5% for genotype GT, indicating a significantly higher rate in the GT group compared to the TT group (p = 0.024). In the rs8099917 genotype, TT was significantly associated with higher serum miRNA-122 levels than GT (p < 0.001). The TT group had significantly better outcomes than the GT group (p = 0.005). The Mann-Whitney U test showed significant differences in pre-LT and post-LT anti-HCV titers between the IL-28B genotypes (TT and GT) (p values of 0.006 and 0.027, respectively). These results suggested that the IL-28B rs8099917 genotype TT may play a significant role in modulating immune responses, both in terms of anti-HCV titers and the risk of ACR, possibly mediated through miRNA-122 levels.

Langerhans Cell Histiocytosis or Acute Cellular Rejection?

Langerhans cell histiocytosis (LCH) is a rare malignant disorder of epidermal antigen presenting cells. It is characterized by infiltration of various tissues with dendritic cells (Langerhans cells, LC) that express CD1a or CD207 (langerin), often leading to organ dysfunction. A patient with LCH required liver transplantation (LT) for LCH-associated biliary-tract disease. Cholangiopathy developed after LT. The question arose: In this patient, did LC in damaged liver-allograft biliary epithelium signify acute cellular rejection (ACR) or recurrent LCH? We evaluated immunohistochemical identification of LC (CD1a, CD207) in the proposita and in 14 ACR patient samples as distinguishing between ACR and recurrent LCH. Among 15 patient samples, 3 (20%) marked with neither antibody. Among the remaining 12 samples (80%), 4 (26.7%)-including that from the proposita-had cells marking for both antigens within bile-duct epithelium as well as in surrounding portal-tract connective tissue, 2 (13.3%) had cells marking for both antigens in one region or the other, but not in both, and 6 (40%) had cells marking for only one antigen in one region or the other. Immunostaining for CD1a and CD207/langerin in the setting of ACR without suspicion of LCH identifies LC in damaged bile ducts. This biomarker pairing proved not to be LCH-specific. Our findings indicate that the presence of these cells alone is insufficient to identify recurrent LCH in the allograft liver.

Donor-derived Cell-free DNA as a New Biomarker for Cardiac Allograft Rejection: a Prospective Study (FreeDNA-CAR)

BackgroundThere is a long-standing need for a non-invasive biomarker that allows monitoring of cardiac allograft rejection, avoiding the need for periodic endomyocardial biopsies (EMB). MethodsMulticenter, observational, prospective study, performed between 2019 and 2023 (NCT 04973943). All patients underwent 7 per-protocol surveillance EMB during the first post-HT year. Donor-derived cell-free DNA (dd-cfDNA) levels were determined before each EMB, using Next Generation Sequencing Technology (Allonext™ assay, Eurofins Genome). The primary endpoint was the association between dd-cfDNA levels and the presence of acute cellular rejection (ACR) in EMB. ResultsThe study included 206 patients from 12 centers, with 1090 pairs of EMB/dd-cfDNA determinations available for analysis. EMB with ACR (n=49) were associated to dd-cfDNA levels significantly higher than those without, median 0.189% (IQR 0.05-0.70) vs 0.095% (0.04-0.23), p=0.013. A dd-cfDNA threshold of 0.10% showed a negative predictive value for ACR of 97%.A statistically significant association between NTproBNP and dd-cfDNA was also found, with an increase of 0.007% dd-cfDNA (95%CI 0.003-0.011) for every 500 units of NTproBNP, p <0.001. The combination of both biomarkers for diagnosis of ACR showed an area under the ROC curve of 0.681, and this combined approach was significantly better than dd-cfDNA alone (area under the ROC curve 0.603), p = 0.016. Using a cut-off point of 0.10% for dd-cfDNA and 1000 UI/ml for NTproBNP, negative predictive value increased to 98.1%. ConclusionsDd-cfDNA may be a useful biomarker to rule out significant ACR in a low-risk population. However, a dd-cfDNA value above normal threshold does not correlate robustly with the presence of disease. The combination with NTproBNP, a readily available biomarker, increased the discrimination power of dd-cfDNA alone.

The ability of an electronic nose to distinguish between complications in lung transplant recipients

Complications like acute cellular rejection (ACR) and infection are known risk factors for the development of chronic lung allograft dysfunction, impacting long-term patient and graft survival after lung transplantation (LTx). Differentiating between complications remains challenging and time-sensitive, highlighting the need for accurate and rapid diagnostic modalities. We assessed the ability of exhaled breath analysis using an electronic nose (eNose) to distinguish between ACR, infection, and mechanical complications in LTx recipients (LTR) presenting with suspected complications. LTR with suspected complications and subsequently proven diagnosis underwent exhaled breath analysis using an eNose. Supervised machine learning was used to assess the eNose’s ability to discriminate between complications. Next, we determined the added value of the eNose measurement on top of standard clinical parameters. In 90 LTR, 161 measurements were performed during suspected complications, with 84 proven diagnoses. The eNose could distinguish between ACR, infection, and mechanical complications with 74% accuracy, and ACR and infection with 82% accuracy. Combining eNose measurements with standard clinical parameters improved diagnostic accuracy to 88% (P =.0139), with 94% sensitivity and 80% specificity. Exhaled breath analysis using eNose technology is a promising, noninvasive, diagnostic modality for distinguishing LTx complications, enabling timely diagnosis and interventions.

Bronchoalveolar lavage cytokine-based risk stratification of clinically-stable lung transplant recipients with undefined rejection: Further insights from a follow-up investigation.

Surveillance bronchoscopies with bronchoalveolar lavage (BAL) and transbronchial biopsies (TBB) are primarily used to detect acute cellular rejection (ACR) or infection in lung transplant (LTx) recipients. We previously identified a BAL protein signature associated with chronic lung allograft dysfunction (CLAD) or death/retransplant in patients with stable minimal (grade A1) ACR. This present study aimed to determine whether similar BAL biomarkers predict outcomes in stable patients when ACR grade is undetermined. The cohort included all adult, first bilateral LTx performed 2010-2017. Clinical status was categorized as unstable or stable based on the presence or absence of a ≥10% drop in FEV1. Clinically-stable patients with grade AX TBB (inadequate biopsies) during the first year post-transplant, not preceded by ACR (grade A≥1 or B≥1), were included. IL6, S100A8, IL10, TNF-receptor-1, IL1α, pentraxin3, and CXCL10 were measured in the BAL using a multiplex bead assay. Associations with subsequent CLAD or death/retransplant were assessed using multivariable Cox proportional hazards models, adjusted for relevant clinical covariates. Among 107 patients with stable AX biopsies at a median of 188 days post-transplant, the median times from biopsy to CLAD and death/retransplant were 972 and 1410 days, respectively. CXCL10 was significantly associated with CLAD, while IL6, S100A8, pentraxin3, TNF-receptor-1, and IL10 were associated with death/retransplant (p<0.05 for all). A focused BAL protein signature in stable patients with ungradable TBB early post-transplant may predict worse outcomes. Such select BAL biomarkers may identify patients who require more aggressive management strategies or closer monitoring.

Therapeutic Plasma Exchange is Associated with Increased Survival in Heart Transplant Recipients Experiencing Severe Primary Graft Dysfunction

BackgroundPrimary graft dysfunction (PGD) remains the leading cause of 30-day mortality post-heart transplantation (HTx). HTx recipients experiencing severe PGD have been found to have high levels of circulating proteins associated with PGD occurrence and post-HTx survival. Whether treating these patients with therapeutic plasma exchange (TPE) can attenuate ongoing immunological and inflammatory processes and improve post-transplant outcomes has not been well-investigated. AimWe aim to examine the impact of treatment with TPE on 30-day and 1-year clinical outcomes of patients experiencing severe PGD post-HTx. MethodsBetween 2010 and 2022, we included 42 HTx patients who developed severe PGD. All included patients were placed on veno-arterial extracorporeal membrane oxygenation. We divided these patients into those who received TPE and those who did not (by physician choice). Endpoints included 30-day and 1-year survival, as well as 1-year-freedom from Any-treated rejection (ATR), acute cellular rejection (ACR), antibody-mediated rejection (AMR), biopsy negative rejection (BNR), cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and freedom from left ventricular dysfunction (LVD) at 1-year post-HTx. ResultsCompared to patients who did not receive TPE, those managed with TPE had increased survival rates at 30 days (78.1% vs. 40%, P=0.007) and at 1-year post-HTx (56.25% vs. 30% P=0.035). However, no statistically significant differences were recorded in other outcomes of interest, including 1-year freedom from CAV, ATR, ACR, AMR, BNR, NF-MACE, or LVD. ConclusionTPE may serve as a promising therapeutic approach in HTx recipients experiencing severe PGD.

Suspicious of Acute Kidney Graft Rejection: Tacrolimus Pharmacokinetics Under Methylprednisolone Therapy.

Acute rejection remains one of the main complications in the first months after transplantation and may influence long-term outcomes. Tacrolimus has proven its usefulness in solid organ transplants and its monitoring through the application of pharmacokinetic concepts to optimize individual drug therapy. This research proposes to evaluate the tacrolimus pharmacokinetic parameters in patients suspected of acute kidney graft rejection under methylprednisolone pulse therapy. Eleven adult tacrolimus-treated renal recipients were selected from a prospective, single-arm, single-center cohort study, with suspicion of acute rejection although in use of methylprednisolone pulses therapy. They were followed up for three months posttransplantation, being tacrolimus trough serum concentrations determined using a chemiluminescent magnetic immunoassay, and pharmacokinetic parameters were estimated by using a nonlinear mixed-effects model implemented by Monolix 2020R1. A tacrolimus trough serum concentration range of 8 to 12 ng.mL-1 was considered therapeutic. Six patients showed acute cellular rejection, and two of them in addition had an antibody- mediated rejection. Tacrolimus trough serum concentration was below the reference range in eight patients. Most patients showed a high tacrolimus concentration intrapatient and pharmacokinetic parameters variability. The obtained pharmacokinetics parameters helped in understanding the kidney recipient patients' tacrolimus behavior, assisting in the improvement of individual drug therapy and reducing the risk of acute rejection episodes.

Incidence of acute cellular and antibody mediated rejection in heart transplantation from a tertiary care center

Abstract Background Heart transplant greatly increases the survival in patients with end stage heart failure. However, cardiologists and cardiothoracic surgeons face difficulty in detecting rejection at times. Post-cardiac transplant surveillance biopsy remains the gold standard for diagnosing rejection and therapeutic intervention. Purpose The objective is to report our experience of monitoring rejection by endomyocardial biopsy (EMB). Methods The index study is an ambispective one where we evaluated all the patients who underwent heart transplant at our center from 1994 to 2021. Results Heart transplant were carried out in 72 patients within a period of 28 years, with majority being done after 2016. The patients mean age was 31.6 years (10-59 years). The commonest indication was dilated cardiomyopathy (67%) followed by ischemic cardiomyopathy (2.5%), congenital heart disease (7%) and other miscellaneous causes (5%). The mean age of donors was 31.8 years (14-55 years). Eight of the 72 patients died without any post cardiac transplant endomyocardial biopsy. The remaining 64 patients underwent cumulatively a total of 271 endomyocardial biopsy procedures. Majority of endomyocaridal biopsies contained three cores (range 1-7). First EMB procedure was performed in 17 (26.6%) patients within first seven days, 35(53.1%) within the second week and 12(20.3%) after 14 days. Histologically rejection was identified in 42 (66%) patients. Thirty-nine (61%) had only acute cellular rejection (ACR), one (1.6%) had only antibody mediated rejection (AMR) and two (3.1%) had mixed ACR and AMR. These 42 patients with rejection had a total of 90 (33.2%) episodes of ACR detected in 271 endomyocardial biopsies. Out of 90 ACR, 44 (48.9%) occurred in less than six months; seventeen (18.9% of 90 ACR) episodes occurred between six and 12 months and 29 (32.2%) after one year. The mean of presentation of first ACR episode was 36 weeks (range 5 days to 3.6 years). There were 172 endomyocardial procedures within one year of transplantation of which 61 (35%) showed rejection. Ninety-nine endomyocardial procedures were performed one year of transplantation of which 29 (29%) showed rejection. Most common grade in both the time period was ACR grade 1R (International Society for Heart and Lung Transplantation (ISHLT) 2004) (72.1% in ≤1 year and 65.5% in &amp;gt;1 year) followed by 2R and 3R. Thirty-eight (90.4%) of 42 patients expired in less than five years since transplantation. Two (4.8%) patients survived between five to ten years post transplantation and two (4.8%) survived more than ten years. The longest cardiac transplant recipient had completed 23 years since cardiac transplant and is alive till date. Conclusions EMB being the gold standard for cardiac allograft rejection, the cardiac pathologists need to be aware of the various grades of rejection including mixed rejection.Acute cellular rejection (ISHLT 2004)