Early Acute Cellular Rejection Research Articles

Alterations in CD4+ T-cell Subsets in Living Donor Liver Transplantation Associated With Graft Rejection

Background and ObjectivesRegulatory T-cells (Tregs) play a key role in immune homeostasis after organ transplantation. However, the role of CD4+ T cell subsets in early acute rejection is still not well understood. Therefore, our aim was to determine changes in CD4+ T-cell subsets in living donor liver transplantation (LDLT). MethodsLDLT patients were assessed for T-cell subsets, Tregs frequencies and their functionality by flow-cytometry at peri and post-transplant in the span of 1year. Results33 patients were followed-up and 11 (33%) patients have developed early acute cellular rejection (ACR). At peri-transplant time point, MFI of Foxp3+ Tregs was significantly increased compared to HC (P=0.04). However, CD4+CD25+Foxp3+/CD127- Tregs numbers and IL-10, IL-17 and TGF-β secreting functional Tregs were significantly decreased at 3-month compared to peri-transplant (P=0.003). But in patients with rejection, CD4+CD25+FOXP3+ and CD4+CD25+CD127-Tregs were significantly decreased at day 3 compared to no rejection group (P=0.048). Patients with rejection also showed significantly decreased numbers of IL-17 and TGF-β secreting CD4+CD25+FOXP3+ Tregs at peri-transplant time (P=0.04, P=0.03) compared to no rejection. Further, rejection group showed decreased terminally differentiated effector memory (TEMRA) at peri-transplant and day 7 (P=0.048 and P=0.01). Additionally, CD4+ central memory (CM) was decreased at peri-transplant (P=0.05), 1-month (P=0.04), 3 to 6-month (P=0.02). Interpretation and ConclusionTregs frequencies were significantly decreased in peri-TX in rejection patients. Further, decreased frequencies of CD4+ TEMRA and CD4+ CM at day 7 and 1month were associated with rejection.

Detrimental impact of early biopsy-proven rejection in liver transplantation.

Existing literature offers conflicting conclusions about whether early acute cellular rejection influences long-term outcomes in liver transplantation. We retrospectively collected donor and recipient data on all adult, first-time liver transplants performed at a single center between 2008 and 2020. We divided this population into two cohorts based on the presence of early biopsy-proven acute cellular rejection (EBPR) within the first 90 days post-transplant and compared outcomes between the groups. There were 896 liver transplants that met inclusion criteria with 112 cases (12.5%) of EBPR. Recipients who developed EBPR had higher biochemical Model for End-Stage Liver Disease scores (28vs. 24, p<.01), but other donor and recipient characteristics were similar. Recipients with EBPR had similar overall survival compared to patients without EBPR (p=.09) but had decreased graft survival (p<.05). EBPR was also associated with decreased time to first episode of late (>90 days post-transplant) rejection (p<.0001) and increased vulnerability to bacterial and viral infection (p<.05). In subgroup analysis of recipients with autoimmune indications for liver transplantation, EBPR had a more pronounced association with patient death (hazard ratio [HR] 3.9, p<.05) and graft loss (HR 4.0, p<.01). EBPR after liver transplant is associated with inferior graft survival, increased susceptibility to late rejections, and increased vulnerability to infection.

Circulating T cell specific extracellular vesicle profiles in cardiac allograft acute cellular rejection

There is a critical need for biomarkers of acute cellular rejection (ACR) in organ transplantation. We hypothesized that ACR leads to changes in donor-reactive T cell small extracellular vesicle (sEV) profiles in transplant recipient circulation that match the kinetics of alloreactive T cell activation. In rodent heart transplantation, circulating T cell sEV quantities (P < .0001) and their protein and mRNA cargoes showed time-specific expression of alloreactive and regulatory markers heralding early ACR in allogeneic transplant recipients but not in syngeneic transplant recipients. Next generation sequencing of their microRNA cargoes identified novel candidate biomarkers of ACR, which were validated by stem loop quantitative reverse transcription polymerase chain reaction (n = 10). Circulating T cell sEVs enriched from allogeneic transplant recipients mediated targeted cytotoxicity of donor cardiomyocytes by apoptosis assay (P < .0001). Translation of the concept and EV methodologies to clinical heart transplantation demonstrated similar upregulation of circulating T cell sEV profiles at time points of grade 2 ACR (n = 3 patients). Furthermore, T cell receptor sequencing of T cell sEV mRNA cargo demonstrated expression of T cell clones with intact complementarity determining region 3 signals. These data support the diagnostic potential of T cell sEVs as noninvasive biomarker of ACR and suggest their potential functional roles.

Does the induction immunotherapy (basiliximab) influence the early acute cellular rejection index after orthotopic heart transplantation?- Preliminary assessment report

The study aimed to determine the influence of induction therapy on the acute cellular rejection (ACR) index in adult heart transplant recipients during the one-year observation. The study population consisted of 256 consecutive adult patients (pts), aged 51.5 (±11.9) years, 199 (77%) men treated with orthotopic heart transplantation (OHT) in the period between 2015 and 2020 in a single high-volume heart transplant center. The endomyocardial biopsies (EMBs) were performed according to the protocol consisting of 7 protocolary EMBs for up to 3 months and 10 EMBs for up to one year after OHT. The rejection index (ACRI) was calculated as the number of scheduled EMBs with the ACR ≥ 2 divided by the total number of protocolary EMBs.The study population was divided into two groups according to the application of basiliximab. The total number of pts. who received basiliximab was 10 (3.9%). The main indications for the usage of the induction therapy were heart retransplantation, mechanical circulatory support (MCS), severe renal insufficiency (eGFR <30 mL/min/1.73 m2), and a panel of reactive antibody (PRA) > 10%. In the group with induction, the mean age was 49 (±14) years; 3 (30%) patients had the MCS prior to OHT, and 3 (30%) patients had heart retransplantation. Four (40%) patients had diabetes mellitus, and 4 (40%) patients had severe renal insufficiency. As maintenance therapy during the observation period, tacrolimus was given to 10 (100%) patients, everolimus to 2 (20%) patients, and MPA to 9 (90%) patients.In the group with no induction, the mean age was 51.8 (±12) years, MCS was used in 56 (23%) patients, 2 (0.8%) patients were retransplanted; 10 (4%) patients had eGFR <30 mL/min/1.73 m2 and 58 (24%) patients had diabetes. Tacrolimus was administered to 243 (99%) patients, cyclosporine to 3 (1%), everolimus to 40 (16%), and mycophenolate to 245 (99.6%) heart recipients.The median one-year ACRI was 0.0, IQR:0.0–0.08 in the group with induction vs. 0.077, IQR: 0.0–0.154 with no induction; p = 0.11. ACRI up to three months was significantly higher in the entire cohort in comparison to up to one year (P < 0.01).The multivariate analysis showed that only everolimus implementation and younger age at the time of transplant influenced patients' mortality rate (P < 0.01).Significant graft rejections (≥ 2R ISHLT) are most common in the first three months after OHT. Patients who are initially at high risk of significant cellular rejection may benefit from induction therapy.

Impact of age and telomere length on circulating T cells and rejection risk after lung transplantation for idiopathic pulmonary fibrosis

Most idiopathic pulmonary fibrosis (IPF) lung transplant recipients (IPF-LTRs) have short telomere (ST) length. Inherited mutations in telomere-related genes are associated with the development of T cell immunodeficiency. Despite this, IPF-LTRs with telomere-related rare variants are not protected from acute cellular rejection (ACR). We set out to determine the impact of both age and telomere length on the circulating T cell compartment and ACR burden of IPF-LTRs. We identified 106 IPF-LTRs who had telomere length testing using flowFISH (57 with short telomeres and 49 with long telomeres) as well as a subset from both cohorts who had cryopreserved PBMC at least 1 time point, 6 months posttransplantation. Circulating T cells from before transplantation and at 6 and 12 months posttransplantation were analyzed using multiparameter flow cytometry to study phenotype and functional capacity, and bulk T cell receptor sequencing was performed to study repertoire diversity. Linear regression was used to study the relationship of age and telomere length on early (within 1 year) and late (between 1 and 2 years) ACR. IPF-LTRs with ST were found to have premature "aging" of their circulating T cell compartment, with age-agnostic elevations in posttransplant terminal differentiation of CD8+ T cells, increased granzyme B positivity of both CD8+ and CD4+ T cells, upregulation of the exhaustion marker, CD57, and chemotactic protein CCR5, and enhanced T cell receptor clonal expansion. Additionally, we found a significant decline in early ACR burden with increasing age, but only in the ST cohort. IPF-LTRs with ST have premature "aging" of their circulating T cell compartment posttransplantation and a clear age-related decline in ACR burden.

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

(967) Use of the SherpaPak Cardiac Transport System Improves Freedom from Requirement for Mechanical Circulatory Support, Reduced Early Acute Cellular Rejection and Preserves Early Lv Function When Compared to Conventional Cold Storage

(967) Use of the SherpaPak Cardiac Transport System Improves Freedom from Requirement for Mechanical Circulatory Support, Reduced Early Acute Cellular Rejection and Preserves Early Lv Function When Compared to Conventional Cold Storage

Temporal shifts in safety and efficacy profile of mycophenolate mofetil 2 g versus 3 g daily early after heart transplantation.

Mycophenolate mofetil (MMF) is the gold-standard immunosuppressive agent in heart transplantation (HT), but dose-dependent toxicities (e.g., neutropenia) are frequent. Gut bacteria β-d-glucuronidases (GUS) modulate MMF bioavailability, and changes in the intestinal flora may influence the pharmacokinetics of MMF. The objective of this study was to evaluate the safety and efficacy of MMF 1.5 g every 12 h (q12) [high-dose, HD] versus 1 g q12 [low-dose, LD] and explore the association between neutropenia and GUS. We compared the incidence of acute cellular rejection (ACR) and neutropenia during the first 6 months post-HT. The association between neutropenia and GUS was investigated in an exploratory analysis on a subset of patients with prospectively collected stool data. Stool samples were analyzed using 16S rRNA sequencing. A total of 168 patients (120 MMF-HD, 48 MMF-LD; mean age 55.7 years, 79% male) were studied. Neutropenia occurred in 38.6% of patients at a median of 106 [64-143] days. Freedom from neutropenia was lower in MMF-HD compared with MMF-LD (57% vs. 73%, p=0.03). ACR (≥1R/1B) occurred in 37.5% of patients at a median of 20 [10-96] days, while high-grade ACR (≥2R/3A) occurred in 11.3% at a median of 14 [9-89] days. Freedom from ACR was similar between groups. MMF-LD was associated with more high-grade ACR (hazard ratio [HR] 3.47, 95% confidence interval [CI] 1.09-11.08, p=0.03) during the first month, but less neutropenia (HR 0.54, 95% CI 0.29-1.00, p=0.05) between 1 and 6 months. GUS-producing bacteria were more abundant in neutropenic patients. MMF-LD was associated with higher rates of early high-grade ACR and lower rates of later neutropenia. Further studies are warranted to test whether temporal MMF dose adjustments and gut microbial composition could improve clinical outcomes post-HT.

Nomograms for Predicting the Incidence of Late-Onset Acute Cellular Rejection in Patients After Pediatric Liver Transplantation.

BackgroundLate-onset acute cellular rejection (LACR) is a special type of acute rejection (AR) only rarely studied after pediatric liver transplantation (pLT). Our study aimed to explore the influencing factors of LACR after pLT and establish a nomogram to provide an individualized prediction of LACR after pLT.Materials and MethodsData from 640 children who underwent pLT at Tianjin First Central Hospital from January 2016 to December 2019 were collected as part of this retrospective study. The nomogram was then established through the results of the multivariable analysis.ResultsForty-one patients experienced LACR > 1 ≤ 2 years after pLT. Cold ischemia time, donor-specific antibodies (DSAs), and tacrolimus concentration were independent influencing factors, and a nomogram was established with an AUC value of 0.834 (95% confidence interval, 0.755–0.912). Ten-fold cross-validation showed that the accuracy of the nomogram was about 76%. Sixty-three patients experienced LACR > 2 years after pLT. Child–Pugh grade, cold ischemic time, DSAs, early acute cellular rejection, and tacrolimus concentration were independent influencing factors, and a nomogram was established with an AUC value of 0.827 (95% confidence interval, 0.774–0.881). Ten-fold cross-validation showed that the accuracy of the nomogram was about 80.9%.ConclusionWe established nomograms to predict the incidence of LACR > 1 ≤ 2 and > 2 years after pLT, respectively. The verification results showed that nomograms had good accuracy and clinical practicability.

Clinical Value of Surveillance Biopsies in Pediatric Liver Transplantation.

Although pediatric liver transplantation (LT) results in excellent long-term outcomes, a high incidence of early acute cellular rejection and late graft fibrosis persists. Routine measurement of allograft enzymes may not reliably detect rejection episodes, identify candidates for immunosuppression minimization, or indicate allograft fibrosis. Surveillance biopsies (SBs) can provide valuable information in this regard, but their role in pediatric LT is not fully established. A retrospective cohort of 236 pediatric LT recipients from a high-volume center was studied to characterize the risks and benefits of SB versus for-cause biopsies (FCBs). The study population was 47.1% male and 54.7% Hispanic, and 31% received living donor grafts. Our data suggest that patients in the SB group had better transplant outcomes (rejection-free, graft, and patient survival) compared with patients who had FCBs or who never underwent biopsy. Among 817 biopsies obtained from 236 patients, 150 (18.4%) were SBs. Only 6 patients had a biopsy-related complication, and none were observed in the SB subset. Graft biochemical blood tests did not accurately predict rejection severity on biopsy, with aspartate aminotransferase area under the receiver operating characteristic curve (AUROC) 0.66, alanine aminotransferase AUROC 0.65 (very poor predictions), and gamma-glutamyltransferase AUROC 0.58 (no prediction). SBs identified subclinical rejection in 18.6% of biopsies, whereas 63.3% of SBs had evidence of fibrosis. SBs prompted changes in immunosuppression including dose reduction. Our experience suggests that SB in pediatric LT is safe, offers valuable information about subclinical rejection episodes, and can guide management of immunosuppression, including minimization. Improved outcomes with SB were likely multifactorial, potentially relating to a more favorable early posttransplant course and possible effect of management optimization through SB. Further multicenter studies are needed to examine the role of SBs on long-term outcomes in pediatric LT.

Novel left and right ventricular strain analysis to detect subclinical myocardial dysfunction in cardiac allograft rejection.

Early detection of acute cellular rejection (ACR) by echocardiography shows potential clinical benefit as ACR remains a significant contributor to morbidity and mortality. This retrospective, longitudinal study sought to investigate the use of novel left (LV) and right ventricular (RV) strain analysis to detect biopsy proven ACR. 46 heart transplant patients (Mean age 46 ± 16years) with biopsy proven ACR were grouped according to biopsy results: 1R-ACR (n = 36) and 2R-ACR (n = 10). Serial two-dimensional transthoracic echocardiography with strain analysis was performed. Echocardiographic parameters were serially measured: (1) rejection free period (0R-ACR); (2) pre-ACR period (pre-ACR); (3) during ACR (1R-ACR or 2R-ACR) and (4) post-ACR (Post-ACR). Significant reductions for LV Global Longitudinal Strain (LV GLS) and LV Early diastolic Strain rate (LV ESr) were observed between 0R-ACR and pre-ACR (LV GLS 0R-ACR: 17.3% vs Pre-2R ACR: 15.4%, p = 0.016; LV ESr 0R-ACR: 1.00/s vs Pre-2R ACR: 0.74/s, p = 0.007) with LV ESr demonstrating the highest sensitivity (92%) and specificity (81%) to predict ACR. LV ESr and the E/LV ESr ratio were significantly different (p = 0.0001; p = 0.016) during pre-1R ACR period vs 0R whereas LV GLS showed no significant differences for grade 1R-ACR. Diastolic mechanical dispersion showed significant increases in dispersion during ACR for the 1R-ACR group and early significant increases pre-2R ACR. Systolic and diastolic RV strain parameters showed a similar trend for both ACR groups. Systolic and diastolic strain parameters can detect myocardial dysfunction before biopsy confirmed 2R-ACR. Early diastolic strain rate parameters are most sensitive detecting subclinical myocardial dysfunction pre-ACR. Novel strain parameters are potentially useful clinical tool for prediction of early ACR in heart transplant.

Early Phase Circulating Donor-Derived Cell-Free DNA in Patients after Lung Transplantation

<h3>Purpose</h3> Detection of donor-derived cell-free DNA (dd-cfDNA) in circulating blood of posttransplant recipients is a clinically informative tool to predict acute allograft injury and rejection, although its reliability and feasibility have not been extensively studied in lung transplantation. Here, we present our preliminary data of dd-cfDNA in lung transplant patients during the early posttransplant phase. <h3>Methods</h3> Eight subjects were included in this study among patients received double lung transplants at our institute between Jun.-Sept. 2020. Re-transplantation cases were excluded per the study protocol. Blood samples were collected at various times from these consented patients before and after transplantation. Dd-cfDNA in obtained blood samples were determined using AlloSure dd-cfDNA test kits (CareDx, Inc). <h3>Results</h3> Of the 8 subjects, none developed severe primary graft dysfunction and two patients presented acute cellular rejection (ACR) after lung transplantation. All subjects exhibited increased dd-cfDNA immediately after transplantation with a peak percentage of dd-cfDNA (range 12-27%) within 48h posttransplant. (Figure 1). Over 2 weeks, dd-cfDNA percentage declined with significant variation reaching a similar level of <5%, although patients with severe systemic conditions displayed an overall lower percentage of circulating dd-cfDNA versus recipient derived cfDNA. One patient with early ACR and early spike in donor specific antibodies (DSA) showed a relative slower decline in dd-cfDNA than the ACR alone case. <h3>Conclusion</h3> To our knowledge, this is the first report of acute time-dependent changes of dd-cfDNA in patients immediately after lung transplantation. Our preliminary data suggest that recipients' systemic condition may mask the appearance of dd-cfDNA. Additional information regarding circulating whole cfDNA in patients may assist in more accurate detection of dd-cfDNA in the acute phase.

Increased early acute cellular rejection events in hepatitis C-positive heart transplantation

Increased utilization of hepatitis C virus (HCV)-positive donors has increased transplantation rates. However, high levels of viremia have been documented in recipients of viremic donors. There is a knowledge gap in how transient viremia may impact acute cellular rejections (ACRs). In this study, 50 subjects received hearts from either viremic or non-viremic donors. The recipients of viremic donors were classified as nucleic acid amplification testing (NAT)+ group, and the remaining were classified as NAT-. All patients were monitored for viremia levels. Endomyocardial biopsies were performed through 180 days, evaluating the incidence of ACRs. A total of 50 HCV-naive recipients received hearts between 2018 and 2019. A total of 22 patients (44%) who received transplants from viremic donors developed viremia at a mean period of 7.2 ± 0.2 days. At that time, glecaprevir/pibrentasvir was initiated. In the viremia period (<56 days), 14 of 22 NAT+ recipients (64%) had ACR vs 5 of 28 NAT- group (18%) (p = 0.001). Through 180 days, 17 of 22 NAT+ recipients (77%) had a repeat rejection biopsy vs 12 of 28 NAT- recipients (43%) (p = 0.02). NAT+ biopsies demonstrated disparity of ACR distribution: negative, low-grade, and high-grade ACR in 84%, 12%, and 4%, respectively, vs 96%, 3%, and 1%, respectively, in the NAT- group (p = 0.03). The median time to first event was 26 (interquartile range [IQR]: 8-45) in the NAT+ group vs 65 (IQR: 44-84) days in the NAT-. Time to first event risk model revealed that NAT+ recipients had a significantly higher rate of ACR occurrences, adjusting for demographics (p = 0.004). Transient levels of viremia contributed to higher rates and severity of ACRs. Further investigation into the mechanisms of early immune activation in NAT+ recipients is required.

Mycophenolate Mofetil Dose and Early Acute Cellular Rejection Post Cardiac Transplantation

Early acute cellular rejection (ACR) after orthotopic heart transplantation (OHT) is associated with adverse long-term outcomes. Data on whether the Mycophenolate mofetil (MMF) dose has any impact on rates of early ACR is lacking. The target MMF dose studied in clinical trials for immunosuppression with OHT has ranged from 2 to 3gm/day. In January of 2016 due to an increase in infectious complications, we modified our institutional policy whereby the target MMF dose was lowered from 3 gm/day to 2gm/day. In this analysis, we examined rates of early rejection stratified by target MMF dose. We performed a retrospective analysis of consecutive OHT recipients at a single center from January 2015 to July 2019. Patients were divided into two groups based on the target MMF dose (3gm vs. 2 gm/day). The rates of ACR warranting a change in immunosuppressive regimen within 4 weeks of OHT (1R/1B or ≥ 2R) were compared between the two groups. Data on other factors that could impact early ACR such as age, gender, race, induction immunosuppression, and PRA was also collected. Univariate and multivariate-adjusted statistical analyses were performed. Of 169 OHT, mean age 53 years and 26% females, 67 patients were in the MMF 3gm/day group (Group 1) and 102 were in the 2 gm/day group (Group 2). Baseline characteristics were similar in both groups. The average daily dose of MMF for the first week after OHT was 2245 ± 724 mg in Group 1 and 1866 ± 525 mg in Group 2 (p<0.001). The incidence of early ACR was higher in Group 2 compared to Group 1 (22% vs. 12%, p=0.06) (Figure1). In this single-center study of OHT recipients comparing daily target MMF dose of 3gm with 2gm in the early post OHT period, there was a trend towards early ACR in the 2gm/day MMF dose group. This suggests that a higher MMF dose of 3gm/day, if tolerated, may help lower rates of early ACR. Further investigation in a larger sample is warranted to validate this finding.

Recipient-Derived Immune Cell Phenotyping of Bronchoalveolar Lavage Identifies Patients with Biopsy Proven Early Acute Cellular Rejection after Lung Transplantation: A Pilot Study

Acute cellular rejection (ACR) is associated with the ultimate development of chronic lung allograft dysfunction. Transbronchial biopsy, the gold standard for the diagnosis of ACR, is associated with potential morbidity. We set out to define the correlation between the recipient-derived immune cell content in bronchoalveolar lavage (BAL) and biopsy proven early ACR (<4 months). We analyzed BAL samples from 8 lung transplant recipients with early ACR and 5 without ACR. Immunophenotyping was performed using spectral flow cytometry; cell origin (donor v recipient) was determined by staining for human leukocyte antigen. T test was used to identify differences in immune cell populations between those with and without ACR. Live CD45+ cells were defined as CD4+ and CD8+ T cells, B cells (CD19+, CD20+), CD56+ lymphocytes, and monocytes (CD14+CD206+/CD64+). BAL was obtained at 1.5 months (range 0.5-3.5) from transplant at time of ACR and at 1.6 months (range 0.5 - 2.8) for non-ACR. The presence of ACR was associated with a statistically significant decrease in the proportion of donor monocytes (Figure 1: Mean 85%, SD 15% v 34%, SD 16%; p <0.001) and donor-derived regulatory T cells (Tregs), defined as CD4+CD25+FOXP3+ (Mean 3%, SD 3% v Mean 9%, SD 3%; p = 0.004). When comparing absolute number of both donor and recipient immune cells found in the BAL, patients with ACR had a statistically significant increase in the number of recipient-derived CD4+ T cells (Mean 7%, SD 5% v 1%, SD 0.05%; p value = 0.02), and a trend towards increased recipient-derived CD8+ T cells (Mean 18%, SD 27% v <1%, SD 1%; p value = 0.17). Biopsy proven, early ACR is associated with a relative decline in donor monocytes and donor Tregs, and increased proportion of recipient-derived CD4+ T cells. These results support further investigation into the role of BAL immune cell phenotyping as a potential less-invasive biomarker for ACR.

Faster Time-to-Therapeutic Tacrolimus Level is Associated with Lower Risk of Cellular Rejection Early after Heart Transplantation

Faster time-to-therapeutic tacrolimus (TTT) levels is associated with lower rates of acute cellular rejection (ACR) in kidney and liver transplantation. Limited data have evaluated this relationship in heart transplant (HT) recipients. Single-center retrospective chart review of patients who received HT from January 1, 2014 to June 30, 2016. Multi-organ transplant recipients, re-transplants, and those who received induction therapy with either basiliximab or thymoglobulin were excluded. A therapeutic tacrolimus concentration was defined as a trough level between 8-15 ng/mL for two consecutive days. The primary outcome was the rates of 30-day ACR in patients who were < and ≥ the median TTT level. Serum creatinine values were also collected for the first 10 post-op days. From a database of 88 HT patients we evaluated 55 patients who did not receive induction therapy (median age=56 (49-65), 73% white, 71% had a VAD prior to HT). The median TTT level was 9 days; patients < the median (n=25) had similar characteristics as those ≥ the median (n=30). Rates of ACR were significantly lower in the < median group (8 v. 43%, p=0.005) (Figure), while serum creatinine values were similar between groups (p>0.05 for each day). Patients without ACR (n=40) had a median TTT level of 8 (6-9.5) days, compared to 10 (9-12) days in the ACR group (n=15) (p=0.01). A multivariate regression model found TTT ≥9 days to be significantly associated with early ACR after adjusting for age, gender, and VAD pre-HT (OR 9.84, 95% CI [1.86-52.90], p=0.007). Quickly achieving a TTT level reduces the risk of ACR early after HT without adversely affecting renal function.

C-reactive Protein and Left Ventricular Thickness Can Predict Acute Cellular Rejection after Heart Transplant

Acute cellular rejection (ACR) remains a major challenge after heart transplant (HT), and it requires endomyocardial biopsy (EMB) as the gold standard for ACR diagnosis. Non-invasive biomarkers have been proposed for early ACR detection; however, it is unclear which biomarker best predict ACR. The objective of our study was to identify non invasive parameters in ACR diagnosis in patients (pts) submitted to HT. Troponin, B-type natriuretic peptide (BNP), C-reactive protein (CRP), Echo data (diastolic diameter [DD], ejection fraction [LVEF], left ventricle (LV) mass, LV posterior wall and LV septum thickness, presence of right ventricular dysfunction [RVDysf] and pericardial effusion [PE]) were obtained in 107 pts, and 224 EMB. The study was conducted from january 2010 to june 2019. Using a multivariate model, we assessed the association of changes of biomarkers and ventricular remodeling parameters with ACR episodes (≥ 2R - ISHLT). For this analysis, we considered the first biopsy performed 30 days after HT to exclude ischemic injury period. ACR was detected in 23 biopsies (10.2%) from all 224 EMB. After 30 days, 9 (12.5%) from 72 EBM showed ACR in pts with no clinical suspicious of ACR (Table 1). The only significant predictors of ACR were CRP (AUC: 0.73), LV posterior wall (AUC=0.74), LV septum thickness (AUC=0.75) and LV mass (AUC=0.79). Troponin and BNP are not useful indicators of ACR in both periods. CRP blood levels, and echocardiographic parameters reflecting LV mass and thickness were the only predictors of ACR after 30 days of HT.

C-REACTIVE PROTEIN AND CARDIAC STRUCTURE MEASURES CAN PREDICT ACUTE CELLULAR REJECTION AFTER HEART TRANSPLANT

Acute cellular rejection (ACR) remains a major challenge after heart transplant (HT), and it requires endomyocardial biopsy (EMB) as the gold standard for ACR diagnosis. Non-invasive biomarkers have been proposed for early ACR detection. The objective of our study was to identify non invasive

Neutrophil-to-lymphocyte ratio predicts early acute cellular rejection in living donor liver transplantation.

PurposeThe aim of this study was to evaluate the predictive value of neutrophil-to-lymphocyte ratio (NLR) in acute cellular rejection (ACR) after living donor liver transplantation (LDLT).MethodsAll consecutive patients who underwent ABO-compatible (ABOc) LDLT from September 2014 to December 2017 were retrospectively reviewed. NLR was calculated on 3 occasions; (1) 4 weeks prior to liver transplantation (LT), (2) the day of LT, and (3) the day before liver biopsy.ResultsAmong 66 patients who underwent ABOc LDLT, ACR was identified in 15 patients (22.7%) on protocol liver biopsy performed routinely on the postoperative day 7. There was no significant difference in NLR at 4 weeks prior to LT and the day of LT between no-ACR and ACR group (2.98 ± 1.92 vs. 2.54 ± 1.15, P = 0.433; 17.9 ± 8.31 vs. 20.5 ± 13.4, P = 0.393). However, NLR was significantly lower in ACR group compared to non-ACR group just prior to liver biopsy (5.82 ± 3.42 vs. 18.4 ± 17.2, P = 0.035). NLR tends to decrease 3.5 days before the onset of ACR. The area under the receiver operating characteristic curve for optimal cut-off value of NLR was 6.49, with sensitivity and specificity of 80.4% and 73.3% respectively.ConclusionNLR has a potential as a noninvasive predictor of early ACR in ABOc LDLT.

A Single-Center Experience of the Optimal Initial Immunosuppressive Strategy for Preventing Early Acute Cellular Rejection in Orthotopic Heart Transplantation Associated With Renal Dysfunction.

Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain. We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant. Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy (P < .05, log rank test). In patients treated with basiliximab, early administration (<24 hours) was associated with a higher freedom from acute rejection compared to ≥24 hours, (72% vs 29%, P < .05). The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy; however, it was only effective when administered within 24 hours.