Marker Of Acute Cellular Rejection Research Articles

Tissue Expression of Programmed Cell Death 1 Ligand1 (PD-L1) in Biopsies of Transplant Livers of Pediatric Patients as a Possible Marker of Acute Cellular Rejection

Introduction: Preclinical models have demonstrated that PD-1 and its ligand programmed death ligand1 (PD-L1) play significant roles in both graft induction and the maintenance of immune tolerance. It has also been suggested that PD-L1 tissue expression may predict graft rejection; however, the available data are sparse and inconclusive. Some studies were conducted on patients with cancer; most of them do not concern the liver, especially within the context of the use of immunohistochemical tests. Therefore, the aim of our study was to assess the relationship between tissue expression of PD-L1 in a unique material, i.e., in the liver biopsies of pediatric patients after transplantation with the presence of acute cellular rejection (ACR). Material and Methods: This retrospective study enrolled 55 biopsies from 55 patients who underwent protocol liver biopsies. The control group consisted of 19 biopsies from 13 patients diagnosed with acute cellular rejection (rejection activity index/RAI/ from 2 to 8). An immunohistochemical (IHC) staining for PD-L1 was performed in all of the liver specimens; its expression was analyzed in different regions of liver tissue (in inflammatory infiltrates and within the endothelium and hepatocytes). The following changes were re-evaluated in each specimen: features of any kind of rejection (acute cellular, antibody-mediated, chronic); the presence and severity of fibrosis (Ishak scale); and the presence of cholestasis and steatosis. Clinical parameters were also evaluated, including tests of liver function (AST, ALT, GGT, bilirubin). Results: The age of patients in the study group ranged from 2.37 to 18.9 years (median 13.87 years), with the time after transplantation being 1–17 years (median 8.36 years). The age of patients in the control group ranged from 1.48 to 17.51 years (median 7.93 years), with their biopsies being taken 0.62–14.39 years (median 1.33 years) after transplantation. We found a statistically significant relationship between PD-L1 expression on inflammatory infiltrates and ACR; however, there was no statistically significant relationship between PD-L1 endothelial expression and ACR. PD-L1 was not positive in the hepatocytes regardless of if it was the study or control group that was under observation. Conclusion: PD-L1 appears to be a promising marker to predict graft rejection.

Peripheral blood eosinophilia as a marker of acute cellular rejection in lung transplant recipients

To assess the association between EOS and the presence of acute cellular rejection in lung transplant recipients. Retrospective study of 583 transbronchial biopsies (TBB) performed in 256 lung transplant patients between 2012 and 2018. We analyzed age, sex, underlying pathology, date of transplant, indications for TBB, presence and degree of ACR, and the simultaneous absolute and relative EOS. ACR were observed in 170 of 583 TBB (29.2%). EOS in patients with ACR were higher than in patients without ACR (203.6 ± 248/mm3 vs 103.1 ± 153/mm3; p < 0.001). High levels of both absolute and relative EOS were associated with the presence of ACR regardless of the underlying disease (odds ratio [OR] 1.003; 95% confidence interval [CI], 1.002-1.004; OR 1.226; 95% CI, 1.120-1.342) and time after transplant (OR 1.003; 95% CI, 1.002-1.004 and OR 1.239; 95% CI, 1.132-1.356). Moreover, both absolute and relative EOS were strongly associated with moderate and severe grades of ACR (OR 3.55; 95% CI, 3.00-4.10 and OR 3.56; 95% CI, 3.00-4.12). EOS are elevated in ACR, especially in moderate or severe ACR. Increased vigilance for ACR is therefore advisable in lung transplant recipients with elevated EOS.

PD-L1 (Programmed Death Ligand 1) as a Marker of Acute Cellular Rejection After Heart Transplantation.

PD-L1 (Programmed Death Ligand 1) as a Marker of Acute Cellular Rejection After Heart Transplantation.

PE-15: REG3α May Be a Novel Marker for Acute Cellular Rejection after Adult Isolated Intestinal Transplantation

PE-15: REG3α May Be a Novel Marker for Acute Cellular Rejection after Adult Isolated Intestinal Transplantation

P937 Left atrial longitudinal strain as a marker of acute cellular rejection in heart transplant recipients: impact of intervendor variability

Abstract Introduction and purpose Preliminary reports suggests that left atrial longitudinal strain (LALS) variables are a sensitive marker of acute cellular rejection (ACR) in heart transplant recipients (HTxR), discriminating between those studies without rejection and those with any grade of rejection. Intervendor variability is a concern in the widespread use of this technique. Our objective was to compare the LALS evaluated by two different softwares. Methods From September 2014 to October 2016 we performed, in 18 consecutive adult HTxR in their first year posttransplantation, serial echocardiographic exams within 3 hours of the routine surveillance endomyocardial biopsies (EMB), in a single centre. Peak average longitudinal strain, and strain rate were measured in the left atrium in the apical four chambers view in all studies, using both softwares, its association with the presence of ACR was investigated, and intervendor variability was evaluated. Results a total of 147 pairs of EMB and echo exams were performed, 65 with no rejection (grade 0R), 82 with any grade of ejection (grades 1R and 2R). Intraclass correlation coeficients for intervendor reproducibility for LALS and LALSR were 0.4 (95%CI 0.26 - 0.57) and 0.3 (95%CI -0.06 - 0.52) respectively. The number of segments evaluable by each software was significantly different. Association of LALS with rejection is shown in the table. Conclusions In this monocentric prospective study, left atrial longitudinal strain variables were found to be a sensitive marker of acute cellular rejection in heart transplant recipients. Although intervendor reproducibility was poor, these results were consistent between both software. Results Software n/N (%)* Variable No ACR ACR≥1 p value Siemens 114/147 (77.5) Peak atrial LS 19.4 ± 7.4 15.5 ± 6.3 0.006 114/147 (77.5) Peak atrial LSR 1.5 ± 0.4 1.3 ± 0.5 0.005 TomTec 131/147 (89.1) Peak atrial LS 19.1 ± 6.2 14.1 ± 5.4 &amp;lt;0.005 131/147 (89.1) Peal atrial LSR 1.0 ± 0.4 0.8 ± 0.3 &amp;lt;0.005 n: number of exams evaluable by each software. N: total numbers of exams. *p = 0.01 for comparison between the proportion of exams evaluable by each software.

The role of FDG-PET in detecting rejection after liver transplantation

BackgroundThe activation and increased metabolic activity of T cells in acute cellular rejection could allow fluoro-2-deoxyglucose positron emission tomography to be utilized for detection of acute cellular rejection. The objective of this study was to evaluate the effectiveness of fluoro-2-deoxyglucose positron emission tomography in detecting acute cellular rejection in the clinical setting. MethodsFluoro-2-deoxyglucose positron emission tomography studies were performed on 88 orthotopic liver transplant patients at 7 and 17 days postoperatively (first positron emission tomography and second positron emission tomography, respectively). Additional studies were performed if patients had suspicion of rejection and at resolution of rejection (third positron emission tomography and fourth positron emission tomography, respectively). A circular region of interest was placed over the liver for semiquantitative evaluation of fluoro-2-deoxyglucose positron emission tomography images by means of standard uptake values. ResultsEighteen of 88 patients in our study (20.5%) had histologically proven acute cellular rejection during a 16 ± 11 day follow-up. There was no significant difference between the standard uptake values of first positron emission tomography among non-rejecters versus rejecters (2.05 ±0.46 non-rejecters versus 1.82 ± 0.40 rejecters, P = .127). Within the rejection cohort, the standard uptake values from the third positron emission tomography (rejection) were higher compared to the first positron emission tomography (baseline) (2.41 ± 0.48 third positron emission tomography versus 1.82 ± 0.41 first positron emission tomography, P < .001). ConclusionIncreased signal on fluoro-2-deoxyglucose positron emission tomography over baseline is associated with acute cellular rejection in liver transplant recipients. Additional prospective validation studies are essential to define the role of fluoro-2-deoxyglucose positron emission tomography scan as an early marker for acute cellular rejection.

Citrulline Level Is a Potent Indicator of Acute Rejection in the Long Term Following Pediatric Intestinal/Multivisceral Transplantation

Citrulline has been advocated as a marker for acute cellular rejection (ACR) in intestinal transplantation; however, its significance as a forewarning in the long-term follow-up remains unknown. This study aimed to investigate the association between citrulline levels and the grading of ACR to establish a cutoff point that accurately predicts ACR beyond 3 months posttransplant in the pediatric patient population. During a 16-year period (1995-2011), a total of 13 499 citrulline samples were prospectively collected from 111 consecutive pediatric intestinal/multivisceral transplant recipients: 2155 were obtained concurrently with intestinal biopsies. There were 185 ACR episodes observed among 74/111 (67%) patients (median follow-up: 4.4 years). Citrulline levels were inversely proportional to the severity of ACR. Negative predictive values for any type of ACR (cutoff, 20 μmol/L) and moderate/severe ACR (cutoff, 10 μmol/L) were 95% and 99%, respectively. When patients were divided according to graft size, diagnostic accuracy using the same cutoff was identical. Similarly, subgroup analysis by the timing of citrulline measurement prior to biopsy varying from 1 to 7 days demonstrated comparable results. Citrulline is a potent indicator as a danger signal for ACR, being an exclusionary, noninvasive biomarker with excellent negative predictive values in the long term after pediatric intestinal/multivisceral transplant.

Uric acid: a prognostic marker not only before but also after heart transplantation☆

Early diagnosis of rejection after heart transplantation is mandatory, since even mild rejection can rapidly progress to more severe rejection. However, the identification of patients at high risk of acute cellular rejection and their non-invasive diagnosis remains a challenge. To identify patients with a high risk of acute cellular rejection during the first post-transplantation year. A retrospective study of 114 consecutive patients submitted to first heart transplantation (between November 2003 and January 2008). The International Society for Heart and Lung Transplantation (ISHLT) grading system was used for the classification of endomyocardial biopsies. Patients were divided into two groups: group A (non-rejecting)--90 patients who had no significant rejection episodes (ISHLT grade <2R); and group B (rejecting)--included 24 patients with moderate or severe rejection episodes (grade > or =2R) during a 1-year post-transplantation follow-up. The Kaplan-Meier method was used for cumulative survival analysis with the Breslow test for assessing statistical differences between curves. The group B patients tended to have more ischaemic aetiology (42% vs 26%, p=0.13) and lower baseline triglycerides (99.1+/-34.2 vs 117.9+/-63.6 mg dl(-1), p=0.17), tended to receive less cardiac allografts from donors of the same ABO blood type (83% vs 92%, p=0.25) and to have longer cardiopulmonary bypass times (108+/-64 min vs 94+/-26 min, p=0.12). Significantly, they had more hyperuricaemia (71% vs 43%, p=0.02) and longer mechanical ventilation times (19.2+/-17.9h vs 14.3+/-5.3h, p=0.031). During follow-up, the group B patients tended to have more severe infections (46% vs 31%, p=0.16), to be more frequently Quilty-positive (50% vs 30%, p=0.073) and to have a higher 1-year mortality (8% vs 2%, p=0.18). Uric acid levels higher than 7.2 mg dl(-1) were identified as the optimal cut-off value to predict acute rejection after heart transplantation (with a sensitivity of 71%, a specificity of 62% and an area under the curve of 0.64). Our work suggests that hyperuricaemia may be a marker of acute cellular rejection that could be another tool helping to identify acute rejection during the follow-up of cardiac-transplanted patients.

Guanylate-binding protein 2 mRNA in peripheral blood leukocytes of liver transplant recipients as a marker for acute cellular rejection

Previously, we reported guanylate-binding protein 2 (GBP2) and interferon regulatory factor 1 (IRF1) elevated in the rat peripheral blood during acute cellular rejection (ACR), which are identified from transcriptome analysis of liver graft, as leukocyte-related gene in liver. In this study, we investigated whether these two genes could differentially diagnose ACR from other types of liver dysfunction (LD) clinically. The mRNAs from leukocytes of 19 patients with ACR and 27 with LD, as well as from liver biopsies of 12 patients with ACR and 12 with LD, were analysed by real-time PCR for GBP2 and IRF1 expression. Sensitivity and specificity were calculated using receiver operator characteristic (ROC) curves. Guanylate-binding protein 2 (GBP2) and interferon regulatory factor 1 (IRF1) gene expression levels in ACR samples were higher than that in controls, and GBP2 expression in blood was higher than that in LD (26.4 +/- 3.1 and 15.6 +/- 1.9, P = 0.0203). Multivariate analysis showed that the ratio GBP2/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was independent of ACR-related factors (OR = 0.911, P = 0.035). GBP2 expression levels in ACR were also higher than that in liver transplantation patients with hepatitis C or no LD. Using a cut-off value of 20, the sensitivity and specificity of GBP2/GAPDH based on ROC curve analysis were 63% and 85% respectively. GBP2 in the patients with LD may be useful for diagnosis of ACR.

Blood Citrulline Level Is an Exclusionary Marker for Significant Acute Rejection After Intestinal Transplantation

Serum citrulline is a marker for acute cellular rejection (ACR) after intestinal transplantation; however, its clinical utility has not yet been established. The goal of this study was to determine clearcut serum levels beyond which the diagnosis of acute rejection could be supported or refuted, and predictors of citrulline levels posttransplant from which more accurate estimates of sensitivity and specificity could be obtained. Since March 2004, we obtained 2135 dried blood spot (DBS) citrulline samples from 57 intestinal transplant recipients at or beyond 3 months posttransplant. Stepwise linear regression was performed to determine the most significant multivariable predictors of the patient's DBS citrulline level. Seven characteristics were associated with a significantly lower citrulline in multivariable analysis: presence of mild, moderate, or severe ACR; presence of bacteremia or respiratory infection; pediatric age; and time from transplant to DBS sample (P<0.00001 in each case). Using a <13 vs. > or =13 micromoles/L cutoff point, the sensitivity for detecting moderate or severe ACR and the negative predictive value were high (96.4% and >99% respectively). Specificity was 54% to 74% in children and 83% to 88% in adults. Citrulline levels <13 micromoles/L should alert the clinical team that a serious problem (rejection or infection) could be looming in a previously stable intestinal recipient. Levels > =13 micromoles/L practically rule out moderate or severe rejection.

Role and significance of plasma citrulline in the early phase after small bowel transplantation in pigs

A reliable serological marker of acute cellular rejection (ACR) after small bowel transplantation (SBTx) is still missing. Plasma citrulline level (PCL) reflects the functional integrity of intestinal mucosa which is partially lost during ACR. The aim of our study was to investigate the role of PCL as marker of ACR after SBTx. Eighteen German landrace pigs were used and divided into three groups. Group 1 (G1), autologous SBTx (n = 4) as control; group 2 (G2), allogeneic SBTx without immunosuppression (IS) (n = 7) and group 3 (G3), allogeneic SBTx with IS (n = 7). IS consisted of tacrolimus and steroids without induction treatment. Observation period was 14 days. Mucosal biopsies were obtained intraoperatively and daily using a Thiry-Vella loop. ACR was differentiated into indeterminate, mild, moderate and severe using a standardized grading schema. PCL was measured daily. An ACR onset occurred generally from postoperative day 4 both in G2 and G3 as mild form and developed differently in the two groups: moderate to severe in G2 and indeterminate to mild in G3. A significant decline of PCL occurred only in cases of moderate and severe ACR, but not in cases of indeterminate and mild ACR. The PCL failed as a marker in the early diagnosis of ACR and became reliable only when advanced mucosal damage was present.

An Analysis of the Association between Serum Citrulline and Acute Rejection among 26 Recipients of Intestinal Transplant

Small preliminary studies suggest that serum citrulline levels may act as a marker for acute cellular rejection in small intestinal transplant recipients. The results comparing serum citrulline concentrations with biopsy-based grades of rejection are summarized here for an expanded group of 26 isolated intestinal and multivisceral transplant recipients. Other factors considered included patient and donor age and sex, ischemia time, serum creatinine, and type of transplant. Straight-line fits reasonably described how each patient's citrulline levels changed over time. Among 21 patients who demonstrated increasing citrulline levels over time, the estimated median time-to-achieve normal citrulline (≥30 μmol/L) was 79 days post-transplant. Using stepwise linear regression, two characteristics were associated with a significantly higher maximum grade of rejection after 14 d post-transplant: longer time-to-achieve normal citrulline (using ranks, p < 0.00001) and the patient not receiving a multivisceral transplant (p = 0.0005). Only the latter characteristic was significantly associated with maximum grade of rejection during the first 14 d post-transplant (p = 0.01). Clearly, time-to-normalization of citrulline was delayed by the incidence of rejection, and in some cases with moderate-to-severe rejection, normalization of citrulline levels never occurred. We plan to further examine the use of citrulline as a marker for rejection in larger prospective studies.

Serum citrulline as a marker of acute cellular rejection for intestinal transplantation

Serum citrulline as a marker of acute cellular rejection for intestinal transplantation

Frequency and significance of left ventricular thickening in transplanted hearts in children

The pediatric myocardium has been shown to thicken markedly during steroid administration for the treatment of pulmonary or neurologic disease. Yet, in the pediatric heart transplant patient, left ventricular (LV) thickening is sometimes used as a marker for rejection without accounting for steroid immunosuppression. The aim of this study was to determine timing and correlates of changes in LV thickness in pediatric cardiac transplant patients. In 11 patients (11 days old to 16 years old), LV thickness (mass) was first measured during the entire post-transplant course. Second, thickness was measured before and during rejection. Last, to separate the independent effects of rejection and steroids on LV mass, echocardiograms were reviewed in the immediate post-transplant period, when our protocol prescribes aromatic changes in steroid closes and rejection episodes were rare. Specifically, the donor heart underwent 5 evaluations: at donation, at peak steroid dose, 5 days after peak steroid dose, at moderate steroid dose, and at very low maintenance dose. LV mass changed most dramatically and consistently during the first 20 to 40 days after transplant. Thereafter, mass had little consistent changes and did not change significantly during any of the 52 rejection episodes. Mass increased 5 days after peak steroid dose (54 ± 30 to 74 ± 38 g/ht 2.7, p < 0.05) and decreased during low maintenance levels of steroids. Thickening was associated with cumulative steroid dose (r = 0.66, p = 0.03) and age (r = − 0.62, p = 0.04). Thus, in pediatric heart transplant patients, as in other pediatric diseases, LV thickening is associated with steroid administration. Thickening may be an unreliable marker for acute cellular rejection.

Proliferating cell nuclear antigen (PCNA) as a diagnostic marker of acute cellular rejection in routinely processed biopsies of renal allografts

Seventy-eight renal allograft biopsies taken for the management of graft dysfunction were analysed retrospectively by labelling with antibodies to proliferating cell nuclear antigen (PCNA) to assess whether this marker could distinguish episodes of rejection. Routinely processed, paraffin-embedded biopsies with focal or diffuse cellular infiltrates were selected and the percentage of infiltrating cells in the cortical interstitium which stained with PCNA antibody were counted (PCNA index). The area of cellular infiltration was also estimated by a morphometric point-counting technique. The biopsies were divided into two groups based on standard clinical criteria; those with acute rejection (n = 31) and those with other causes of graft dysfunction (n = 47). The PCNA index was significantly higher in episodes of acute rejection (7.9%) compared to non-rejection (2.1%). This was independent of time after transplantation. The PCNA index was also greater in rejecting kidneys containing only focal cellular infiltrates (percentage area of cellular infiltration < 13.1%). Thus PCNA staining may be of use in the differential diagnosis of rejection in routinely processed biopsies of renal allografts where there are only focal inflammatory infiltrates, otherwise not diagnostic of cellular rejection.