Rejection Events Research Articles

(291) - Genetic Risk Score (GRS) Predicts Worse Survival in African American Heart Transplant Recipients at 10 Years

s S115 additional serial samples were obtained from each pt (82 samples total). 21 pts were treated for the rejection event, with 17 having consecutive samples available from both the treatment and post-treatment visits required to determine the change in dd-cfDNA following treatment for rejection. Results: For these 17 cases, dd-cfDNA increased more than 2-fold in 3 cases, decreased more than 2-fold in 6 cases, and changed modestly (less than a 2-fold increase or decrease) in 8 cases. In 5 cases where the post-treatment biopsy was graded 0R, suggesting the pt responded favorably to treatment, dd-cfDNA decreased by more than 1.8-fold in 3 cases. Of the 11 samples that did not decrease by at least 2-fold, 6 cases experienced a subsequent 1R or 2R grade rejection event within 30 days of the post-treatment visit, suggesting that the initial treatment may not have been sufficient. Two samples with relatively large (1.9and 3.6-fold) increases in dd-cfDNA following treatment did not show any clinical signs of rejection. Conclusion: Consistent with previously observed rapid-clearance of ddcfDNA from peripheral blood, dd-cfDNA is a quantitative indicator of allograft health. Preliminary data suggest that levels of dd-cfDNA immediately following treatment of a rejection event often decrease when the rejection resolves, but may stay elevated or increase if signs of rejection persist. ddcfDNA may be a useful, non-invasive biomarker to ascertain clinical response to rejection treatment. (Study sponsored by CareDx, Inc.)

(64) - Increased Plasma Levels of Donor-Derived Cell-Free DNA Correlate With Rejection in Heart Transplant Recipients: The CARGO II Multicenter Trial

Donor-derived cell-free DNA (dd-cfDNA) is a potential biomarker of acute cellular rejection (ACR) in organ transplant recipients. We determined plasma levels of dd-cfDNA in heart transplant recipients with a biopsy-confirmed rejection, and compared them to levels of dd-cfDNA in non-rejecting heart transplant recipients. In total, 151 plasma samples from 63 patients (pts) from the CARGO II multicenter trial were included in this study. For 132 samples, a biopsy was performed and graded by up to 4 independent pathologists. 28 samples assigned a biopsy grade of 2R or 3R, by at least 2 pathologists, were classified as rejection (R). 27 samples assigned a biopsy grade of 0R, by 4 pathologists, were classified as non-rejection (NR). Samples from up to two prior visits leading up to R and NR events constituted the remaining 96 samples. Circulating cfDNA purified from plasma was sequenced to quantify levels of dd-cfDNA. Using RNA extracted from mononuclear cells, AlloMap® score was determined. Standard statistical measures of correlation and significance were used. dd-cfDNA levels were significantly higher (P=0.017) in pts undergoing biopsy-confirmed rejection (R, mean 1.7%) compared to stable pts (NR, mean 0.99%). An ROC curve yielded the AUC of 0.68 (95% CI 0.56-0.80). The mean AlloMap® score in these samples was 24.3 for NR and 28.3 for R, (P=0.007). As for the dd-cfDNA results, the AUC for the Allomap® score of these samples was 0.68 (95% CI 0.56-0.80). However, levels of dd-cfDNA and AlloMap® score were not significantly correlated, suggesting that each may provide complementary information. The two results were scaled to equivalent ranges and additively combined per sample. The resulting combined score differentiated R from NR (P<0.0001) with an AUC of 0.78 (95% CI 0.67-0.87). We analyzed 16 cases with biopsy-confirmed ACR and 2 serial samples preceding the rejection event, and found that in 10 cases the levels of dd-cfDNA were elevated in preceding samples as early as 25 days prior to rejection event. dd-cfDNA is a useful biomarker of heart-transplant rejection. This non-invasive test may aid in the long-term monitoring of allograft health and identification of patients with ACR. Used in combination with AlloMap®, the utility of the dd-cfDNA test is further increased. (Study sponsored by CareDx, Inc.)

(292) - Donor-Derived Cell-Free DNA Decreases Following Effective Treatment of Acute Cellular Rejection in Heart Transplant: Recipients: The CARGO II Multicenter Trial

Cell-free DNA (cfDNA) originating from the donor organ and circulating in the blood of the transplant recipient is a promising biomarker of organ health. Elevated levels relative to normal recipient-derived background levels may indicate on-going or acute organ damage. Here, we perform an observational study of allograft-derived cfDNA in a subset of patients (pts) treated for a biopsy-confirmed rejection event.

First report of behavioural lateralisation in mosquitoes: right-biased kicking behaviour against males in females of the Asian tiger mosquito, Aedes albopictus.

Lateralisation (i.e. functional and/or structural specialisations of left and right sides of the brain) of aggressive traits has been studied in a number of vertebrates, while evidence for invertebrates is scarce. Mosquito females display aggressive responses against undesired males, performing rejection kicks with the hind legs. In this research, we examined lateralisation of kicking behaviour in females of the Asian tiger mosquito, Aedes albopictus. We found a right-biased population-level lateralisation of kicking behaviour. Four repeated testing phases on mosquito females confirmed the preferential use of right legs. However, when left legs were used, the mean number of kicks per rejection event was not different to that performed with right legs. Both left and right kicking behaviour lead to successful displacement of undesired partners. This is the first report about behavioural lateralisation in mosquitoes.

Pharmacogenomics: personalizing pediatric heart transplantation.

In recent years, outcomes for pediatric cardiac transplantation (PCTx) have steadily improved, with current 5-year overall survival rates estimated at 83%.1 This progress may be attributed to improvements in pretransplantation management, selection of donor hearts, surgical technique, prevention and treatment of rejection, and minimization of treatment-related adverse events. Despite these advances, children who receive cardiac transplants experience significant morbidity and mortality, and there is considerable variability in outcomes, much of which cannot be explained by known clinical risk factors. One source of interindividual variability is genetic variation in the host. There is growing evidence that genomic variation leads to differences in immune response, response to therapies, and susceptibility to adverse outcomes such as malignancy and infection.2–4 This review will focus on the effect of variation in genes that encode enzymes, transporters, and drug target molecules that influence drug response. After review of the foundational principles of pharmacogenomics, evidence for the pharmacogenomic effects on cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus will be reviewed and clinical implications of these findings discussed. Given the limited nature of evidence from studies of PCTx patients, support will also be drawn from non-PCTx research and pediatric renal transplantation. Genetic studies of nonpharmacogenes such as those in immunomodulatory pathways and variation in the donor genotype may contribute to risk prediction but are beyond the scope of this review. ### Genetic Variation DNA variation can alter biological function through several mechanisms (Figure 1). Variation within the coding sequence or in intron/exon borders can change the protein product through changes in start codons, stop codons, splice sites, or within the coding sequence, leading to nonsense-mediated decay or altered protein function. Other variants associated with pharmacogenomic outcomes are not predicted to change the encoded protein. These synonymous and …

Précipités rétro-cornéens annulaires

To investigate the incidence and outcome of cornea transplant rejection following endothelial keratoplasty (EK) and penetrating keratoplasty (PK) for Fuchs endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK).Multicenter cohort study.Patients registered on the United Kingdom Transplant Registry (UKTR) who had an EK or PK for FED or PBK between April 1, 2005 and March 31, 2011 were included. Data were collected from UKTR forms at 1 and 2 years. Postoperative steroid use varies between surgeons and cannot be captured in this reporting system. Rejection events were identified as those recorded as endothelial rejection.A total of 3486 corneal transplants were undertaken: 1973 for FED, 1513 for PBK. For FED, 2-year rejection-free survival was 93% (95% confidence interval [CI] 90%–94%) for PK and 94% (95% CI 92%–96%) for EK (P = .3). In transplants that had a rejection episode, 50% of PKs (17) and 60% of EKs (15) subsequently failed. For PBK, 2-year rejection-free survival for PK was 88% (95% CI 86%–90%) and 90% (95% CI 86%–92%) for EK (P = .6). In transplants that had a rejection episode, 85% of PKs (41) and 76% of EKs (22) subsequently failed. Inflammation (ie, conjunctival injection, presence of keratic precipitates and intraocular signs) at the time of surgery for patients with FED was significant for developing rejection: 3.5 times greater compared with those with no inflammation (P = .02).There is no significant difference in rejection-free survival between EK and PK for FED or PBK. The presence of inflammation is an important risk factor, and attention to its control before and following surgery is important.

Effect of donor-specific antibodies and panel reactive antibodies in living donor liver transplant recipients.

PurposePreformed circulating donor-specific antibodies (DSAs) immunologically challenge vascular endothelium and the bile duct. However, the liver is an immune-tolerant organ and can avoid immunological challenges. This study was undertaken to analyze the effects of DSAs after adult living donor liver transplantation (LDLT).MethodsWe retrospectively reviewed 219 LDLT patients' records treated at our center.ResultsOf the 219 patients, 32 (14.6%) were DSA (+) and 187 (85.4%) were DSA (-). Class I DSAs were present in 18 patients, class II in seven patients, and both in seven patients. Seven patients (3.2%) showed DSA to HLA-A, four (1.8%) to HLA-B, seven (3.2%) to HLA-DR, and 14 (6.4%) to two or more HLAs. More DSAs were observed in female recipients than male recipients in the DSA (+) group. The DSA (+) group showed significantly higher levels of class I and II panel reactive antibody (PRA) than did the DSA (-) group. No significant intergroup differences were found between incidences of primary nonfunction, acute rejection, vascular complication, or biliary complication. There were no significant differences in graft survival rates between the two groups. However, the recipients with multiple DSAs tended to have more acute rejection episodes and events of biliary stricture and lower graft survival rates than did patients in the DSA (-) group.ConclusionIn LDLT, the presence of multiple DSAs and high PRA seemed to be associated with poor graft outcomes, although our results did not reach statistical significance. Large cohort studies are necessary to clarify the impact of DSA and PRA in LDLT.

Negative Impact of Underlying Non–Insulin-dependent Diabetes Mellitus Nephropathy on Long-term Allograft Survival in Kidney Transplantation: A 10-Year Analysis From a Single Center

IntroductionWe analyzed the relationship between underlying nephropathy and long-term outcomes in kidney transplant recipients. MethodsWe retrospectively analyzed data from 678 patients who underwent kidney transplantation (KTx) between 1998 and 2011. Recipients with 13 major nephropathies were evaluated for graft and patient survival, and causes of graft loss. ResultsThe best 10-year graft survival rates (100%) were in the patients with autosomal-dominant polycystic kidney disease, preeclampsia, Alport syndrome, and purpura nephritis. The worst rate (50.8%) was in patients with non–insulin-dependent diabetes mellitus nephropathy (NIDDMN; P = .039). Causes of graft-loss in the NIDDM patients included chronic rejection (6 cases), acute rejection (3 cases), infection (2 cases), and cardiovascular event (2 cases). Significant risk factors for graft loss were donor age (P < .01) and NIDDMN (P < .01). ConclusionUnderlying NIDDMN before KTx was a significant risk factor for long-term graft function. Immunologic factors and nonimmunologic factors influenced the long-term outcomes in patients with underlying NIDDMN.

Future direction of immunosuppression in lung transplantation.

Immunosuppression regimens have helped improve rejection episodes following lung transplantation, but long-term outcomes are still not comparable with cardiac, hepatic, or renal transplantation. This review summarizes the immunobiology that contributes to rejection events and future opportunities in outcomes on the basis of providing optimized delivery of the immunosuppression based on immune-monitoring techniques, taking into account individual patient pharmacokinetics and phenotypic variance. Drug toxicities, narrow therapeutic drug monitoring windows, and current immunoassays currently do not assist in detecting the global degree of immunosuppression. The currently available randomized control trials for induction therapy or maintenance therapies do not provide additional benefits compared with previously reported retrospective trials. To push beyond the current barriers, transplant teams are focusing on the role of pharmacokinetics, assessing phenotypic variable to potentially modify to quadruple therapy and using extracorporeal photopheresis. Conventional practice for the choices of immunosuppression is being evaluated on the basis of randomized control trials as opposed to retrospective studies or single-center trials. The future direction of immunosuppression will be continued by dynamic processes taking into consideration measures to improve tolerance, reducing treatment burden, and providing the best level of evidence while accounting for rejection, infections, renal function, and other comorbidities.

Novel multivariate methods for integration of genomics and proteomics data: applications in a kidney transplant rejection study.

Multi-omics research is a key ingredient of data-intensive life sciences research, permitting measurement of biological molecules at different functional levels in the same individual. For a complete picture at the biological systems level, appropriate statistical techniques must however be developed to integrate different 'omics' data sets (e.g., genomics and proteomics). We report here multivariate projection-based analyses approaches to genomics and proteomics data sets, using the case study of and applications to observations in kidney transplant patients who experienced an acute rejection event (n=20) versus non-rejecting controls (n=20). In this data sets, we show how these novel methodologies might serve as promising tools for dimension reduction and selection of relevant features for different analytical frameworks. Unsupervised analyses highlighted the importance of post transplant time-of-rejection, while supervised analyses identified gene and protein signatures that together predicted rejection status with little time effect. The selected genes are part of biological pathways that are representative of immune responses. Gene enrichment profiles revealed increases in innate immune responses and neutrophil activities and a depletion of T lymphocyte related processes in rejection samples as compared to controls. In all, this article offers candidate biomarkers for future detection and monitoring of acute kidney transplant rejection, as well as ways forward for methodological advances to better harness multi-omics data sets.

Corneal graft rejection 10 years after penetrating keratoplasty in the cornea donor study.

The aim of this study was to assess the effect of donor and recipient factors on corneal allograft rejection and evaluate whether a rejection event was associated with graft failure. One thousand ninety subjects undergoing penetrating keratoplasty for a moderate risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) were followed for up to 12 years. Associations of baseline recipient and donor factors with the occurrence of a rejection event were assessed in univariate and multivariate proportional hazards models. Among 651 eyes with a surviving graft at 5 years, the 10-year graft failure (±99% confidence interval) rates were 12% ± 4% among eyes with no rejection events in the first 5 years, 17% ± 12% in eyes with at least 1 probable, but no definite rejection event, and 22% ± 20% in eyes with at least 1 definite rejection event. The only baseline factor significantly associated with a higher risk of definite graft rejection was a preoperative history of glaucoma, particularly when previous glaucoma surgery had been performed and glaucoma medications were being used at the time of transplant (10-year incidence 35% ± 23% compared with 14% ± 4% in eyes with no history of glaucoma/intraocular pressure treatment, P = 0.008). Patients who experienced a definite rejection event frequently developed graft failure raising important questions as to how we might change acute and long-term corneal graft management. Multivariate analysis indicated that previous use of glaucoma medications and glaucoma filtering surgery was a significant risk factor related to a definite rejection event.

A Systematic Review of Conversion From Calcineurin Inhibitor to Mammalian Target of Rapamycin Inhibitors for Maintenance Immunosuppression in Kidney Transplant Recipients

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2) = 68%, p < 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2) = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2) = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.

The natural history of lung function after lung transplantation for α(1)-antitrypsin deficiency.

Lung transplantation (LT) is an established treatment for end-stage lung diseases, including chronic obstructive pulmonary disease (COPD) associated with α1-antitrypsin deficiency (AATD). We sought to compare the post-transplantation course of patients with AATD and AAT-replete COPD. Between June 1991 and January 2008, a total of 231 patients with AAT-replete COPD and 45 with AATD underwent LT at Cleveland Clinic. Data reviewed included baseline recipient, donor, and surgical data; all spirometry evaluations; acute cellular rejection (ACR) events; and survival data. Endpoints included temporal change in FEV1, severity of ACR, and survival. A longitudinal temporal decomposition model was used for analysis. Comparison of overall rates of FEV1 decline in AATD and AAT-replete patients with COPD showed no significant differences (P > 0.09). However, although the single LT patients had similar trends in FEV1 in both groups, patients with AATD with double LT declined faster (P < 0.002) than the AAT-replete patients. No differences in the frequency or severity of ACR episodes were observed (P = 0.32). Furthermore, there was no difference in early or late mortality between patients with AATD and patients with AAT-replete COPD (P > 0.09). Although overall the post-LT FEV1 slope, severity of ACR, and survival among patients with AATD is similar to that of AAT-replete patients with COPD, patients with AATD with double LT have a faster rate of FEV1 decline. These findings support the eligibility of patients with AATD for LT, and suggest the need for additional studies to better understand the difference between single and double LT in AATD.

Mesenchymal stem cell treatment for chronic renal failure.

Chronic renal failure is an important clinical problem with significant socioeconomic impact worldwide. Despite advances in renal replacement therapies and organ transplantation, poor quality of life for dialysis patients and long transplant waiting lists remain major concerns for nephrologists treating this condition. There is therefore a pressing need for novel therapies to promote renal cellular repair and tissue remodeling. Over the past decade, advances in the field of regenerative medicine allowed development of cell therapies suitable for kidney repair. Mesenchymal stem cells (MSCs) are undifferentiated cells that possess immunomodulatory and tissue trophic properties and the ability to differentiate into multiple cell types. Studies in animal models of chronic renal failure have uncovered a unique potential of these cells for improving function and regenerating the damaged kidney. Nevertheless, several limitations pertaining to inadequate engraftment, difficulty to monitor, and untoward effects of MSCs remain to be addressed. Adverse effects observed following intravascular administration of MSCs include immune rejection, adipogenic differentiation, malignant transformation, and prothrombotic events. Nonetheless, most studies indicate a remarkable capability of MSCs to achieve kidney repair. This review summarizes the regenerative potential of MSCs to provide functional recovery from renal failure, focusing on their application and the current challenges facing clinical translation.

Causes of Graft Loss After Kidney Transplantation Following Rabbit-Antithymocyte Gobulin Induction and Steroid-Sparing Maintenance.

Purpose: We analyzed specific factors associated with graft loss in the setting of a steroid-free immunosuppression environment and rabbit-antithymocyte globulin (r-ATG) induction. Methods: 1693 kidney transplants were performed over a 10-year span at our institution. Risk factors for graft loss, defined as loss of kidney function due to patient death or necessitating chronic dialysis, and/or re-transplantation, were evaluated by multivariate analysis. Death-censored data was further stratified by biopsy findings and causes of graft loss. Results: The study group included 1151 patients who underwent kidney transplant from November 2001 to December 2011 under a steroid sparing protocol with r-ATG induction. A total of 215 graft losses occurred (18.7%), with a mean follow up of 51.9 ± 30.6 months. Excluding death with a functioning graft (n=81) as the reason for graft loss, 134 graft losses (11.6%) were included in the final analysis. Table 1 summarizes other factors associated (P < 0.05) with graft loss in the study group. Surgical complications (e.g. hemorrhage, urinary leak, lymphoceles, etc.) required a re-operation. Infection included CMV, BK virus, or other opportunistic infections. All rejection events (n=52) occurred in grafts that were eventually lost. The most significant cause of graft loss was due to acute rejection (n=21, O.R. 29.5 [95% CI: 4.34-200.6], P <0.01), which included ACR, AMR and mixed ACR/AMR. There were no significant correlations between graft loss and patient age, race, gender, donor type (living vs. deceased, ECD vs SCD), or length of time on dialysis.Table: No Caption available.Conclusions: The reasons for graft failure have not been well described in a large cohort of kidney transplants using steroid minimization and r-ATG induction. Despite an acceptable rate of graft loss with this protocol, acute rejection serves as an ominous risk factor for graft loss. Infections, which may be related to over-treatment of rejection, as well as surgical complications and delayed graft function were also significant risk factors. Strategies to minimize these risk factors may help to prevent graft loss.

Evaluation of Calcineurin Activity as a Biomarker of the State of Immunosuppression in Heart-Transplanted Patients.

Background: Given the potential opportunities offered by a pharmacodynamic approach to finely tune the immunosuppressive (IS) strategies, we have conducted two clinical studies to monitor calcineurin activity (CN-a) for the first 24 months following heart transplantation (HTx). Methods: Patients were eligible if their IS treatment included cyclosporine (CsA). A pilot monocenter study was first conducted with 51 patients enrolled and CN-a measurement at least once a month during the first 6 months after HT and then every 3 months. Then, a tricenter study was conducted with 40 patients enrolled and CN-a measurements at a higher frequency than in the pilot study. CN-a was determined in mononuclear cells. Endomyocardial biopsies were routinely performed to assess acute rejection. Coronagraphy was yearly performed to assess chronic rejection/chronic allograft vasculopathy (CAV). The occurrence of infections and malignancies was recorded to assess adverse events related to over-immunosuppression. Results: In the pilot study, CN-a was linked to both acute rejection and CAV. The survival without acute rejection was significantly lower in patients who displayed CN-a values below 13 pmol/mg/min during the first 2 months after HTx as compared to patients who exhibited CN-a values above this level (9% vs 48%, p=0.002). The survival without CAV was significantly lower in patients who displayed CN-a values below 16 pmol/mg/min as compared to patients who exhibited CN-a values above this level (51% vs 84%, p=0.0135). In addition, the occurrence of cancer and infections tended to be higher in patients displaying very low CN-a levels. These preliminary results were confirmed in the tricenter study. Conclusion: These results show that both acute rejection, CAV and CsA-related adverse events were paradoxically accompanied by a decreased CN-a, similarly to our recent findings in lung transplantation (Sanquer et al, 2013). We anticipate that the low CN-a levels associated with rejection could contribute to the toxicity induced by CsA, especially as its dosage is generally increased when AR is suspected.

Protocol for Intestine Transplantation Across Positive Crossmatch With Preformed Donor Specific Antibodies - A Single Center Experience.

AIM: We designed and utilized a protocol for immunosuppression for intestine transplantation across positive crossmatch with evidence of class I and/or class II donor specific antibodies (DSA). Patients were evaluated for rejection and infection events with comparison to procedure matched controls on standard protocol of immunosuppression. METHODS: We utilize a protocol for intestine and multivisceral transplantation for patients with high panel reactive antibodies (PRA) or a positive flow crossmatch. We added to our standard protocol consisting of tacrolimus at goal trough 15-20ng/mL, solumedrol taper, thymoglobulin at 2mg/kg on post operative day (POD) 0, 2 and 4, and basiliximab 20mg once monthly beginning POD 14. Patients with positive prospective or retrospective crossmatch were additionally given rituximab 150mg/m2 beginning 4 hours preoperatively and intravenous immunoglobulin (IVIg) 1 gram/kg. DSA was sent for clinical evaluation on monthly intervals. Patients were screened for rejection by endoscopic evaluation and biopsy of small intestine on a routine basis. RESULTS: Four patients were transplanted in 2013 across positive T and B cell flow crossmatch. Two received isolated intestine transplants (IT) and two had multivisceral transplantation (MVT). During a six month follow-up, none of the patients had episodes of rejection or cytomegalovirus (CMV) infection. One patient developed major infection and two developed minor infections. All four patients saw a significant decrease in their pre-existing DSA titers using this regimen. Among procedure-matched controls with negative final crossmatch on standard management (no preoperative rituximab or IVIg), two developed mild acute cellular rejection and two developed minor infections. CONCLUSIONS: We report our protocol for immunosuppression for IT and MVT across a positive crossmatch. This allowed for transplant despite the presence of positive crossmatch and significant class I and/or II DSA with lower rejection rates but potentially increased risk for major infections compared to controls.

Three-year results of an investigator-driven multicenter, international, randomized open-label de novo trial to prevent BOS after lung transplantation

Chronic lung allograft dysfunction (CLAD), predominantly manifest as bronchiolitis obliterans syndrome (BOS), is the primary cause of morbidity and death after lung transplantation. We assessed the efficacy and safety of 2 de novo immunosuppression protocols to prevent BOS. This was a multicenter, prospective, international, randomized (1:1) open-label superiority study of de novo enteric-coated mycophenolate sodium (MPS) vs delayed-onset everolimus (RAD), both arms in combination with cyclosporine (CsA) monitored by 2-hour post-dose (C2) levels, and corticosteroids. Target C2 levels were lower in the RAD group because RAD is known to potentiate CsA nephrotoxicity. Cytolytic induction therapy was not used. Patients were stratified at entry for cystic fibrosis. Confirmation of anastomotic healing was required for randomization. Primary efficacy was freedom from BOS Grade 1 on intention-to-treat (ITT) analysis. Secondary efficacy parameters were patient and graft survival and severity of rejection. Treatment failure was defined by graft loss, patient death, drug cessation, or need for other therapy. The 3-year freedom from BOS Grade 1 was 70% for MPS (n = 80) vs 71% for RAD (n = 84; p = 0.95 by log-rank) in ITT but was lower in the RAD arm of the per-protocol population (p = 0.03). The 3-year survival was 84% (MPS) vs 76% (RAD; p = 0.19 by log-rank). Thirteen patients switched from MPS vs 31 from RAD (p < 0.01). Days on MPS were greater than days on RAD (p < 0.01). Rejection events proven by biopsy specimen were more common on MPS (p = 0.02), as were leucopenia (p < 0.01), diarrhea (p < 0.01), and cytomegalovirus infection (p = 0.04). Venous thromboembolism was more frequent on RAD (p = 0.02). Creatinine at 3 years was 160 ± 112 μmol/1iter in MPS patients vs 152 ± 98 μmol/1iter in RAD patients (p = 0.67). This 3-year ITT analysis found no significant difference between arms but was underpowered to accept the null hypothesis that RAD and MPS have equivalent efficacy in preventing BOS or death after lung transplantation.

Kin rejection: social signals, neural response and perceived distress during social exclusion.

Across species, kin bond together to promote survival. We sought to understand the dyadic effect of exclusion by kin (as opposed to non-kin strangers) on brain activity of the mother and her child and their subjective distress. To this end, we probed mother-child relationships with a computerized ball-toss game Cyberball. When excluded by one another, rather than by a stranger, both mothers and children exhibited a significantly pronounced frontal P2. Moreover, upon kin rejection versus stranger rejection, both mothers and children showed incremented left frontal positive slow waves for rejection events. Children reported more distress upon exclusion than their own mothers. Similar to past work, relatively augmented negative frontal slow wave activity predicted greater self-reported ostracism distress. This effect, generalized to the P2, was limited to mother- or child-rejection by kin, with comparable magnitude of effect across kin identity (mothers vs. children). For both mothers and children, the frontal P2 peak was significantly pronounced for kin rejection versus stranger rejection. Taken together, our results document the rapid categorization of social signals as kin relevant and the specificity of early and late neural markers for predicting felt ostracism.

Rejection quantity in kidney transplant recipients is associated with increasing intracellular interleukin-2 in CD8+ T-cells

BackgroundCD8+ T-cells and interleukin-2 play an important role during organ rejection in kidney transplant recipients. Numerous studies showed increased interleukin-2 levels during acute rejection. The aim of our study is to show an association between intracellular interleukin-2 in CD8+ T-cells and the incidence of those who underwent organ rejection in kidney transplant recipients. Methods407 transplant recipients were included into this study. The rejection incidence was investigated from the patient records. White blood cells from recipients were separated using a ficoll gradient. The cells were double-gated (CD3+ and CD8+) for the analysis of cellular percentage for intracellular interleukin-2 with a flow cytometer. ResultsThe percentage of CD8+ cells with detectable intracellular interleukin-2 was significantly higher in renal transplant recipients with a documented rejection compared to recipients without any history of rejection (9.06±0.50, N=133 vs. 4.28±0.24, N=274, p<0.0001, t-test). Further, there was a significant increase in patients with one (8.02±0.54, N=80, p<0.0001, t-test), two (10.40±1.17, N=33, p<0.0001, t-test) or three (11.82±1.58, N=18, p<0.0001, t-test) rejection events. ConclusionsPast studies showed, that during acute organ rejection intracellular interleukin-2 is increased in cytotoxic T-cells, supposed to be a marker for this event. We were able to show, that intracellular interleukin-2 in CD8+ T-cells is also increased after organ rejection. Furthermore it seems to depend on the quantity of rejection events. Further studies in recipients with increased intracellular interleukin-2 in cytotoxic CD8+ T-cells and documented history of organ rejection are needed to identify this as a possible risk factor for further rejection events.