The aim was to evaluate the association of molecular‐level human leukocyte antigen (HLA) mismatching with post‐transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We ...retrospectively analyzed all primary cardiac transplant recipients between 01/1984‐06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor‐recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody‐verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA‐DR AAMM load had inferior 1‐year graft survival (hazard ratio HR, 1.14; 95% confidence interval CI, 1.01–1.28). The HLA‐AB AAMM load showed no impact on graft survival. In the subgroup with available split‐level information, we observed an inferior graft survival for a higher HLA‐DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04–1.44) and a higher risk for rejection for an increasing HLA‐AB (HR, 1.70; 95% CI, 1.29–2.24) and HLA‐DR (HR, 1.32; 95% CI, 1.09–1.61) AAMM load. No impact on the development of CAV was found. Molecular‐level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.
The adapted Heart Donor Score Angleitner, Philipp; Kaider, Alexandra; Smits, Jacqueline M. ...
Transplant international,
March 2021, Letnik:
34, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
The Heart Donor Score (HDS) predicts donor organ discard for medical reasons and survival after heart transplantation (HTX) in the Eurotransplant allocation system. Our aim was to adapt the ...HDS for application in the United Network for Organ Sharing (UNOS) registry. To adjust for differences between the Eurotransplant and UNOS registries, the “adapted HDS” was created (aHDS) by exclusion of the covariates “valve function,” “left‐ventricular hypertrophy,” and exclusion of “drug abuse” from the variable “compromised history.” Two datasets were analyzed to evaluate associations of the aHDS with donor organ discard (n = 70 948) and survival (n = 19 279). The aHDS was significantly associated with donor organ discard odds ratio 2.72, 95% confidence interval (CI) 2.68–2.76, P < 0.001; c‐statistic: 0.937). The score performed comparably in donors <60 and ≥60 years of age. The aHDS was a significant predictor of survival as evaluated by univariate Cox proportional hazards analysis (hazard ratio 1.04, 95% CI 1.01–1.07, P = 0.023), although the association lost significance in a multivariable model. The aHDS predicts donor organ discard. Negative effects of most aHDS components on survival are likely eliminated by highly accurate donor selection processes.
Abstract
We present a case of severe gastroparesis in a recipient of orthotopic heart transplantation. Although a rare condition after heart transplantation, it is a potential cause of significant ...morbidity, including vomiting, aspiration and pneumonia. Moreover, impaired gastric emptying alters the pharmacokinetics of immunosuppressive medication with increased risk of severe side effects. Herein, we describe a diagnostic and therapeutic strategy that was successfully applied in a patient with gastroparesis.
The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible ...rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.
Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).
Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.
Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).
Summary
Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 ...consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow‐up ≤1‐year post‐transplant and patients with early CAV were excluded. CMV‐infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow‐up was 7.5 years (IQR: 5.6–10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1‐year post‐HTx was detected in the univariate (P = 0.16) and multivariable hazard ratio (HR), 1.36; confidence interval (CI), 0.89–2.07; P = 0.16 Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02–1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06–2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long‐term follow‐up.
The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell–mediated ...rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.
We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies.
Genome-wide microarrays (19,462 genes) were used to define mRNA changes ...correlating with dysfunction (left ventricular ejection fraction LVEF ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival.
Dysfunction is correlated with dedifferentiation—decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection.
Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury.
Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB).
Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest.
Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.
Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability ...to assess injury, potentially confusing it with rejection, whereas molecular changes have potential to distinguish injury from rejection. Building on previous studies of transcripts associated with T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), we explored transcripts reflecting injury.
Microarray data from 889 prospectively collected endomyocardial biopsies from 454 transplant recipients at 14 centers were subjected to unsupervised principal component analysis and archetypal analysis to detect variation not explained by rejection. The resulting principal component and archetype scores were then examined for their transcript, transcript set, and pathway associations and compared to the histology diagnoses and left ventricular function.
Rejection was reflected by principal components PC1 and PC2, and by archetype scores S2TCMR, and S3ABMR, with S1normal indicating normalness. PC3 and a new archetype score, S4injury, identified unexplained variation correlating with expression of transcripts inducible in injury models, many expressed in macrophages and associated with inflammation in pathway analysis. S4injury scores were high in recent transplants, reflecting donation-implantation injury, and both S4injury and S2TCMR were associated with reduced left ventricular ejection fraction.
Assessment of injury is necessary for accurate estimates of rejection and for understanding heart transplant phenotypes. Biopsies with molecular injury but no molecular rejection were often misdiagnosed rejection by histology.TRAIL REGISTRATION. ClinicalTrials.gov NCT02670408FUNDING. Roche Organ Transplant Research Foundation, the University of Alberta Hospital Foundation, and Alberta Health Services.
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