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HE staining of rat myocardium (×100). (A) Normal myocardium; (B) myocardial tissues sampled 5 days after organ transplantation; (C) myocardial tissues sampled 7 days after organ transplantation; (D) rats are intraperitoneally injected with cyclosporine A at a dose of 20 mg/kg one day pre-transplantation and at a dose of 10 mg/kg post-transplantation for 5 days, and then myocardial tissues are sampled; (E) rats are intraperitoneally injected with cyclosporine A at a dose of 20 mg/kg one day pre-transplantation and at a dose of 10 mg/kg post-transplantation for 7 days, and then myocardial tissues are sampled.
Source publication
The aim of this study was to identify metabolite biomarkers associated with acute rejection after heart transplantation in rats using a LC-MS-based metabolomics approach. A model of heterotopic cardiac xenotransplantation was established in rats, with Wistar rats as donors and SD rats as recipients. Blood and cardiac samples were collected from bla...
Citations
... Metabolomics refers to the study of small molecule substrates, intermediates, and byproducts of cellular metabolism within biospecimens and has emerged as a powerful tool across the spectrum of cardiovascular disease [44]. Preclinical mouse models have demonstrated that circulating metabolites including C16 sphinganine, choline, and D-glutamine are highly sensitive and specific for the early diagnosis of rejection in a heterotopic model of cardiac xenotransplantation [45]. Animal models have also been leveraged to better understand cardiac metabolism during ex situ perfusion. ...
Purpose of Review
Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival.
Recent Findings
Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care.
Summary
The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.
... D-glutamine exhibited good diagnostic capability for the diagnosis of the early acute rejection after heart transplantation with a high sensitivity and specificity. 38 Moreover, inhibition of glutamine metabolism was considered to prevent graft rejection by inhibiting generation and function of effector T cells. In fully mismatched skin and heart allograft transplantation models, the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON) combined with the glycolytic inhibitor 2-deoxyglucose (2-DG) and the anti-type II diabetes drug metformin, were demonstrated to prevent or delay graft rejection. ...
Background
Antibody-mediated rejection (AMR) is emerging as the main cause of graft loss after kidney transplantation. Our previous study revealed the gut microbiota alternation associated with AMR in kidney transplant recipients, which was predicted to affect the metabolism-related pathways.
Methods
To further investigate the shifts in intestinal metabolic profile among kidney transplantation recipients with AMR, fecal samples from kidney transplant recipients and patients with end-stage renal disease (ESRD) were subjected to untargeted LC-MS-based metabolomics.
Results
A total of 86 individuals were enrolled in this study, including 30 kidney transplantation recipients with AMR, 35 kidney transplant recipients with stable renal function (KT-SRF), and 21 participants with ESRD. Fecal metabolome in patients with ESRD and kidney transplantation recipients with KT-SRF were parallelly detected as controls. Our results demonstrated that intestinal metabolic profile of patients with AMR differed significantly from those with ESRD. A total of 172 and 25 differential metabolites were identified in the KT-AMR group, when compared with the ESRD group and the KT-SRF group, respectively, and 14 were common to the pairwise comparisons, some of which had good discriminative ability for AMR. KEGG pathway enrichment analysis demonstrated that the different metabolites between the KT-AMR and ESRD groups or between KT-AMR and KT-SRF groups were significantly enriched in 33 or 36 signaling pathways, respectively.
Conclusion
From the metabolic point of view, our findings may provide key clues for developing effective diagnostic biomarkers and therapeutic targets for AMR after kidney transplantation.
... Neopterin and B2, and thromboxane A2 metabolomic biomarkers are found to be elevated during heart allograft rejection [72]. Recently, liquid chromatography-tandem mass spectrometry (LC-MS)-based metabolomics analysis identified 4 metabolite biomarkers in serum, including D-tagatose, choline, C16 sphinganine, and D-glutamine that had high sensitivity and specificity levels for detection of early acute allograft rejection in rats [73]. Sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) is another biomarker that has been studied in heart transplantation patients and its levels are found to be decreased in cardiac tissue and serum of patients with heart transplant rejection [74]. ...
For most patients with end stage heart failure, heart transplantation is the treatment of choice. Allograft rejection is one of the major post transplantation complication and can result in poor graft outcome and survival. Recent advancements in science and technology offer an opportunity to integrate genomic and other omics-based biomarkers into clinical practice, facilitating noninvasive evaluation of allograft for diagnostic and prognostic purposes. Among several omics, genomics including gene expression profiling of blood immune cell components and donor- derived cell free DNA (ddcfDNA) are of special interest to researchers. Several studies have investigated levels of ddcfDNA and miroRNAs in blood as potential markers for early detection of allograft rejection. One of the achievements in the field of genomics is AlloMap, Gene Expression Profiling (GEP) of Peripheral Blood Mononuclear cells (PBMC), which can identify 11 differentially expressed genes and help with detection of moderate/severe acute cellular rejection in stable heart transplant recipient. In recent years, utilization of GEP of PBMC for identifying differentially expressed genes to diagnose acute antibody mediated rejection and cardiac allograft vasculopathy has yielded promising results. Advancements in the field of metabolomic and proteomic as well as their potential implications have been further discussed in this paper.
... Moreover, MS can also be combined with chromatographic methods (LC or GS) to improve metabolite separation. These technologies allow the investigation of metabolic changes in disease models and organ physiology, including Tx [23]. ...
In solid organ transplantation (Tx), both survival rates and quality of life have improved dramatically over the last few decades. Each year, the number of people on the wait list continues to increase, widening the gap between organ supply and demand. Therefore, the use of extended criteria donor grafts is growing, despite higher susceptibility to ischemia-reperfusion injury (IRI) and consecutive inferior Tx outcomes. Thus, tools to characterize organ quality prior to Tx are crucial components for Tx success. Innovative techniques of metabolic profiling revealed key pathways and mechanisms involved in IRI occurring during organ preservation. Although large-scale trials are needed, metabolomics appears to be a promising tool to characterize potential biomarkers, for the assessment of graft quality before Tx and evaluate graft-related outcomes. In this comprehensive review, we summarize the currently available literature on the use of metabolomics in solid organ Tx, with a special focus on metabolic profiling during graft preservation to assess organ quality prior to Tx.
... Lin et al (2017) recently used a heterotopic HTx rat model to determine the metabolic profile post-BSD in serum. 136 They found a panel of 4 metabolites, D-tagatose, choline, C16 sphinganine and D-glutamine, could accurately diagnose early rejection. ...
Introduction
In parallel to the clinical maturation of heart transplantation over the last 50 years, rejection testing has been revolutionized within the systems biology paradigm triggered by the Human Genome Project.
Areas covered
We have co-developed the first FDA-cleared diagnostic and prognostic leukocyte gene expression profiling biomarker test in transplantation medicine that gained international evidence-based medicine guideline acceptance to rule out moderate/severe acute cellular cardiac allograft rejection without invasive endomyocardial biopsies. This work prompted molecular re-classification of intragraft biology, culminating in the identification of a pattern of intragraft myocyte injury, in addition to acute cellular rejection and antibody-mediated rejection. This insight stimulated research into noninvasive detection of myocardial allograft injury. The addition of a donor-organ specific myocardial injury marker based on donor-derived cell-free DNA further strengthens the noninvasive monitoring concept, combining two complementary noninvasive blood-based measures, host immune activity-related risk of acute rejection as well as cardiac allograft injury.
Expert opinion
This novel complementary noninvasive heart transplant monitoring strategy based on leukocyte gene expression profiling and donor-derived cell-free DNA that incorporates longitudinal variability measures provides an exciting novel algorithm of heart transplant allograft monitoring. This algorithm’s clinical utility will need to be tested in an appropriately designed randomized clinical trial.
Primary graft dysfunction is an important cause of morbidity and mortality after cardiac transplantation. Donor brain stem death (BSD) is a significant contributor to donor heart dysfunction and primary graft dysfunction. There remain substantial gaps in the mechanistic understanding of peritransplant cardiac dysfunction. One of these gaps is cardiac metabolism and metabolic function. The healthy heart is an "omnivore," capable of utilizing multiple sources of nutrients to fuel its enormous energetic demand. When this fails, metabolic inflexibility leads to myocardial dysfunction. Data have hinted at metabolic disturbance in the BSD donor and subsequent heart transplantation; however, there is limited evidence demonstrating specific metabolic or mitochondrial dysfunction. This review will examine the literature surrounding cardiometabolic and mitochondrial function in the BSD donor, organ preservation, and subsequent cardiac transplantation. A more comprehensive understanding of this subject may then help to identify important cardioprotective strategies to improve the number and quality of donor hearts.
