Gene expression profile at single cell level of CD45+ immune cells in both peripheral blood mononuclear cells (PBMCs) and allograft biopsy samples obtained from kidney transplant recipients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE230606 | GEO | 2026/01/15
REPOSITORIES: GEO
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Project description:Acute rejection threatens kidney allograft longevity. Cell-free DNA (cfDNA) is a real-time marker of organ injury and immune response. DNA methylation is an epigenetic marker that regulates gene expression. We aim to elucidate differential methylation of total plasma cfDNA between pediatric kidney transplant recipients in the presence compared to the absence of acute rejection. In doing so, we hope to exploit the property of cfDNA as a real-time biomarker and build on available testing to identify genes and processes participating in acute allograft rejection pathophysiology in kidney transplantation. Twenty plasma cfDNA samples from pediatric kidney transplant recipients were collected at the time of allograft biopsy. Using whole genome bisulfite sequencing (WGBS), differentially methylated cytosines were identified in presence vs absence of acute rejection. Separate analyses were performed comparing those with borderline rejection to those with rejection, and to those without rejection. Differentially methylated cytosines were then assessed for gene associations and pathway enrichments. Acute rejection was present in 7 biopsies, borderline rejection in 4 biopsies, and no rejection in 9 biopsies. In the comparison of acute rejection to non-rejection biopsies, there were 34,356 differentially methylated cytosines corresponding to 1,269 associated genes, and 533 enriched pathways. These numbers were all substantially greater (4x-13x) than the comparisons made between acute rejection against those with borderline rejection, and between non-rejection against borderline rejection. Prominently enriched pathways between samples of individuals with and without acute rejection were related to immune cell regulation, inflammatory response, lipid metabolism, and tryptophan-kynurenine metabolism. Our data suggest methylation plays a role in development of or response to acute kidney allograft rejection. Specifically, differentially methylated pathways associated with acute rejection include those related to immune and inflammatory responses.
2025-04-25 | GSE275017 | GEO
Project description:Short-term kidney transplant rejection rates have vastly improved. Unfortunately, the focus is still on clinical acute rejection, whereas patients with no graft dysfunction and subclinical rejection without protocol biopsies would be treated as having no ongoing injury. Molecular diagnostic tests to detect rejection are still reliant on the current gold standard, kidney histology. Our work is the first to examine molecular profiles in matched tissue and blood samples from a prevalent kidney transplant recipient population. We show molecular evidence, in blood and tissue, that subclinical rejection is a precursor of clinical rejection and that non-alloimmune injury to the graft can be distinguished from immune activation. Our work supports consideration of tissue molecular profiling for a comprehensive understanding of noninvasive diagnostics.
2025-12-01 | GSE249451 | GEO
Project description:Gene expression profile at single cell level of CD45+ immune cells in both peripheral blood mononuclear cells (PBMCs) and allograft biopsy samples obtained from kidney transplant recipients
| PRJNA961900 | ENA
Project description:Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (P<0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC=0.88, P<0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (P=0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that non-response to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor. Transcriptional profiles of 40 renal allograft biopsy samples were analyzed using Illumina HumanRef-8 v3.0 BeadChips (Illumina, San Diego, CA). Expression profiles were investigated in total RNA isolated from biopsy samples of 18 patients with steroid responsive acute rejection and 18 patients with steroid resistant acute rejection. Four biopsies, taken during acute decrease of graft function but with no histomorphologic indication of rejection, were included as controls.
2013-05-21 | E-GEOD-47097 | biostudies-arrayexpress
Project description:We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.
| S-EPMC11292417 | biostudies-literature
Project description:T cells are central mediators of transplant rejection, yet the differentiation trajectories that sustain this process remain incompletely defined. To delineate the differentiation trajectory of CD8+ T cells, we performed single-cell transcriptomic profiling of matched allograft and peripheral blood mononuclear cell (PBMC) samples obtained from the same patient.
2026-01-15 | GSE313511 | GEO
Project description:Steroid-refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid-refractory acute rejection. Eighty-three kidney transplant recipients (1995-2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (P<0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT-1 as an independent covariate (AUC=0.88, P<0.0000001). In the validation set, MT-1 expression was also significantly associated with steroid resistance (P=0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that non-response to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc-requiring anti-inflammatory effect of the glucocorticoid receptor.
2013-05-21 | GSE47097 | GEO
Project description:Exploration of genes associated with acute and chronic rejection associated with obliterative airway disease Keywords: other
2005-10-08 | GSE3418 | GEO
Project description:Complications due to long-term administration of immunosuppressive therapy increase the morbidity and mortality of liver transplant recipients. Discontinuation of immunosuppressive drugs in recipients spontaneously developing operational tolerance could substantially lessen this burden. However, this strategy results in the development of rejection in a high proportion of recipients who require lifelong immunosuppression. Thus, there is a need to identify predictive factors of successful drug withdrawal and to define the clinical and histological outcomes of operationally tolerant liver recipients. Methods. We enrolled 102 stable liver transplant recipients in an immunosuppression withdrawal trial in which drugs were gradually discontinued over a 6-9 month period. Patients with stable graft function and no signs of rejection in a liver biopsy conducted 12 months after cessation of immunosuppressive therapy were considered operationally tolerant. Results. Out of the 98 recipients who completed the study, immunosuppression discontinuation was successful in 41 recipients and rejection occurred in 57. Rejection episodes were mild and were resolved in all cases. Development of tolerance was independently associated with time elapsed since transplantation, recipient age, and male gender. No histological damage was apparent in protocol biopsies performed after successful drug withdrawal.
2012-01-09 | GSE28842 | GEO
Project description:T cell-mediated rejection (TCMR) remains a challenge in kidney transplantation. Based on a histopathological biopsy examination, patients can be classified into groups defining their kidney’s status, i.e. no rejection (NR), borderline rejection (BR) and acute rejection (AR). Yet, this classification is not perfect, since for the borderline cases, a number of patients may or may not require further clinical intervention. Although in other studies, detection of early signs of rejection in the urine proteome was already attempted, these results failed to be replicated. Thus, a robust method of classification by biopsy proteome profiling may provide a possible solution. Unlike for urine or small extracellular vesicle’s analysis, biopsy proteome directly reflects the subclinical changes leading to allograft loss. Kidney tissue biopsies from patients classified into NR, BR and AR groups based on the current Banff guidelines were subjected to a mass spectrometry based proteomic profiling. Using qualitative, quantitative, profile and ROC analysis, a set of four proteins (i.e., GNB4, PDK1, AGXT and CD73) was chosen for further validation using immunohistochemical (IHC) methods. Proteomic analysis identified 2547 proteins across all groups with their abundance profiles showing high degree of similarity between the BR and AR datasets. In a quantitative comparison, GNB4 and AGXT emerged as the proteins significantly differentiating the groups with the highest fold change. Moreover, AGXT was indicated as a potential biomarker candidate following a ROC analysis. Morover, PDK1 and CD73 were found to best classify the samples in a binary fashion. These candidate biomarkers were validated using an IHC approach, where only upregulation of GNB4 in immune cells and PDK1 in macrophages could be confirmed, with no significant changes in the tubular epithelium. Based on these results, GNB4 and PDK1 presence in the immune cells and macrophages has been identified as an interesting target for further extensive studies. If their relevance was to be confirmed in a large patient cohort, their analysis could potentially serve an extension of the already established histopathological classification in the context of kidney transplant rejection. This retrospective study was approved by the Bioethics Committee of the Medical University of Gdańsk no. NKBBN/201/2021.
2025-10-27 | PXD064523 | Pride