Pre-Transplant recipients’ clinical and immunological features are independently associated with the development of delayed graft function in kidney transplantation
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Paola Pontrelli
PROVIDER: E-MTAB-10747 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Delayed graft function (DGF) is associated with a reduced long-term graft survival. Ischemia-reperfusion damage and donors' features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the role of recipients' characteristics in the development of DGF to discover early genomics biomarkers in peripheral blood mononuclear cells (PBMC) in order to identify patients at risk. We prospectively enrolled 932 kidney graft recipients from 466 donors for both kidneys. A total of 226 recipients experienced DGF. Among the 466 donors, 290 couples of recipients both patients presented with early graft function (EGF, group A), 50 couples experienced DGF (group B) and 126 couples of recipients were discordant as one presented DGF and the other promptly recovered graft function (group C). In group C we randomly selected 10 couples of DGF/EGF recipients. Peripheral blood mononuclear cells (PBMC) were harvested before transplantation; their transcriptomic profile was investigated by a microarray approach and microarray results were validated by qPCR in an independent group (DGF n=25; EGF n=25). In the whole study group, DGF was independently associated with both donors’ and recipient’s features. Moreover, group A, B and C presented significant differences in both donors’ and recipients’ characteristics. In group C of patients, DGF was significantly associated with body mass index, dialysis modality and number of mismatches. Two-hundred and seventy-three genes were differentially expressed before transplantation in discordant EGF/DGF patients of group C. Their main biological functions were immune dysfunction and inflammation. Among the differentially expressed genes, we observed a significant increase in the expression of CCR2, the MCP-1 receptor, in DGF patients. CCR-2 and MCP-1 up-regulation was confirmed in an independent cohort of patients. Our results suggest that recipients' clinical and immunological features, potentially modulated by dialysis modality, are associated with the development of DGF independently of donors' features.
2022-10-01 | GSE159636 | GEO
Project description:Because of world-wide shortage of renal grafts, kidney transplantation (KTx) from donors after cardiac death (DCD) is an alternative way to KTx from brain-dead donors. Although the prognosis of DCD KTx is gradually improving, the graft often undergoes delayed graft function (DGF) rendering the control of DGF essential for post-KTx patient care. To know the etiology of the DGF, we performed genome-wide gene expression profiling using renal biopsy samples performed at 1 hour after KTx from DCD and compared the data with those of KTx from living donors (LD). A total of 526 genes were differentially expressed between them. Genes involved in acute inflammation were activated, while metabolic pathways were consistently down-regulated in DCD. All of these findings imply inferior performance of the DCD grafts relative to LD grafts. We identified several genes of which expression levels were correlated well with parameters indicating short- and long-term prognosis of the DCD patients. In addition, we identified several genes encoding secretory proteins that might reflect the performance of the graft and be potent non-invasive biomarkers. Our data provide good source for candidates of biomarker that are potentially useful for control of DGF. Keywords: disease state analysis
2008-02-08 | GSE10419 | GEO
Project description:To identify early markers to predict post-transplantation outcomes we performed a transcriptome analysis in pre-implantation kidney biopsies from deceased donors searching for genes associated with DGF and graft function one year post-transplantation.
2014-12-01 | GSE54888 | GEO
Project description:The frequency of delayed function of kidney transplants varies greatly and is associated with the quality of graft, donor age, and the duration of cold ischemia time. Body weight differences between donor and recipient can affect primary graft function. The underlying mechanism is poorly understood. Here, we have transplanted kidney grafts from commensurate body weight (L-WD) or reduced body weight (H-WD) donor rats into syngeneic or allogeneic recipients. 24 hours post-transplantation, serum creatinine level in H-WD recipients was significantly higher compared to that of L-WD recipients indicating impaired primary graft function. We detected a 10 fold higher transcription of IL-6 and dramatically increased tubular destruction in grafts from H-WD recipients. This was accompanied by decreased expression of genes associated with kidney function and an up-regulation of other genes such as cytochrome P450 isoforms, FosL and Trib3 as revealed by DNA microarray analysis. A single application of IL-6 into L-WD recipients is sufficient to impair primary graft function and to cause tubular damage. Whereas, immediate neutralization of IL-6 receptor signaling rescued primary graft function resulting in low serum creatinine levels, well-preserved kidney graft architecture and a normalized gene expression profile. These findings have strong clinical implication as anti-IL6R treatment of patients receiving grafts from lower-weight donors could be used to improve primary graft function. The dataset comprises eight samples divided into four sample groups. Each group represents rat kidneys collected after allogeneic transplantation under a certain condition and includes two biological replicates. The first group is characterized by a high body weight difference between donor and recipient, rats in the second group exhibit a low weight difference. Group three and four are similar to group one, but underwent an additional treatment with anti-IL6R mAb or prednisolone immediately after transplantation.
2010-04-08 | E-GEOD-15813 | biostudies-arrayexpress
Project description:Delayed graft function (DGF) is commonly defined as dialysis in the first week post-transplant. This definition, though readily applicable, is too generic and unable to distinguish between “types� of DGF or time needed to recover function. We aimed to profile biological pathways in DCD kidney donors that correlate with DGF and discriminate different durations. N=30 DCD kidney biopsies were selected from the UK Quality in Organ Donation biobank and stratified according to DGF duration (immediate function, IF n=10; “short-DGF� (1-6 days), SDGF n=10; “long-DGF� (7-22 days), LDGF n=10). Samples were matched for donor and recipient demographics and analysed by label-free quantitative proteomics, yielding identification of N=3,378 proteins. Ingenuity Pathway Analysis on differentially abundant proteins showed that SDGF kidneys presented stress response pathways upregulation, while LDGF presented impaired response to stress, compared to IF. LDGF showed extensive metabolic deficits compared to IF and SDGF. DCD kidneys requiring dialysis only in the first week post-transplant present acute cellular injury at donation, alongside repair pathways upregulation. In contrast, DCD kidneys requiring dialysis longer beyond 7 days present minimal metabolic and antioxidant responses, suggesting current DGF definitions might not be adequate in distinguishing different types of injury in the donor kidneys contributing to DGF.
2024-05-23 | PXD038196 | Pride
Project description:Because of world-wide shortage of renal grafts, kidney transplantation (KTx) from donors after cardiac death (DCD) is an alternative way to KTx from brain-dead donors. Although the prognosis of DCD KTx is gradually improving, the graft often undergoes delayed graft function (DGF) rendering the control of DGF essential for post-KTx patient care. To know the etiology of the DGF, we performed genome-wide gene expression profiling using renal biopsy samples performed at 1 hour after KTx from DCD and compared the data with those of KTx from living donors (LD). A total of 526 genes were differentially expressed between them. Genes involved in acute inflammation were activated, while metabolic pathways were consistently down-regulated in DCD. All of these findings imply inferior performance of the DCD grafts relative to LD grafts. We identified several genes of which expression levels were correlated well with parameters indicating short- and long-term prognosis of the DCD patients. In addition, we identified several genes encoding secretory proteins that might reflect the performance of the graft and be potent non-invasive biomarkers. Our data provide good source for candidates of biomarker that are potentially useful for control of DGF. Experiment Overall Design: This investigation was approved by the Institutional Review Boards of our centers. Written informed consent was obtained from each patient or legal guardian before enrollment. Consecutive patients undergoing either a living (n =15) or DCD KTx (n = 14) at this center were prospectively enrolled. The immunosuppressive regimen was similar in all patients, consisting of basiliximab, tacrolimus or cyclosporine with prednisone and mycophenolate mofetil. All kidney grafts were procured at this canter using in situ regional cooling technique from DCD. All donors after cardiac death from this hospital were classified as type IV in this study. The cause of donor death was cerebrovascular disease in all cases. Although most of those cases required HD (0-22 days) after KTx because of DGF, the function of all of transplanted kidneys eventually recovered. All kidney grafts from LD were procured by open nephrectomy in this study. All graft biopsies were performed one hour after reperfusion during kidney transplant operation using biopsy needles. All biopsy samples were stored immediately in RNA later (Applied Biosytems). Total cellular RNA was extracted from frozen samples using RNeasy (Qiagen, Valencia, CA, USA). For DNA microarray experiments, 200 ng aliquots of total RNA were labeled using the Agilent Low RNA Input Fluorescent Linear Amplification Kit (Agilent Technologies, CA) according to the manufacturerâs instructions. RNA purified from each kidney graft was used for microarray analysis (Cy5-labeled), with pooled RNA derived from normal kidneys (Homan Kidney Total RNA #636529 BD, Franklin Lakes, NJ, USA) as a template control (Cy3-labeled). After checking the labeling efficiency, 1 ïg aliquots of Cy3-labeled normal control RNA and Cy5-labeled RNA from individual grafts were mixed, and then hybridized to Agilent Human 1A (Ver. 2) Microarrays (Product No.G4110B) according to the manufacturerâs hybridization protocol. After washing, the microarray slides were analyzed with an Agilent Microarray scanner and software (scanner model G2565BA). Data analysis was performed using Agilent Feature Extraction software (Ver. A.7.1.1), and Excel 2007 (Microsoft).
2008-04-07 | E-GEOD-10419 | biostudies-arrayexpress
Project description:We previously observed reduced graft survival for kidney transplants having interstitial fibrosis with subclinical inflammation, but not fibrosis alone, on 1-year protocol biopsy. The current study aimed to determine whether fibrosis with inflammation at 1 year is associated with renal functional decline in a low-risk transplant cohort and to characterize the nature of the inflammation. Subjects were living-donor, tacrolimus/mycophenolate-treated transplant recipients without overt risk factors for reduced graft survival (n=151). Transplants with normal histology (n=86) or fibrosis alone (n=45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, while those having fibrosis with inflammation (n=20) had declining glomerular filtration rate and reduced graft survival. Immunohistochemistry confirmed increased interstitial T-cells and macrophages/dendritic cells in the fibrosis with inflammation group. Gene expression was performed on a subset of biopsies in each group and demonstrated increased expression of transcripts related to innate and cognate immunity in transplants having fibrosis with inflammation. Pathway- and pathological process-specific analyses of microarray profiles revealed that, in fibrosis with inflammation, over-expressed transcripts were enriched for potentially damaging immunological activities including Toll-like receptor signaling, antigen presentation/dendritic cell maturation, interferon gamma-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes. Thus, fibrosis with inflammation in 1-year protocol biopsies is associated with reduced graft survival and function and with a rejection-like gene expression signature even in recipients with no clinical risk for inferior outcome. Early interventions aimed at altering rejection-like inflammation may favor improved long-term KTx survival. We analyzed gene expression from a group of 65 renal transplant recipients. Patient groups were carefully selected to include patients on the same immunosuppression (Prograf-MMF-Pred), transplant type (LD), absence of over post-transplant complications (AR, BK, DGF). For each patient a 1 year protocol biopsy was examined by conventional histology and gene expression. By histology the patients were categorized as histologically normal (n=25, i/cg/ci=0), IF/TA (n=24, i/cg=0, ci>0) and IFTA+i (n=16, cg=0, i/ci>0). This dataset is part of the TransQST collection.
2010-11-01 | E-GEOD-22459 | biostudies-arrayexpress
Project description:The frequency of delayed function of kidney transplants varies greatly and is associated with the quality of graft, donor age, and the duration of cold ischemia time. Body weight differences between donor and recipient can affect primary graft function. The underlying mechanism is poorly understood. Here, we have transplanted kidney grafts from commensurate body weight (L-WD) or reduced body weight (H-WD) donor rats into syngeneic or allogeneic recipients. 24 hours post-transplantation, serum creatinine level in H-WD recipients was significantly higher compared to that of L-WD recipients indicating impaired primary graft function. We detected a 10 fold higher transcription of IL-6 and dramatically increased tubular destruction in grafts from H-WD recipients. This was accompanied by decreased expression of genes associated with kidney function and an up-regulation of other genes such as cytochrome P450 isoforms, FosL and Trib3 as revealed by DNA microarray analysis. A single application of IL-6 into L-WD recipients is sufficient to impair primary graft function and to cause tubular damage. Whereas, immediate neutralization of IL-6 receptor signaling rescued primary graft function resulting in low serum creatinine levels, well-preserved kidney graft architecture and a normalized gene expression profile. These findings have strong clinical implication as anti-IL6R treatment of patients receiving grafts from lower-weight donors could be used to improve primary graft function.
2009-07-22 | GSE15813 | GEO
Project description:Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. We investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in HLA-matched sibling recipients prior to HSCT. We measured genome-wide DNA methylation levels in peripheral blood of 91 HSCT donors using Illumina Infinium HumanMethylation450 BeadChips. We showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We identified distinct DNA methylation marks in graft donors that are associated with aGVHD severity status in recipients. Together, our findings suggest that ‘epigenetic matching’ of HSCT donor-recipient pairs in a clinical setting may be used in conjunction with genetic matching to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.
| EGAS00001001287 | EGA
Project description:In deceased donor kidney transplantation, acute kidney injury (AKI) prioir to surgery is a major determinant of delayed graft function (DGF), but AKI is histologically silent and difficult to assess. We hypothesized that a molecular measurement of AKI would add power to conventional risk assessments to predict the early poor allograft function at first week post transplantation. We performed microarrays on implantation biopsies taken during reperfusion in 70 deceased donor kidneys from 53 donors. Early poor function was classified by two definitions on day 7 post-transplantation: serum creatinine greater than 265 umol/L (3 mg/dL) or the requirement for dialysis. Donor age and related risk scores (Irish, Schold, KDRI) associated with worse early function, as expected, but histologic features (glomerulosclerosis; pathology risk scores (Remuzzi, MAPI)) correlated with donor age but not with poor function. However, molecular AKI signal, previously defined in kidneys with early injury, was the best single predictor of poor allograft function. The combination of donor age and the AKI signal improved the prediction of poor function. In addition, asssessments of tissue quality particularly donor age, Banff ct, Irish and KDRI scores, showed negative correlative trend with late graft function, whereas the AKI signal did not. Thus donor age and the molecular AKI signal are the main predictors of early impaired function, but have little impact on survival.
2013-02-13 | E-GEOD-37838 | biostudies-arrayexpress