Discovery of novel differentially expressed genes related to interstitial fibrosis and tubular atrophy among kidney transplantation recipients by mRNA-sequencing
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE218048 | GEO | 2023/08/30
REPOSITORIES: GEO
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Project description:Background: Despite significant improvements in short-term kidney transplant survival, comparable increases in 5 and 10-year outcomes have not been achieved. Chronic allograft nephropathy (CAN) is a major cause of late graft loss. Toxic nephropathy and inadequate long-term immunosuppression are possible factors. We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure, and gene expression. Methods: Sixty-one kidney recipients received mycophenolate mofetil (MMF), and prednisone (P). Randomized patients received concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Findings: Comparing sirolimus/MMF/P to cyclosporine/MMF/P at two years, there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dl; p=0.008), significantly higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 cc/min; p=0.008), iothalamate GFR (60.6 vs. 49.2 cc/min; p= 0.018), and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p=0.013). Regression analysis of calculated GFR’s from 1 to 36 months yielded a positive slope for sirolimus of 3.36 ml/min/year, and a negative slope for cyclosporine of –1.58 ml/min/year (p=0.008). Gene expression profiles of kidney biopsies with higher Banff CAN scores confirmed significant up regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. Interpretation: At two years the sirolimus-treated patients have better renal transplant function, a diminished prevalence of CAN, and down regulated expression of genes responsible for the progression of CAN. All may provide for an alternative natural history with improved graft survival. Keywords = Cyclosporine Keywords = Sirolimus Keywords = Transplantation Keywords = DNA microarrays Keywords = calcineurin inhibitors Keywords: parallel sample. This dataset is part of the TransQST collection.
2004-09-23 | E-GEOD-1743 | biostudies-arrayexpress
Project description:Kidney transplantation remains the optimal therapeutical option for end stage kidney disease. Current immunosuppressive regimens are efficient in combating acute kidney rejection. However, the insight in chronic kidney allograft injury remains limited. Simultaneously, pregnancy in kidney recipients appears more prevalent than during dialysis treatment. Due to ethical issues comprehensive studies on the impact of current immunosuppressive regimens on pregnancy are challenging. Omics- technology enables the systemic insight into biology both of immunity and pregnancy beyond up-to-date collected knowledge. The aim of the study was to investigate the proteomic status of lymphocytes obtained from pregnant female rats under immunosuppressive treatment. The group of 10 pregnant Wistar rat females, 5 of which treated with tacrolimus, mofetil mycophenolate and glicocorticosteroids, 5 used as control. The lymphocytes were obtained and analyzed with mass-spectrometry. The outcomes were verified statistically in terms of proteins up- and down regulation.
2023-03-11 | PXD035571 | Pride
Project description:Tacrolimus (Tac) is an effective anti-rejection agent in kidney transplantation, but its off-target effects make withdrawal desirable. While studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs. unsuccessful Tac removal are unknown. We performed microarray analyses of PBMC RNA from subjects enrolled in the Clinical Trials in Organ Transplantation-09 study in which stable kidney transplant recipients were randomized to Tac withdrawal or maintenance of standard immunosuppression beginning 6-mo post-transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a distinct, T cell-specific, downregulatory, and pro-apoptotic gene program. Functional analyses suggested stronger donor-reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data suggest that successful Tac withdrawal can unleash an active, protective pro-apoptotic T cell program, and provide the foundation for developing strategies to promote this protective immunological phenotype in kidney transplant recipients.
2020-02-18 | GSE145408 | 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. 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:The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated. Molecular signatures characterizing CNIT samples were identified. The recognized CNIT gene signature was most common in patients with decreased graft function and histological evidence of IF/TA.
2014-06-01 | GSE53605 | GEO
Project description:The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated. Molecular signatures characterizing CNIT samples were identified. The recognized CNIT gene signature was most common in patients with decreased graft function and histological evidence of IF/TA. To test CNIT contribution to CAD progression, kidney biopsies from transplant recipients with histological diagnosis of CNIT (n=14), acute rejection (ACR, n=13), and CAD with IF/TA (n=10), including 18 Normal allografts, were analyzed using gene expression microarrays.
2014-06-01 | E-GEOD-53605 | biostudies-arrayexpress
Project description:To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.
2020-06-24 | GSE153021 | GEO
Project description:Background: Despite significant improvements in short-term kidney transplant survival, comparable increases in 5 and 10-year outcomes have not been achieved. Chronic allograft nephropathy (CAN) is a major cause of late graft loss. Toxic nephropathy and inadequate long-term immunosuppression are possible factors. We performed a randomized prospective trial comparing calcineurin inhibitor (CNI)-free to CNI-based immunosuppression to determine the impact on renal function, structure, and gene expression. Methods: Sixty-one kidney recipients received mycophenolate mofetil (MMF), and prednisone (P). Randomized patients received concentration-controlled sirolimus or cyclosporine. Two years post-transplant 55 patients underwent renal function studies, 48 (87%) underwent transplant biopsies; all classified by Banff scoring and 41 by DNA microarrays. Findings: Comparing sirolimus/MMF/P to cyclosporine/MMF/P at two years, there was a significantly lower serum creatinine (1.35 vs. 1.81 mg/dl; p=0.008), significantly higher Cockroft-Gault glomerular filtration rate (GFR) (80.4 vs. 63.4 cc/min; p=0.008), iothalamate GFR (60.6 vs. 49.2 cc/min; p= 0.018), and Banff 0 (normal) biopsies (66.6 vs. 20.8%; p=0.013). Regression analysis of calculated GFR’s from 1 to 36 months yielded a positive slope for sirolimus of 3.36 ml/min/year, and a negative slope for cyclosporine of –1.58 ml/min/year (p=0.008). Gene expression profiles of kidney biopsies with higher Banff CAN scores confirmed significant up regulation of genes responsible for immune/inflammation and fibrosis/tissue remodeling. Interpretation: At two years the sirolimus-treated patients have better renal transplant function, a diminished prevalence of CAN, and down regulated expression of genes responsible for the progression of CAN. All may provide for an alternative natural history with improved graft survival. Keywords = Cyclosporine Keywords = Sirolimus Keywords = Transplantation Keywords = DNA microarrays Keywords = calcineurin inhibitors Keywords: parallel sample
2004-09-23 | GSE1743 | GEO
Project description:Skin gene expression signatures, including intrinsic subset, are associated with improvement during Mycophenolate mofetil (MMF) treatment.
2014-07-25 | GSE59785 | GEO
Project description:Donor organ shortage, growing waiting lists and organ discard rates are key problems in kidney transplantation. Donor organ quality is a critical factor determining post-transplant graft outcomes. However, organ quality is difficult to predict. Balancing the use of marginal donors without affecting outcomes is a main issue in the transplant field. The decision of acceptance of a kidney organ for transplantation is mainly based on donor organ biopsy findings, even though there are recognized limitations. The lack of better measures of organ quality at the time of transplantation as a predictor of performance graft outcome is a serious clinical challenge. Herein, we propose the use of a limited set of genes that captures intrinsic biology of kidney donor organs to improve available scoring systems. We studied gene expression in 192 deceased donor kidney biopsies and evaluated short-term outcomes which included delayed graft function and eGFR (high versus low) at 24 months for 168 kidney transplant recipients.
2022-06-13 | GSE147451 | GEO