Gene-Expression Profiles and Age of Donor Kidney Biopsies Obtained Before Transplantation Distinguish Medium Term Graft Function

ArticleinTransplantation 83(8):1048-54 · April 2007with11 Reads
DOI: 10.1097/01.tp.0000259960.56786.ec · Source: PubMed
Abstract
Donor factors such as age profoundly influence long-term graft function after cadaveric renal transplantation, but the molecular signature of these aspects in the allograft remains unknown. We analyzed the genome-wide gene expression signature of donor kidney biopsies of different ages obtained before transplantation. Subsequent analysis compared expression profiles from allografts with excellent function versus impaired function at 1 yr after engraftment. Differential expression profiles were analyzed on the level of molecular function and biologic role, as well as by analysis of co-regulation through transcription factors, regulatory networks, and protein-protein interaction data utilizing extended bioinformatics. The 15 subjects with excellent transplant function defined as calculated GFR>or=45 mL/min/1.73 m2 at 1 yr exhibited a distinctly different gene expression profile than the matched 16 subjects with impaired function defined as calculated GFR<45 mL/min/1.73 m2. Donor kidneys from recipients with impaired allograft function showed activation of genes mainly belonging to the functional classes of immunity, signal transduction, and oxidative stress response. Two-thirds of these genes exhibited at least one protein interacting partner, suggesting choreographed intracellular events differentiating the two recipient groups. However, donor age may have confounded some of the associations found between gene profiles and graft function. In summary, a distinctive gene expression profile in the donor kidney at transplantation together with donor age predicts medium term allograft function in recipients of cadaveric allografts.
    • "At the transcriptional level, the response to tissue injury presents as a reduction in the expression of genes related to cell transport and an up-regulation of cell cycle, repair and tissue remodelling transcripts along with embryonic pathways like wnt and notch [23, 24]. In addition, genes associated with immune, signal transduction , and oxidative stress responses have been shown to be increased in donor biopsies from recipients with impaired function post-transplantation [25]. The mRNA expression of well-known acute kidney injury (AKI) biomarkers like LCN2 and HAVCR1/KIM-1 has been found to be significantly increased in recipients developing delayed graft function (DGF) [26]. "
    [Show abstract] [Hide abstract] ABSTRACT: Despite its long-standing status as the diagnostic "gold standard", the renal transplant biopsy is limited by a fundamental dependence on descriptive, empirically-derived consensus classification. The recent shift towards personalized medicine has resulted in an increased demand for precise, mechanism-based diagnoses, which is not fully met by the contemporary transplantation pathology standard of care. The expectation is that molecular techniques will provide novel pathogenetic insights that will allow for the identification of more accurate diagnostic, prognostic, and therapeutic targets. Here we review the current state of molecular renal transplantation pathology. Despite significant research activity and progress within the field, routine adoption of clinical molecular testing has not yet been achieved. The recent development of novel molecular platforms suitable for use with formalin-fixed paraffin-embedded tissue will offer potential solution for the major barriers to implementation. The recent incorporation of molecular diagnostic criteria into the 2013 Banff classification is a reflection of progress made and future directions in the area of molecular transplantation pathology. Transcripts related to endothelial injury and NK cell activation have consistently been shown to be associated with antibody-mediated rejection. Prospective multicenter validation and implementation of molecular diagnostics for major entities remains an unmet clinical need in transplantation. It is expected that an integrated system of transplantation pathology diagnosis comprising molecular, morphological, serological, and clinical variables will ultimately provide the greatest diagnostic precision.
    Full-text · Article · Aug 2015
    • "In fact, in the last years, several drugs have been studied as inhibitors of karyopherin trafficking (e.g., importazole, Ivermectin)145146147148. Also, several studies employing microarray methodologies have been undertaken to select potential pharmacological targets useful to minimize the onset of acute rejection. Kainz et al. [149], performing a complex genome-wide analysis using nucleic materials isolated from graft tissues obtained before and one-year post-transplantation, identified 52 genes able to accurately discriminate patients with excellent versus poor renal function. Up-regulated genes in patients with reduced graft function were involved in immunity and defense, signal transduction and response to oxidative stress, while down-regulated genes were mainly involved in metabolism, ion binding and transport. "
    [Show abstract] [Hide abstract] ABSTRACT: Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients' quality of life. Significant improvements in one-year renal allograft and patients' survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%-5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, "omics" techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient's genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.
    Full-text · Article · Feb 2015
    • "Indeed, reduced oxidative damage, as shown by reduced levels of oxidation and apoptosis, at 6 months after transplantation correlated with a better recovery of renal function in kidney allografts [13]. In terms of kidney aging, genetic factors may influence tissue damage and the related loss of function in elderly recipients [14]. Gene expression profiling using microarrays or quantitative PCR has become a benchmark in research into novel and informative monitoring assays for KT [15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Conflicting results have been reported regarding the effects of donor age, recipient age and donor-recipient age difference on short- and long-term outcomes after kidney transplantation. The aim of this study was to evaluate the effects of recipient age on graft function, oxidative stress, and gene expression after renal transplantation. Fifty male Fischer 344 rats [25 young (Y, 4 months), 25 senior (S, 16 months)] were randomized to 6 groups: 2 sham groups (Y and S, n = 5 in each group) and 4 renal transplant groups[young-to-young (Y-Y), young-to-senior (Y-S), senior-to-young (S-Y), senior-to-senior (S-S), (n = 10 in each group)]. The left kidneys were transplanted from donor to recipient. After 12 weeks, systematic blood pressure, graft weight, graft function, histology and oxidative stress were measured. Microarray analysis and quantitative real-time PCR confirmation were performed to study gene expression in the grafts. There were no differences in renal graft function between young and senior kidney cross-transplantation. Transplanted kidneys showed no significant differences in glomerulosclerosis index compared to non-transplanted kidneys but had significantly different tubulointerstitium scores compared to age-matched controls. Senior rats had lower SOD activity and higher MDA content than young rats. SOD activity was significantly lower and MDA content significantly higher in the Y-S group than in the Y-Y group. There were 548 transcript differences between senior and young kidneys with 36 upregulated and 512 downregulated transcripts. There were 492 transcript differences between Y-S and Y-Y groups with 127 upregulated and 365 downregulated transcripts. There were 1244 transcript differences between the S-Y and S-S groups with 680 upregulated and 574 downregulated transcripts. Oxidative stress and gene expression profile was significantly different in the Y-S compared to the S-Y group. The identified differences were mainly in the MAPK and insulin signal pathways, making these potential targets for therapeutic intervention.
    Full-text · Article · Jun 2013
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