Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies

Scherer, Andreas; Krause, Andreas; Walker, John R.; Korn, Alexander; Niese, D.; Raulf, Friedrich

doi:10.1097/01.tp.0000068481.98801.10

Cited by 95 publications

(54 citation statements)

References 28 publications

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“…Comparison of the gene sets upregulated in late graft injury in four published studies concerning kidney transplantation 12 and was among the genes upregulated in 6-mo biopsies from kidneys that displayed CAN at 1 yr compared with 6-mo biopsies from kidneys that remained healthy at 1 yr, in a study by Scherer et al 11 (exhaustive gene list provided by the authors).…”

Section: Identification Of Trib1 Mrna As a Potential Biomarker Of Chrmentioning

confidence: 99%

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Ashton‐Chess

Giral

Mengel³

et al. 2008

Journal of the American Society of Nephrology

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Diagnosis of the specific cause of late allograft injury is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. This study sought previously unrecognized biomarkers for specific histologic diagnoses of late graft scarring by comparison of gene sets from published microarray studies. Tribbles-1 (TRIB1), a human homolog of Drosophila tribbles, was identified to be a potentially informative biomarker. For testing this, mRNA expression in 76 graft biopsies, 71 blood samples, and 11 urine samples were profiled from independent cohorts of renal transplant patients with different histologic diagnoses recruited at two European centers. TRIB1 but not TRIB2 or TRIB3 was found to be a potential blood and tissue biomarker of chronic antibody-mediated rejection, an active immune-mediated form of chronic allograft failure associated with a poor prognosis. TRIB1 mRNA levels in peripheral blood mononuclear cells discriminated patients with chronic antibody-mediated rejection from those with other types of late allograft injury with high sensitivity and specificity. TRIB1 was also upregulated in a rodent model of chronic cardiac vasculopathy, suggesting that this biomarker may be useful in other solid-organ transplants and across species. It was determined that TRIB1 is expressed primarily by antigen-presenting cells and activated endothelial cells. Overall, these data support the potential use of TRIB1 as a biomarker of chronic antibody-mediated allograft failure.

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Section: Identification Of Trib1 Mrna As a Potential Biomarker Of Chrmentioning

confidence: 99%

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Ashton‐Chess

Giral

Mengel³

et al. 2008

Journal of the American Society of Nephrology

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“…As to kidney transplant, various reports have emphasized the capacity of microarray technology to find genes and elucidate molecular pathways that are involved in the progression of renal allograft damage (16)(17)(18)(19)(20)(21). Identification of prognostic factors in the transplantation setting may lead to the development of improved intervention strategies and may contribute to a better understanding of the pathophysiology of CAN.…”

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confidence: 99%

Urinary Expression of Kidney Injury Markers in Renal Transplant Recipients

Szeto

Kwan²,

Lai³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: The outcome of renal transplantation after an episode of acute rejection is difficult to predict, even with an allograft biopsy. We examined whether urinary expression of specific biomarker mRNA could be used as a noninvasive prognostic marker in kidney transplant recipients.Design, setting, participants, & measurements: We studied 63 kidney transplant recipients who require graft biopsy because of progressive worsening of kidney function. The mRNA of neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 (KIM-1), IL-18, surfactant protein-C, and S100 calcium-binding proteins A8 and A9 in urinary sediment were quantified.Results: Urinary expressions of neutrophil gelatinase-associated lipocalin, KIM-1, and IL-18, but not other target genes, were significantly different between histologic groups (P < 0.0001 for all). After followed for an average of 39.7 ؎ 21.1 months, the rate of renal function decline significantly correlated with urinary KIM-1 expression (r ‫؍‬ ؊0.434, P ‫؍‬ 0.0004) but not other target genes. At 48 months, the graft survival rate for the high and low KIM-1 groups were 46.2 and 78.6%, respectively. After adjusting for confounding variables, each log of higher urinary KIM-1 expression conferred an ϳ2.9-fold higher risk of developing graft failure (95% confidence interval, 1.3-to 6.2-fold; P ‫؍‬ 0.006). The result remained similar when only patients with no acute cellular rejection were analyzed.Conclusions: In kidney allograft recipients, urinary KIM-1 expression provides prognostic information in relation to the rate of renal function decline, irrespective of the kidney pathology.

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“…This technique allows for the identification of genes that are expressed cooperatively or are coregulated by a given treatment or stimulus. Microarray analysis has been successfully used to study many aspects of transplantation, including graft rejection (19,20) and early transplant rejection prognosis (21). Recently, several groups have used this approach in an attempt to identify specific markers for CD4 ϩ CD25 ϩ Treg cells.…”

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confidence: 99%

Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival

Lee

Mansfield²,

Hsieh³

et al. 2005

The Journal of Immunology

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Recent studies have demonstrated that both mouse and human αβTCR+CD3+NK1.1−CD4−CD8− double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8+ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 ± 11.1 days) compared with untreated controls (22.8 ± 10.5 days; p < 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q < 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including FcεRIγ subunit and CXCR5, which are >50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival.

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Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies

Abstract: Identified expression patterns seem to be highly prognostic of the development of renal CR.

Cited by 95 publications

References 28 publications

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Tribbles-1 as a Novel Biomarker of Chronic Antibody-Mediated Rejection

Urinary Expression of Kidney Injury Markers in Renal Transplant Recipients

Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival

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