Molecular Profiling of Anemia in Acute Renal Allograft Rejection Using DNA Microarrays

Chua, Mei-Sze; Barry, Christopher T.; Salvatierra, Oscar; Sarwal, Minnie M.

doi:10.1034/j.1600-6143.2003.30104.x

Cited by 42 publications

(29 citation statements)

References 25 publications

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“…It is also important for homeostasis of CD4 ϩ CD25 ϩ /CD4 ϩ CD25 Ϫ FOXP3 ϩ regulatory T cells (43) and TGF-␤-producing Th3 (44) cells that are known to have suppressive activity. The exact mechanisms driving and maintaining spontaneous tolerance in these patients yet remains unclear; however, there are data emerging about the diverse roles of tissue and peripheral TGF-␤ in protective (43) and injurious (45) alloresponses. The finding of increased expression of certain molecular markers of regulatory T cells in TOL patients over CR patients suggests differences in T cell subsets between these two groups.…”

Section: Discussionmentioning

confidence: 99%

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance

Brouard

Mansfield

Braud

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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336

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Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous ''operational tolerance'' with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a ''tolerant footprint'' of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted.kidney transplantation ͉ microarray ͉ tolerant ͉ genomics ͉ immunosuppression titration D espite continuous improvement in renal allograft survival over the last decade, the half-life of renal allografts has increased marginally because of accrual of chronic graft nephropathy from drug-related nephrotoxicity and chronic rejection (1, 2). Patients facing life-long immunosuppression (IS) have increased risk of infection and malignancy (3), whereas insufficient immunosuppressive drug exposure or interruption usually increases rejection risk (4). However, spontaneous and long-term graft acceptance is observed in a small number of patients after solid-organ transplantation (5, 6), years after total withdrawal of immunosuppressive drugs, confirming that a clinical operational state of tolerance to a mismatched graft, described as ''a state of quiescence of the transplanted organ, functioning without a destructive immune response'' (7), can indeed occur and exist in humans. However, the frequency of this observation in the kidney transplant population is unknown and, currently, we cannot identify patients primed to develop this immune adaptation or monitor for the stability of this status of ''operational tolerance.'' The operationally tolerant kidney transpla...

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Section: Discussionmentioning

confidence: 99%

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance

Brouard

Mansfield

Braud

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

336

312

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“…An increased inflammatory response including rejection seems to downregulate genes that are involved in erythropoiesis (29). It has also been shown that in patients who return to hemodialysis after graft failure and who undergo nephrectomy have a lower high-sensitivity C-reactive protein level and lower requirements for rh-EPO with higher hemoglobin levels than in patients who have returned to hemodialysis but did not undergo nephrectomy (30).…”

Section: Causes and Correlatesmentioning

confidence: 99%

Pottransplantation Anemia

Winkelmayer

Chandraker²

2008

Clinical Journal of the American Society of Nephrology

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In recent years, there has been an increasing interest in studying the anemia that occurs after kidney transplantation. Although many of the guidelines for the treatment of kidney transplant patients, including those for anemia, are extrapolated from recommendations for patients with chronic kidney disease, there are important differences in the cause of and response to anemia in kidney transplant recipients. In addition to the correlation of anemia with kidney function as in native renal disease, many other factors are associated with the development of anemia after transplantation, including the use of medications and the inflammation/immune response. Given the lack of large, well-designed, prospective studies, the consequences of anemia, the response to treatment, and the cost-effectiveness of treatment in the posttransplantation setting are also poorly understood.Clin J Am Soc Nephrol 3: S49 -S55, 2008S49 -S55, . doi: 10.2215 A lthough anemia has been investigated with great interest and intensity in patients with chronic kidney disease (CKD), including the dialysis population, studies of the prevalence and clinical relevance of posttransplantation anemia (PTA) were scarce until a few years ago. One could argue that patients with a functioning kidney transplant are similar to patients with chronic native renal insufficiency (not on dialysis) and that evidence from the CKD population could be extrapolated to these kidney transplant recipients (KTR) (1). There are, however, at least three important reasons that such an extrapolation may not be legitimate: The presence of immunosuppressant agents and other transplant-related medications, the altered inflammatory milieu, and the history of prolonged maintenance dialysis therapy in most KTR. The altered inflammatory milieu is due to the systemic immune response to the presence of alloantigen, leading to a proinflammatory state that increases erythropoietin (EPO) resistance. Inadequate dialysis and activation of cytokines by dialysis membranes have also been shown to cause EPO resistance, but whether these factors have long-term consequences that carry over after transplantation are unknown. These and other factors may confound the validity of extrapolating scientific findings and clinical experience from the CKD (not on dialysis) population. Thus, it seems essential to establish evidence directly from the KTR population rather than through inference from patients with CKD. This article provides a critical review of the evidence on PTA. Course of Anemia after TransplantationTwo major developments have influenced the degree of anemia in patients with renal failure at the time of transplantation. The first is the widespread use of EPO for dialysis patients and patients with CKD. This has had the effect of reducing the degree of anemia in potential transplant recipients and decreased the likelihood of immunologic sensitization in patients as a result of the decreased need for blood transfusions before transplantation. Although decreasing the number of blood transfus...

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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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Molecular Profiling of Anemia in Acute Renal Allograft Rejection Using DNA Microarrays

Cited by 42 publications

References 25 publications

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance

Pottransplantation Anemia

Urinary Expression of Kidney Injury Markers in Renal Transplant Recipients

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