Activation of counter-regulatory mechanisms in a rat renal acute rejection model

Edemir, Bayram; Kurian, Sunil M.; Eisenacher, Martin; Lang, Detlef; Müller‐Tidow, Carsten; Gabriëls, Gert; Salomon, Daniel R.; Schlatter, Eberhard

doi:10.1186/1471-2164-9-71

Cited by 26 publications

(23 citation statements)

References 61 publications

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“…Second, we found that IFϩi was associated with upregulation of immune/ inflammatory pathways linked with acute cellular rejection. [17][18][19][20][21][22][23] The results lend credence to the view that early surveillance histology with or without targeted molecular analysis provides important prognostic information. 10,24 They also suggest that analysis of intragraft innate and adaptive immune pathways during early posttransplantation years 25 may provide the basis for interventions to subvert chronic deterioration in a subset of recipients with clinical expectations of excellent long-term outcome.…”

supporting

confidence: 54%

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Park

Griffin

Cornell³

et al. 2010

Journal of the American Society of Nephrology

198

168

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Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation. We studied 151 living-donor, tacrolimus/mycophenolate-treated recipients without overt risk factors for reduced graft survival. Transplants with normal histology (n ϭ 86) or fibrosis alone (n ϭ 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n ϭ 20) exhibited a decline in GFR and reduced graft survival. Immunohistochemistry confirmed increased interstitial T cells and macrophages/dendritic cells in the group with both fibrosis and inflammation, and there was increased expression of transcripts related to innate and cognate immunity. Pathway-and pathologic process-specific analyses of microarray profiles revealed that potentially damaging immunologic activities were enriched among the overexpressed transcripts (e.g., Toll-like receptor signaling, antigen presentation/dendritic cell maturation, IFN-␥-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes). Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes. Early interventions aimed at altering rejection-like inflammation may improve long-term survival of kidney allografts.

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supporting

confidence: 54%

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Park

Griffin

Cornell³

et al. 2010

Journal of the American Society of Nephrology

198

168

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“…The observance of high MMP-7 expression in the kidney at the time of AR has also been previously reported in chronic kidney rejection, 27 human kidney aging, 28 and a rat renal AR model. 29 MMP-7 is a collagenase-related connective-tissue-degrading metalloproteinase and plays a role in the breakdown of extracellular matrix in normal physiologic processes, tissue remodeling during injury, 30 and neutrophil influx to sites of injury. 31 SERPRING1 regulates leukocyte trafficking and complement (inactivating C1r, C1s, MASP2, and C3b proteases), 32 which is also locally regulated in the kidney during ischemia reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

Integrative Urinary Peptidomics in Renal Transplantation Identifies Biomarkers for Acute Rejection

Ling

Sigdel²,

Lau³

et al. 2010

Journal of the American Society of Nephrology

123

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Noninvasive methods to diagnose rejection of renal allografts are unavailable. Mass spectrometry followed by multiple-reaction monitoring provides a unique approach to identify disease-specific urine peptide biomarkers. Here, we performed urine peptidomic analysis of 70 unique samples from 50 renal transplant patients and 20 controls (n ϭ 20), identifying a specific panel of 40 peptides for acute rejection (AR). Peptide sequencing revealed suggestive mechanisms of graft injury with roles for proteolytic degradation of uromodulin (UMOD) and several collagens, including COL1A2 and COL3A1. The 40-peptide panel discriminated AR in training (n ϭ 46) and test (n ϭ 24) sets (area under ROC curve Ͼ0.96). Integrative analysis of transcriptional signals from paired renal transplant biopsies, matched with the urine samples, revealed coordinated transcriptional changes for the corresponding genes in addition to dysregulation of extracellular matrix proteins in AR (MMP-7, SERPING1, and TIMP1). Quantitative PCR on an independent set of 34 transplant biopsies with and without AR validated coordinated changes in expression for the corresponding genes in rejection tissue. A six-gene biomarker panel (COL1A2, COL3A1, UMOD, MMP-7, SERPING1, TIMP1) classified AR with high specificity and sensitivity (area under ROC curve ϭ 0.98). These data suggest that changes in collagen remodeling characterize AR and that detection of the corresponding proteolytic degradation products in urine provides a noninvasive diagnostic approach.

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“…Analysis of the graft leukocyte pattern revealed massive upregulation of nearly all genes of pro-and antiinflammatory cell types analyzed on aTX postoperative day 4 ( (17,18,28,29). Upregulation of these genes (exception: neutrophil granulocytes: CD66, 3.1 6 0.3, P , 0.05) was not detected on aTX postoperative day 1 (meaning that significant graft infiltration had not yet started at that time).…”

Section: Real-time Pcr Analysismentioning

confidence: 99%

Potential of Noninvasive Serial Assessment of Acute Renal Allograft Rejection by ¹⁸F-FDG PET to Monitor Treatment Efficiency

Reuter

Schnöckel²,

Edemir³

et al. 2010

J Nucl Med

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We propose 18 F-FDG PET as a method to monitor acute rejection of allogeneic renal transplants in a rat model. Methods: Allogeneically transplanted (aTX) rats (binephrectomized Lewisbrown Norway to Lewis) served as the renal transplant model. aTX rats treated with cyclosporine A (CSA) served as a therapy monitoring group. Healthy control rats, rats with acute CSA nephrotoxicity, rats with acute tubular necrosis, syngeneically transplanted (sTX) rats, and aTX rats treated with CSA since postoperative day 0 served as controls. After surgery, renal glucose metabolism was assessed in vivo serially up to postoperative day 7 by performing small-animal PET 3 h after intravenous injection of 30 MBq of 18 F-FDG. Mean radioactivity (cps/mm 3 of tissue) was measured and the percentage injected dose calculated. Results were confirmed by histologic, functional, and autoradiographic analysis. Results: Renal 18 F-FDG uptake was significantly elevated at postoperative day 4 in aTX rats, when compared with control, sTX, acute tubular necrosis, or CSA-treated rats (P , 0.05). In vivo 18 F-FDG uptake correlated with the results of autoradiography and with inflammatory infiltrates observed on histologic examination. Notably, 18 F-FDG PET assessed the response to therapy 48 h earlier than the time at which serum creatinine decreased and when histologic examination still showed signs of allograft rejection. In aTX rats, the CSA-susceptible graft infiltrate was dominated by activated cytotoxic T cells and monocytes/macrophages. Conclusion: 18 F-FDG PET is an option to noninvasively assess early response to therapy in rat renal allograft rejection.

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Activation of counter-regulatory mechanisms in a rat renal acute rejection model

Cited by 26 publications

References 61 publications

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Integrative Urinary Peptidomics in Renal Transplantation Identifies Biomarkers for Acute Rejection

Potential of Noninvasive Serial Assessment of Acute Renal Allograft Rejection by ¹⁸F-FDG PET to Monitor Treatment Efficiency

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Activation of counter-regulatory mechanisms in a rat renal acute rejection model

Cited by 26 publications

References 61 publications

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Integrative Urinary Peptidomics in Renal Transplantation Identifies Biomarkers for Acute Rejection

Potential of Noninvasive Serial Assessment of Acute Renal Allograft Rejection by 18F-FDG PET to Monitor Treatment Efficiency

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Potential of Noninvasive Serial Assessment of Acute Renal Allograft Rejection by ¹⁸F-FDG PET to Monitor Treatment Efficiency