Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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The clinical and genomic significance of donor-specific antibody (DSA) positive/C4d negative and DSA negative/C4d negative transplant glomerulopathy

ABSTRACT: We investigated the clinical, histopathologic and genomic features of donor-specific antibody (DSA) +/C4d- and DSA-/C4d- transplant glomerulopathy (TGP) using microarrays. Comparison of the gene expression profiles of DSA-/C4d- TGP biopsies with ptc+g score > 1 to normal and IFTA (Interstitial Fibrosis and Tubular Atrophy) biopsies by microarrays revealed increased expression of quantitative cytotoxic T cell--associated transcripts (QCAT). However, CAMR (chronic antibody-mediated rejection) and DSA+/C4d- TGP had increased expression of QCAT, interferon-gamma and rejection induced, constitutive macrophage-associated, natural killer cell-associated, and DSA selective transcripts. B cell and endothelial cell associated transcripts expression were upregulated only in CAMR biopsies. Our results suggest that while DSA+/C4d- TGP should be classified under CAMR, DSA-/C4d- TGP with ptc+g score > 1 probably develops through a chronic cellular immune response. Total of 57 arrays included in this study. G1. Normal transplant kidney biopsies (N= 12); G2. Non-specific IFTA (N= 17); G3. TGP DSA-/C4d- (N=8); G4. TGP DSA+/C4d- (N= 9); G5. CAMR/TGP C4d+/DSA+ (N= 11)

ORGANISM(S): Homo sapiens

SUBMITTER: Bin Ye

PROVIDER: E-GEOD-44131 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy.

Hayde Nicole N Bao Yi Y Pullman James J Ye Bin B Calder R Brent RB Chung Monica M Schwartz Daniel D Lubetzky Michelle M Ajaimy Maria M de Boccardo Graciela G Akalin Enver E

Clinical journal of the American Society of Nephrology : CJASN 20130912 12

<h4>Background</h4>This study investigated the mechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays.<h4>Design, setting, participants, & measurements</h4>This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified accord ...[more]

PMID: 24030736

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Project description:We study the global gene expression profiles of TGP patients with or without graft loss to determine if a clinical and/or gene expression profile can predict allograft survival. Transplant glomerulopathy (TGP) carries a poor prognosis and is associated with decreased allograft survival. In a large series of kidney transplant recipients, graft loss was observed in 38% of TGP patients at 5 years compared to 5% in patients without TGP. Among patients with TGP, predictors of poor outcome included C4d deposition in the peritubular capillaries, higher serum creatinine and proteinuria at diagnosis, the severity of interstitial fibrosis, and GBM duplication (higher Banff M-bM-^@M-^Xchronic glomerulopathy [cg]M-bM-^@M-^Y score), and the presence of DSA. However, the importance of microvascular inflammation determined by peritubular capillaritis (ptc) and glomerulitis (g) scores and the strength of DSA has not been explored thoroughly. We have recently reported the intragraft gene expression profiles of TGP patients, with or without DSA. However, the association between gene expression profiles of biopsies and the allograft survival has not been investigated. In this study, in addition to known clinical and demographic factors associated with poor outcomes in TGP, we specifically aimed to investigate if intragraft gene expression profiles by microarrays, microvascular inflammation scores, and the strength of DSA determined by mean fluorescence intensity (MFI) values could predict allograft loss in TGP patients. The study population was derived from renal allograft biopsies diagnosed with TGP at Montefiore Medical Center, Bronx, NY from January 2009 to December 2012. All biopsies were clinically indicated for elevated creatinine or proteinuria. A retrospective chart review was conducted to record clinical, demographic, immunological, and histopathological parameters and graft outcomes. Graft loss was defined as requiring dialysis and/or retransplantation during follow-up. Of the 525 patients who underwent clinically indicated transplant kidney biopsies, 52 patients (10%) had diagnosis of TGP. Median follow up time after the biopsy was 23 months (range, 1-46). Seventeen patients (32%) lost their allografts (defined by return to dialysis or re-transplantation) at a median time of 16 months (range, 1-44). A subgroup of patients who were enrolled in the IRB-approved M-bM-^@M-^\Immune Monitoring StudyM-bM-^@M-^] and had clinically indicated biopsy samples were included in the analysis. A total of 28 biopsy samples (8 graft loss and 20 functioning allograft) were used for gene expression profiling.

Project description:The presence of Donor-Specific anti-HLA Antibodies (DSA) is associated with an increased risk of both acute and chronic antibody-mediated rejection (AMR) in kidney allografts. AMR has remained challenging in kidney transplantation and is the major cause of late allograft loss. However, not all patients with DSA develop AMR, leading to the question of whether this represents accommodation, if other protective mechanisms exist or if this is actually a state of pre-rejection. Clinical and histological features, and gene expression profiles of kidney biopsy and blood samples of donor-specific antibody (DSA)+ patients without rejection were compared to antibody-mediated rejection (AMR) patients to elucidate the mechanisms involved in prevention of AMR. Of the 71 DSA+ patients, 46 had diagnosis of AMR and 25 did not show rejection. 50 DSA- patients without rejection were used as control. A subgroup of patients with available biopsy (n=61) and blood samples (n=54) were analyzed by microarrays. Both, DSA+/AMR+ and DSA+/AMR- biopsies showed increased expression of gene transcripts associated with cytotoxic T, natural killer cells, macrophages, interferon-gamma and rejection compared to DSA- biopsies. Regulatory T cell transcripts were up-regulated in DSA+/AMR+ and B cell transcripts in DSA+/AMR- biopsies. Whole blood gene expression analysis showed increased immune activity in only DSA+/AMR+ patients. There were no differentially expressed tolerant genes studied (n=14) in the blood or biopsy specimens of DSA+/AMR- patients. During a median 36 months follow-up, 4 DSA+/AMR- patients developed AMR, 12 continued to have DSAs but 9 lost DSAs. Gene expression profiles did not predict the development of AMR or persistence of DSAs. These results indicate increased immune activity in DSA+/AMR- biopsies despite lack of histologic findings of rejection. All clinically indicated kidney transplant biopsies performed at our institution after January 2009 were reviewed and 263 patients with anti-HLA antibody testing at the time of biopsy were identified. There were 71 DSA+ and 192 DSA- patients (Figure 1). Of the 71 DSA+ patients, 46 had biopsy diagnosis of acute AMR (n=9) or chronic AMR (n=37), and 25 had normal histopathology or minimal non-specific interstitial fibrosis/tubular atrophy (IFTA). Of the 192 DSA- patients, 50 patients with normal histology and/or mild non-specific IFTA were used as a control group. Clinical and histopathological findings of these 3 groups (DSA+/AMR+, DSA+/AMR- and DSA-) were analyzed. A subgroup of patients who were enrolled in the Institutional Review Board-approved âImmune Monitoring Studyâ who had clinically indicated biopsy (n=61) and whole blood samples (n=54) stored were used for genomic analysis. Twenty-eight biopsy and blood samples from DSA+/AMR+ patients, 13 biopsy and 14 blood samples from DSA+/AMR- patients, and 20 biopsy and 12 blood samples from DSA- patients, were available for microarray analysis.

Dataset Information

The clinical and genomic significance of donor-specific antibody (DSA) positive/C4d negative and DSA negative/C4d negative transplant glomerulopathy

Publications

The clinical and genomic significance of donor-specific antibody-positive/C4d-negative and donor-specific antibody-negative/C4d-negative transplant glomerulopathy.

Similar Datasets

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