Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Department of Surgery, Division of Transplantation Surgery, Mayo Clinic, Rochester, Minnesota, USA.
Journal of the American Society of Nephrology (Impact Factor: 9.34). 11/2010; 21(11):1987-97. DOI: 10.1681/ASN.2010010049
Source: PubMed


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 = 86) or fibrosis alone (n = 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n = 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-γ-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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    • "Studies have shown that infiltrating inflammatory cells are detected in IF/TA and contribute to long-term renal allograft failure [58,59]. For example, infiltrating monocytes/macrophages and their related chemokines/cytokines influence the long-term survival of renal allografts [60,61]. "
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    ABSTRACT: Although kidney transplantation has been an important means for the treatment of patients with end stage of renal disease, the long-term survival rate of the renal allograft remains a challenge. The cause of late renal allograft loss, once known as chronic allograft nephropathy, has been renamed "interstitial fibrosis and tubular atrophy" (IF/TA) to reflect the histologic pattern seen on biopsy. The mechanisms leading to IF/TA in the transplanted kidney include inflammation, activation of renal fibroblasts, and deposition of extracellular matrix proteins. Identifying the mediators and factors that trigger IF/TA may be useful in early diagnosis and development of novel therapeutic strategies for improving long-term renal allograft survival and patient outcomes. In this review, we highlight the recent advances in our understanding of IF/TA from three aspects: pathogenesis, diagnosis, and treatment.
    Fibrogenesis & Tissue Repair 10/2014; 7(1):15. DOI:10.1186/1755-1536-7-15
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    • "Another study looked at gene expression in CAN/IFTA biopsies describing “pathogenesis-based transcript sets” for injured/diseased tissue [16]. Profiling of 150 kidney transplant biopsies to study the impact of inflammation with fibrosis, showed that Toll-like receptor signaling, antigen presentation/dendritic cell maturation, IFN-gamma-inducible response and cytotoxic T lymphocyte-associated changes were associated with inflammatory changes [4]. "
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    ABSTRACT: Background: Chronic Allograft Nephropathy (CAN) is a clinical entity of progressive kidney transplant injury. The defining histology is tubular atrophy with interstitial fibrosis (IFTA). Using a meta-analysis of microarrays from 84 kidney transplant biopsies, we revealed growth factor and integrin adhesion molecule pathways differentially expressed and correlated with histological progression. A bioinformatics approach mining independent datasets leverages new and existing data to identify correlative changes in integrin and growth factor signaling pathways. Results: Analysis of CAN/IFTA Banff grades showed that hepatocyte growth factor (HGF), and epidermal growth factor (EGF) pathways are significantly differentially expressed in all classes of CAN/IFTA. MAPK-dependent pathways were also significant. However, the TGFβ pathways, albeit present, failed to differentiate CAN/IFTA progression. The integrin subunits β8, αv, αμ and β5 are differentially expressed, but β1, β6 and α6 specifically correlate with progression of chronic injury. Results were validated using our published proteomic profiling of CAN/IFTA. Conclusions: CAN/IFTA with chronic kidney injury is characterized by expression of distinct growth factors and specific integrin adhesion molecules as well as their canonical signaling pathways. Drug target mapping suggests several novel candidates for the next generation of therapeutics to prevent or treat progressive transplant dysfunction with interstitial fibrosis.
    BMC Genomics 04/2013; 14(1):275. DOI:10.1186/1471-2164-14-275 · 3.99 Impact Factor
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    • "Protocol biopsies obtained in the first years after transplantation have shown interstitial fibrosis/tubular atrophy (IF/TA). This finding has been correlated with later allograft dysfunction and loss (Nankivell et al., 2003; Park et al., 2010). Both allogen dependent and independent factors determine IF/TA. "
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    ABSTRACT: Ischemia/reperfusion (I/R) injury is an inevitable consequence of organ transplantation and a major determinant of patient and graft survival in kidney transplantation. Renal I/R injury can lead to fibrosis and graft failure. Although the exact sequence of events in the pathophysiology of I/R injury remains unknown, the role of inflammation has become increasingly clear. In this perspective, mesenchymal stromal cells (MSCs) are under extensive investigation as potential therapy for I/R injury, since MSCs are able to exert immune regulatory and reparative effects. Various preclinical studies indicate the beneficial effects of MSCs in ameliorating renal injury and accelerating tissue repair. These versatile cells have been shown to migrate to sites of injury and to enhance repair by paracrine mechanisms instead of by differentiating and replacing the injured cells. The first phase I studies of MSCs in human renal I/R injury and kidney transplantation have been started, and results are awaited soon. In this review, preliminary results and opportunities of MSCs in human renal I/R injury are summarized. We might be heading towards a cell-based paradigm shift in the treatment of renal I/R injury.
    Frontiers in Immunology 07/2012; 3:162. DOI:10.3389/fimmu.2012.00162
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