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      Non-invasive quantification of collagen turnover in renal transplant recipients

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          Abstract

          Kidney allograft failure due to chronic injury/rejection remains the main cause of graft loss in renal transplant recipients (RTR). Here, we investigated whether specific biomarkers of extracellular matrix (ECM) turnover are associated with allograft function and chronic kidney disease (CKD) stage in RTR. Seventy-eight patients who attended the University Medical Center Groningen for a routine check-up after kidney transplantation were enrolled in the study. Plasma and/or 24h-urine samples were collected and specific matrix-metalloproteinase-generated neo-epitope fragments of collagens were measured by enzyme-linked immunosorbent assay. Our results demonstrated that urinary levels of C3M, a marker for collagen type III degradation, correlated with estimated glomerular filtration rate (eGFR; r = 0.58, p<0.0001), with lower levels detected in the urine of patients with advanced CKD. In addition, plasma levels of Pro-C6, a marker for collagen type VI formation, significantly increased with disease progression and correlated with eGFR (r = -0.72, p<0.0001). Conversely, plasma C3M and urinary Pro-C6 levels showed no correlation with renal function. We identified two neo-epitope biomarkers of tissue turnover associated with ECM remodeling and fibrosis that can stratify patients by CKD stage. This is as promising first step towards non-invasive monitoring of ECM turnover in the kidneys.

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          Most cited references36

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          Renal interstitial fibrosis: mechanisms and evaluation.

          Tubulointerstitial injury in the kidney is complex, involving a number of independent and overlapping cellular and molecular pathways, with renal interstitial fibrosis and tubular atrophy (IFTA) as the final common pathway. Furthermore, there are multiple ways to assess IFTA. Cells involved include tubular epithelial cells, fibroblasts, fibrocytes, myofibroblasts, monocyte/macrophages, and mast cells with complex and still incompletely characterized cell-molecular interactions. Molecular mediators involved are numerous and involve pathways such as transforming growth factor (TGF)-β, bone morphogenic protein (BMP), platelet-derived growth factor (PDGF), and hepatocyte growth factor (HGF). Recent genomic approaches have shed insight into some of these cellular and molecular pathways. Pathologic evaluation of IFTA is central in assessing the severity of chronic disease; however, there are a variety of methods used to assess IFTA. Most assessment of IFTA relies on pathologist assessment of special stains such as trichrome, Sirius Red, and collagen III immunohistochemistry. Visual pathologist assessment can be prone to intra and interobserver variability, but some methods employ computerized morphometery, without a clear consensus as to the best method. IFTA results from on orchestration of cell types and molecular pathways. Opinions vary on the optimal qualitative and quantitative assessment of IFTA.
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            The collagen VI-related myopathies: muscle meets its matrix.

            The collagen VI-related myopathy known as Ullrich congenital muscular dystrophy is an early-onset disease that combines substantial muscle weakness with striking joint laxity and progressive contractures. Patients might learn to walk in early childhood; however, this ability is subsequently lost, concomitant with the development of frequent nocturnal respiratory failure. Patients with intermediate phenotypes of collagen VI-related myopathy display a lesser degree of weakness and a longer period of ambulation than do individuals with Ullrich congenital muscular dystrophy, and the spectrum of disease finally encompasses mild Bethlem myopathy, in which ambulation persists into adulthood. Dominant and recessive autosomal mutations in the three major collagen VI genes-COL6A1, COL6A2, and COL6A3-can underlie this entire clinical spectrum, and result in deficient or dysfunctional microfibrillar collagen VI in the extracellular matrix of muscle and other connective tissues, such as skin and tendons. The potential effects on muscle include progressive dystrophic changes, fibrosis and evidence for increased apoptosis, which potentially open avenues for pharmacological intervention. Optimized respiratory management, including noninvasive nocturnal ventilation together with careful orthopedic management, are the current mainstays of treatment and have already led to a considerable improvement in life expectancy for children with Ullrich congenital muscular dystrophy.
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              Role of matrix metalloproteinases in renal pathophysiologies.

              Matrix metalloproteinases (MMPs) are a large family of proteinases that remodel extracellular matrix (ECM) components and cleave a number of cell surface proteins. MMP activity is regulated via a number of mechanisms, including inhibition by tissue inhibitors of metalloproteinases (TIMPs). Originally thought to cleave only ECM proteins, MMP substrates are now known to include signaling molecules (growth factor receptors) and cell adhesion molecules. Recent data suggest a role for MMPs in a number of renal pathophysiologies, both acute and chronic. This review will focus on the expression and localization of MMPs and TIMPs in the kidney, as well as summarizing the current information linking these proteins to acute kidney injury, glomerulosclerosis/tubulointerstitial fibrosis, chronic allograft nephropathy, diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 April 2017
                2017
                : 12
                : 4
                : e0175898
                Affiliations
                [1 ]Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands
                [2 ]Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                [3 ]Nordic Bioscience A/S, Herlev, Denmark
                [4 ]Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark
                [5 ]Department of Pathology and Medical Biology, Division of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
                University of Campinas, BRAZIL
                Author notes

                Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SHN, FG and MAK are full-time employees at Nordic Bioscience. All other authors have no competing financial interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: EGDS PO HAMM.

                • Formal analysis: EGDS SHN HAMM.

                • Funding acquisition: MAK PO FG.

                • Investigation: EGDS SHN HAMM.

                • Methodology: EGDS SHN PO HAMM.

                • Resources: EGDS SHN SB MAS HVG SJLB FG.

                • Supervision: SB MAK PO HAMM FG.

                • Writing – original draft: EGDS SHN HAMM.

                • Writing – review & editing: EGDS SHN SB MAK MAS HVG SJLB PO FG.

                ‡ These authors are shared first authors on this work.

                Article
                PONE-D-16-39407
                10.1371/journal.pone.0175898
                5400243
                28430784
                c29aa58a-58f7-4a07-b4f4-eebd13a8c4d0
                © 2017 Stribos et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 October 2016
                : 2 April 2017
                Page count
                Figures: 3, Tables: 2, Pages: 11
                Funding
                Funded by: Danish Research Fund (Den Danske Forskningsfond)
                Funded by: funder-id http://dx.doi.org/10.13039/501100001826, ZonMw;
                Award ID: 114021010
                Award Recipient :
                This work was supported by the Danish Research Fund (Den Danske Forskningsfond) and the Netherlands Organization for Health Research and Development (ZonMw; grant number 114021010, PO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Proteins
                Collagens
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Urine
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Urine
                Biology and Life Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Urine
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Transplantation
                Organ Transplantation
                Renal Transplantation
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Urinary System Procedures
                Renal Transplantation
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Creatinine
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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