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      Evaluation of the Diagnostic Potential of uPAR as a Biomarker in Renal Biopsies of Patients with FSGS

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          Abstract

          Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are primary glomerulopathies leading to proteinuria, known as podocytopathies, which share syndromic and morphological similarities. Morphological similarity occurs in cases of FSGS in which the sclerotic lesion was not sampled in renal biopsy, due to the focal nature of the disease. Differentiating these entities is very important, especially in cases of suspected FSGS but with sclerotic lesion not sampled, as they are diseases that apparently have different pathogenic mechanisms and prognosis. The difference in uPAR expression in situ among these two entities may be related to a distinct molecular mechanism involved in pathogenesis. Thus, finding biomarkers involved in the pathogenesis and that can also help in differential diagnosis is very relevant. The aim of this work was to evaluate the potential of urokinase-type plasminogen activator receptor (uPAR) as a biomarker in renal biopsies of patients with podocytopathies ( n = 38). Immunohistochemistry showed that FSGS ( n = 22) had increased uPAR expression in podocytes compared with both the MCD group ( n = 16; p = 0.0368) and control group ( n = 21; p = 0.0076). ROC curve ( p = 0.008) showed that this biomarker has 80.95% of specificity in biopsies of patients with FSGS. Therefore, uPAR presented a high specificity in cases of podocytopathies associated with sclerosis and it can be considered a potential biomarker for FSGS.

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          Regulation of cell signalling by uPAR.

          Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process.
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            Focal Segmental Glomerulosclerosis.

            Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.
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              Minimal Change Disease.

              Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
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                Author and article information

                Contributors
                Journal
                Dis Markers
                Dis. Markers
                DM
                Disease Markers
                Hindawi
                0278-0240
                1875-8630
                2019
                2 May 2019
                : 2019
                : 1070495
                Affiliations
                1Discipline of General Pathology, Institute of Biological and Natural Sciences of Federal University of Triângulo Mineiro, Praça Manoel Terra, 330, Nossa Senhora da Abadia, 38025-015 Uberaba, Minas Gerais, Brazil
                2Discipline of Parasitology, Institute of Biological and Natural Sciences of Federal University of Triângulo Mineiro, Av. Getúlio Guaritá, No. 130, Nossa Senhora da Abadia, 38025-440 Uberaba, Minas Gerais, Brazil
                3Human Immunology Research and Education Group, Technical School of Health of Federal University of Paraíba, Cidade Universitária, 58059-900 João Pessoa, Paraíba, Brazil
                Author notes

                Guest Editor: Yuri Battaglia

                Author information
                http://orcid.org/0000-0002-0615-1446
                http://orcid.org/0000-0002-0762-4014
                http://orcid.org/0000-0002-7961-6996
                http://orcid.org/0000-0001-5518-5231
                http://orcid.org/0000-0002-2966-7621
                http://orcid.org/0000-0003-0851-5298
                http://orcid.org/0000-0003-2523-2097
                http://orcid.org/0000-0002-0471-1454
                Article
                10.1155/2019/1070495
                6525920
                31191741
                0697631a-c096-4885-b797-99029d9a35a5
                Copyright © 2019 Crislaine Aparecida da Silva et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 7 December 2018
                : 12 February 2019
                : 5 March 2019
                Funding
                Funded by: Fundação de Ensino e Pesquisa de Uberaba
                Funded by: Fundação de Amparo à Pesquisa do Estado de Minas Gerais
                Funded by: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico
                Categories
                Research Article

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