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      Association of Glomerular Complement C4c Deposition With the Progression of Diabetic Kidney Disease in Patients With Type 2 Diabetes

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          Abstract

          Objectives: As accumulating data supporting the potential role of the complement system in the pathogenesis of diabetic kidney disease (DKD), the present study aimed to explore the association of glomerular complement C4c deposition with the baseline clinicopathological characteristics and the prognosis of DKD in type 2 diabetes (T2DM) patients.

          Methods: A total of 79 T2DM patients with biopsy-proven DKD were enrolled. Clinicopathological features and renal outcomes were compared between groups divided by the glomerular C4c deposition patterns and median values of serum C4. Renal outcomes were defined by doubling of serum creatinine level or progression to end-stage renal disease (ESRD). A Cox proportional hazards model was employed to identify the risk factors associated with renal events.

          Results: Patients with glomerular C4c deposition had worse renal insufficiency than those without C4c deposits, along with higher 24-h urinary protein, triglyceride, but lower serum albumin and higher interstitial inflammation score. Besides, serum C4 levels positively correlated with urinary protein and serum C3 levels. During 21.85 ± 16.32 months of follow-up, Kaplan-Meier curve analysis showed significantly faster deterioration of renal function for patients with positive glomerular C4c deposition as well as higher levels of serum C4. More specifically, more than 50% of the patients with glomerular C4c had co-deposition of C3c or C1q, and patients with glomerular complement complex of C4c and one or two of C3/C1q deposition had more severe proteinuria and a higher rate of DKD progression than those with negative C4c deposits. The univariate Cox regression indicated that factors of combined serum and glomerular C4, urinary protein, serum creatinine, serum C3, combined glomerular C4c and IgM and interstitial inflammation were associated with an increased risk of DKD, but only glomerular C4c intensity (HR 1.584, 95% CI [1.001, 2.508], p = 0.0497), as well as baseline age and diabetic neuropathy, were independent risk factors for renal survival by the multivariate Cox analysis.

          Conclusions: Glomerular C4c deposition was associated with deteriorated renal function and outcomes in patients with T2DKD. Glomerular C4c deposition was an independent risk factor for DKD progression.

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          Most cited references 29

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          Pathologic classification of diabetic nephropathy.

          Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.
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            The role of complement in inflammatory diseases from behind the scenes into the spotlight.

            Our understanding of the biology of the complement system has undergone a drastic metamorphosis since its original discovery. This system, which was traditionally primarily described as a "complement" to humoral immunity, is now perceived as a central constituent of innate immunity, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement is an assembly of proteins found in the blood and body fluids and on cell surfaces. Soluble complement components form the proteolytic cascade, whose activation leads to the generation of complement effectors that target various cells involved in the immune response. Membrane-bound receptors and regulators transmit signals from complement effectors to target cells and limit complement activation to the surfaces of pathogens and damaged or activated host cells. The multiple interconnections among complement proteins, immune cells, and mediators provide an excellent mechanism to protect the organism against infections and support the repair of damaged tissues. However, disturbances in this "defense machinery" contribute to the pathogenesis of various diseases. The role of complement in various inflammatory disorders is multifaceted; for example, the activation of complement can significantly contribute to inflammation-mediated tissue damage, whereas inherited or acquired complement deficiencies highly favor the development of autoimmunity.
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              Transcriptome Analysis of Human Diabetic Kidney Disease

              OBJECTIVE Diabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney biopsy samples. RESEARCH DESIGN AND METHODS Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. DKD samples were significant for their racial diversity and decreased glomerular filtration rate (~25–35 mL/min). Stringent statistical analysis, using the Benjamini-Hochberg corrected two-tailed t test, was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. Two different web-based algorithms were used to define differentially regulated pathways. RESULTS We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli, and 330 probesets were commonly differentially expressed in both compartments. Pathway analysis highlighted the regulation of Ras homolog gene family member A, Cdc42, integrin, integrin-linked kinase, and vascular endothelial growth factor signaling in DKD glomeruli. The tubulointerstitial compartment showed strong enrichment for inflammation-related pathways. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in a different set of DKD samples. CONCLUSIONS Our studies have cataloged gene-expression regulation and identified multiple novel genes and pathways that may play a role in the pathogenesis of DKD or could serve as biomarkers.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                02 September 2020
                2020
                : 11
                Affiliations
                Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University , Nanjing, China
                Author notes

                Edited by: Junji Xing, Houston Methodist Research Institute, United States

                Reviewed by: Yong Du, Hospital for Special Surgery, United States; Jun Wada, Okayama University, Japan

                *Correspondence: Changying Xing cyxing62@ 123456126.com

                This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work and share senior authorship

                ‡These authors share first authorship

                Article
                10.3389/fimmu.2020.02073
                7492595
                Copyright © 2020 Duan, Sun, Nie, Chen, Zhang, Zhu, Huang, Qian, Zhao, Xing, Zhang and Yuan.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 4, Tables: 7, Equations: 0, References: 36, Pages: 13, Words: 8070
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81300573
                Award ID: 81670628
                Award ID: 81870469
                Funded by: Natural Science Foundation of Jiangsu Province 10.13039/501100004608
                Award ID: BK20131030
                Award ID: BK20191075
                Funded by: China Scholarship Council 10.13039/501100004543
                Award ID: 201608320124
                Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions 10.13039/501100012246
                Categories
                Immunology
                Original Research

                Immunology

                renal pathology, complement, c4, progression, diabetic kidney disease

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