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1
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Gleeson PJ, Monteiro RC. The Role of Mucosal Immunity: What Can We Learn From Animal and Human Studies? Semin Nephrol 2024; 44:151566. [PMID: 40082160 DOI: 10.1016/j.semnephrol.2025.151566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025]
Abstract
Immunoglobulin A (IgA) is a key actor in the mucosal immune system, which moderates interactions between the host and environmental factors such as food antigens and commensal microorganisms. The pathogenesis of IgA nephropathy (IgAN) involves a multistep process starting with deglycosylation of mucosally derived, polymeric IgA1 (dg-IgA1) that reaches the circulation. Modified O-glycans on dg-IgA1 are targeted by IgG-autoantibodies, leading to the formation of circulating immune complexes that deposit in the glomerular mesangium. Infections of mucosal surfaces trigger flares of primary IgAN, while inflammatory bowel disease and liver cirrhosis are important causes of secondary IgAN, supporting a mucosal source of nephritogenic IgA1. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T-cell-dependent or T-cell-independent B-cell differentiation into IgA-secreting plasma cells. Herein we review the literature concerning mucosal immune function and how it is altered in this disease. We discuss recent evidence supporting a causal role of gut microbiota dysbiosis in IgAN pathogenesis.
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Affiliation(s)
- Patrick J Gleeson
- Paris Cité University, Center for Research on Inflammation, Paris, France; Inserm, UMR1149; CNRS EMR8252; Inflamex Laboratory of Excellence; Nephrology Department.
| | - Renato C Monteiro
- Paris Cité University, Center for Research on Inflammation, Paris, France; Inserm, UMR1149; CNRS EMR8252; Inflamex Laboratory of Excellence; Immunology laboratory of Bichat hospital, Paris, France
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2
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Ronsin C, Braud P, Kandel-Aznar C, Dujardin A, Petit C, Larmet D, Garandeau C, Deltombe C, Le Clech A, Leman C, Blancho G, Schurder J, Couvrat-Desvergnes G, Ville S. Clinical Presentation, Pathological Spectrum, and Outcomes of Alcoholic Cirrhosis-Related Immunoglobulin A Nephropathy. Kidney Int Rep 2024; 9:1369-1378. [PMID: 38707818 PMCID: PMC11069013 DOI: 10.1016/j.ekir.2024.02.1397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Immunoglobulin A nephropathy (IgAN) associated with cirrhosis is frequent but often overlooked because it is largely considered silent. Until now, little has been known about their presentation and outcomes. Methods We conducted a retrospective multicenter study on patients with kidney biopsy-proven cirrhosis-related IgAN (cirrhosis-IgAN), diagnosed between 2009 and 2022. We mixed them up with 83 primary IgAN (pIgAN) diagnosed during the same period, using a partitioning clustering approach, to determine common clinicopathological profiles. Results All the 46 patients with cirrhosis-IgAN had an excessive alcoholic consumption. Clinical presentation was severe with acute kidney injury (AKI) in 79%; alternative causes of AKI was found in 62% of cases. Three clinicopathological clusters were identified as follows: the first one represented chronic involvement, the second one could be assimilated to mild disease, and the third one corresponded to a membranoproliferative glomerulonephritis (MPGN) pattern and was associated with heavy proteinuria and intrinsic AKI (without alternative causes). Whereas the first 2 clusters were equally distributed between pIgAN and cirrhosis-IgAN, the third was more frequent in patients with cirrhosis. The cumulative mortality rate in cirrhosis-IgAN was 26% and 46% at 1-year and 3-years, respectively. Steroid exposure and moderate or severe AKI were associated with higher mortality and steroid exposure was associated with the occurrence of severe infection. Conclusion Our results suggest that high AKI incidence is related to extrinsic causes in most cases but can also be driven by IgA-dominant MPGN in a subset of patients. Steroid use was associated with infectious disease and mortality. Further studies are needed to clarify the role of immunosuppressive treatment in cirrhosis-IgAN patients.
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Affiliation(s)
- Charles Ronsin
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Pierre Braud
- Department of Nephrology, Dialysis and Transplantation, Departmental Hospital of Vendée, La Roche-sur-Yon, France
| | | | | | - Clémence Petit
- Department of Nephrology, Saint Nazaire Hospital, Saint Nazaire, France
| | - David Larmet
- Department of Nephrology, Saint Nazaire Hospital, Saint Nazaire, France
| | - Claire Garandeau
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Clément Deltombe
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Alice Le Clech
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Claire Leman
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Gilles Blancho
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Juliet Schurder
- Department of Nephrology, Broussais Hospital, Saint-Malo, France
| | - Grégoire Couvrat-Desvergnes
- Department of Nephrology, Dialysis and Transplantation, Departmental Hospital of Vendée, La Roche-sur-Yon, France
| | - Simon Ville
- Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France
- Centre de Recherche en Transplantation et Immunologie UMR 1064, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes, Nantes, France
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3
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Stamellou E, Seikrit C, Tang SCW, Boor P, Tesař V, Floege J, Barratt J, Kramann R. IgA nephropathy. Nat Rev Dis Primers 2023; 9:67. [PMID: 38036542 DOI: 10.1038/s41572-023-00476-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/26/2023] [Indexed: 12/02/2023]
Abstract
IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN vary from asymptomatic with microscopic or intermittent macroscopic haematuria and stable kidney function to rapidly progressive glomerulonephritis. IgAN has been proposed to develop through a 'four-hit' process, commencing with overproduction and increased systemic presence of poorly O-glycosylated galactose-deficient IgA1 (Gd-IgA1), followed by recognition of Gd-IgA1 by antiglycan autoantibodies, aggregation of Gd-IgA1 and formation of polymeric IgA1 immune complexes and, lastly, deposition of these immune complexes in the glomerular mesangium, leading to kidney inflammation and scarring. IgAN can only be diagnosed by kidney biopsy. Extensive, optimized supportive care is the mainstay of therapy for patients with IgAN. For those at high risk of disease progression, the 2021 KDIGO Clinical Practice Guideline suggests considering a 6-month course of systemic corticosteroid therapy; however, the efficacy of systemic steroid treatment is under debate and serious adverse effects are common. Advances in understanding the pathophysiology of IgAN have led to clinical trials of novel targeted therapies with acceptable safety profiles, including SGLT2 inhibitors, endothelin receptor blockers, targeted-release budesonide, B cell proliferation and differentiation inhibitors, as well as blockade of complement components.
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Affiliation(s)
- Eleni Stamellou
- Department of Nephrology, School of Medicine, University of Ioannina, Ioannina, Greece
- Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Claudia Seikrit
- Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Sydney C W Tang
- Division of Nephrology, Department of Medicine, University of Hong Kong, Hong Kong, China
| | - Peter Boor
- Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
- Department of Pathology, RWTH Aachen University, Aachen, Germany
| | - Vladimir Tesař
- Department of Nephrology, 1st Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | - Jürgen Floege
- Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Jonathan Barratt
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Rafael Kramann
- Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany.
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands.
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4
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Double glomerulopathies or two-faced janus? A challenging case in the COVID-19 era. J Nephrol 2023; 36:225-228. [PMID: 35666373 PMCID: PMC9169020 DOI: 10.1007/s40620-022-01351-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/10/2022] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 very often causes kidney involvement through various mechanisms including: acute tubular injury, virus cell invasion, vascular damage due to hypercoagulability and finally dysregulation of the immune system. Even though there are no pathognomonic morphologic features that can rule out or confirm direct damage by SARS-CoV-2, the latest literature suggests that there may be some association. SARS-CoV-2 infection represents a poor prognostic factor, regardless of pulmonary involvement. We report a challenging case with complex renal biopsy findings suggestive of collapsing glomerulopathy and focal proliferative IgA-dominant glomerulonephritis in a patient affected by active hepatitis C virus (HCV), SARS-CoV-2 infection and personal history of cocaine abuse.
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5
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Xu L, Li Y, Wu X. IgA vasculitis update: Epidemiology, pathogenesis, and biomarkers. Front Immunol 2022; 13:921864. [PMID: 36263029 PMCID: PMC9574357 DOI: 10.3389/fimmu.2022.921864] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is the most common systemic vasculitis in children, characterized by diverse clinical manifestations with a wide spectrum ranging from isolated cutaneous vasculitis to systemic involvement. The incidence of IgAV is geographically and ethnically variable, with a prevalence in autumn and winter, suggesting a driving role that genetic and environmental factors play in the disease. Although IgAV has a certain degree of natural remission, it varies widely among individuals. Some patients can suffer from severe renal involvement and even progress to end-stage renal disease. Its pathogenesis is complex and has not been fully elucidated. The formation of galactose-deficient IgA1 (Gd-IgA1) and related immune complexes plays a vital role in promoting the occurrence and development of IgAV nephritis. In addition, neutrophil activation is stimulated through the binding of IgA to the Fc alpha receptor I expressed on its surface, resulting in systemic vascular inflammation and tissue damage. Starting from the epidemiological characteristics, this article will review the role of immunological factors such as Gd-IgA1, autoantibodies, circulating immune complexes, complement system, cellular immunization, and the contributions of environmental and genetic factors in the pathogenesis of IgAV, and conclude with the major biomarkers for IgAV.
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Argentova V, Aliev T, Dolgikh D, Pakanová Z, Katrlík J, Kirpichnikov M. Features, modulation and analysis of glycosylation patterns of therapeutic recombinant immunoglobulin A. Biotechnol Genet Eng Rev 2022; 38:247-269. [PMID: 35377278 DOI: 10.1080/02648725.2022.2060594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Increasing the production of recombinant antibodies while ensuring high and stable protein quality remains a challenge in mammalian cell culture. This review is devoted to advances in the field of obtaining stable and optimal glycosylation of therapeutic antibodies based on IgA, as well as the subsequent issues of glycosylation control of glycoproteins during their production. Current studies also demonstrate a general need for a more fundamental understanding of the use of CHO cell-based producer cell lines, through which the glycoprofile of therapeutic IgA antibodies is produced and the dependence of glycosylation on culture conditions could be controlled. Optimization of glycosylation improves the therapeutic efficacy and can expand the possibilities for the creation of highly effective glycoprotein therapeutic drugs. Current status and trends in glycan analysis of therapeutic IgA, dominantly based on mass spectrometry and lectin microarrays are herein summarised as well.
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Affiliation(s)
- Victoria Argentova
- Department of Bioengineering, School of Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Teimur Aliev
- Department of Chemical Enzymology, School of Chemistry, Lomonosov Moscow State University, Moscow, Russia
| | - Dmitry Dolgikh
- Department of Bioengineering, School of Biology, Lomonosov Moscow State University, Moscow, Russia.,Institute of Bioorganic Chemistry, Russian Academy of SciencesShemyakin-Ovchinnikov, Moscow, Russia
| | - Zuzana Pakanová
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Jaroslav Katrlík
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Mikhail Kirpichnikov
- Department of Bioengineering, School of Biology, Lomonosov Moscow State University, Moscow, Russia.,Institute of Bioorganic Chemistry, Russian Academy of SciencesShemyakin-Ovchinnikov, Moscow, Russia
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7
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Ren W, Bian Q, Cai Y. Mass spectrometry-based N-glycosylation analysis in kidney disease. Front Mol Biosci 2022; 9:976298. [PMID: 36072428 PMCID: PMC9442644 DOI: 10.3389/fmolb.2022.976298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 07/18/2022] [Indexed: 11/14/2022] Open
Abstract
Kidney disease is a global health concern with an enormous expense. It is estimated that more than 10% of the population worldwide is affected by kidney disease and millions of patients would progress to death prematurely and unnecessarily. Although creatinine detection and renal biopsy are well-established tools for kidney disease diagnosis, they are limited by several inevitable defects. Therefore, diagnostic tools need to be upgraded, especially for the early stage of the disease and possible progression. As one of the most common post-translational modifications of proteins, N-glycosylation plays a vital role in renal structure and function. Deepening research on N-glycosylation in kidney disease provides new insights into the pathophysiology and paves the way for clinical application. In this study, we reviewed recent N-glycosylation studies on several kidney diseases. We also summarized the development of mass spectrometric methods in the field of N-glycoproteomics and N-glycomics.
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Affiliation(s)
- Weifu Ren
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Qi Bian
- Department of Nephrology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yan Cai
- Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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8
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Bazigh I, Patel E, Khan U, Ghalib N, Singh A. A Case of Adult-Onset IgA Vasculitis in a Cirrhotic Patient. Cureus 2022; 14:e27812. [PMID: 36106304 PMCID: PMC9454305 DOI: 10.7759/cureus.27812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2022] [Indexed: 11/05/2022] Open
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9
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Gligorijević N, Minić S, Nedić O. Structural changes of proteins in liver cirrhosis and consequential changes in their function. World J Gastroenterol 2022; 28:3780-3792. [PMID: 36157540 PMCID: PMC9367231 DOI: 10.3748/wjg.v28.i29.3780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 06/07/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
The liver is the site of synthesis of the majority of circulating proteins. Besides initial polypeptide synthesis, sophisticated machinery is involved in the further processing of proteins by removing parts of them and/or adding functional groups and small molecules tailoring the final molecule to suit its physiological purpose. Posttranslational modifications (PTMs) design a network of molecules with the common protein ancestor but with slightly or considerably varying activity/localization/purpose. PTMs can change under pathological conditions, giving rise to aberrant or overmodified proteins. Undesired changes in the structure of proteins most often accompany undesired changes in their function, such as reduced activity or the appearance of new effects. Proper protein processing is essential for the reactions in living beings and crucial for the overall quality control. Modifications that occur on proteins synthesized in the liver whose PTMs are cirrhosis-related are oxidation, nitration, glycosylation, acetylation, and ubiquitination. Some of them predominantly affect proteins that remain in liver cells, whereas others predominantly occur on proteins that leave the liver or originate from other tissues and perform their function in the circulation. Altered PTMs of certain proteins are potential candidates as biomarkers of liver-related diseases, including cirrhosis. This review will focus on PTMs on proteins whose structural changes in cirrhosis exert or are suspected to exert the most serious functional consequences.
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Affiliation(s)
- Nikola Gligorijević
- Department of Metabolism, University of Belgrade-Institute for the Application of Nuclear Energy, Belgrade 11080, Serbia
| | - Simeon Minić
- Centre of Excellence for Molecular Food Sciences and Department of Biochemistry, University of Belgrade-Faculty of Chemistry, Belgrade 11000, Serbia
| | - Olgica Nedić
- Department of Metabolism, University of Belgrade-Institute for the Application of Nuclear Energy, Belgrade 11080, Serbia
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10
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Zhang X, Lv J, Liu P, Xie X, Wang M, Liu D, Zhang H, Jin J. Poly-IgA Complexes and Disease Severity in IgA Nephropathy. Clin J Am Soc Nephrol 2021; 16:1652-1664. [PMID: 34607844 PMCID: PMC8729420 DOI: 10.2215/cjn.01300121] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 09/21/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVES Poly-IgA immune complex formation and glomerular deposition play a key role in IgA nephropathy. Our study sought to develop a new methodology for one-step serologic detection of poly-IgA levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A novel ELISA method using recombinant CD89 as a "capturing" probe was established for detecting poly-IgA immune complex in plasma. We applied semiquantitative measurements of these poly-IgA indices in patients recruited at Peking University First Hospital who had IgA nephropathy or other kidney disease types, as compared with healthy controls. The longitudinal trend of the poly-IgA index and the association with pathologic parameters and treatment responses were evaluated. Finally, we analyzed the molecular composition of poly-IgA complexes in patients by mass spectrometry. RESULTS Recombinant CD89-mounted ELISA plates specifically captured plasma poly-IgA. The levels of poly-IgA immune complex (26.7 [interquartile range (IQR) 17.1-42.6] U/ml) in IgA nephropathy were significantly higher than those in healthy controls (15.5 [IQR 10.7-20.0] U/ml; P<0.001) or in controls with non-IgA nephropathy disease (14.8 [IQR 10.5-21.9] U/ml; P<0.001). Higher levels of poly-IgA immune complex were associated with lower eGFR and worse kidney outcome. Accuracy parameters and concordant statistics showed good discrimination between IgA nephropathy and healthy controls based on poly-IgA index levels (area under the curve [AUC], 0.78; 95% confidence interval [95% CI], 0.72 to 0.83; P<0.001), significantly outperforming galactose-deficient IgA1 levels (AUC, 0.70; P=0.05). Corticosteroid and immunosuppressant treatments lowered poly-IgA indices. After a recombinant CD89-directed workflow in conjunction with mass spectrometry, we also analyzed the molecular composition of IgA immune complex in patients with IgA nephropathy. CONCLUSIONS Higher level of recombinant CD89-bound poly-IgA immune complex was associated with the severity of the disease and with treatment response to steroids and immunosuppressants.
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Affiliation(s)
- Xue Zhang
- Renal Division, Peking University First Hospital, Beijing, China,Peking University Institute of Nephrology, Beijing, China,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jicheng Lv
- Renal Division, Peking University First Hospital, Beijing, China,Peking University Institute of Nephrology, Beijing, China,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Pan Liu
- Division of Nephrology and Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xinfang Xie
- Division of Nephrology and Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Manliu Wang
- Renal Division, Peking University First Hospital, Beijing, China,Peking University Institute of Nephrology, Beijing, China,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Dan Liu
- Proteomics Laboratory, Medical and Health Analytical Center, Peking University, Beijing, China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Beijing, China,Peking University Institute of Nephrology, Beijing, China,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China,Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jing Jin
- Division of Nephrology and Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Guliaev SV, Strizhakov LA, Chebotareva NV, Moiseev SV. Role of the intestinal MALT in pathogenesis of the IgA-nephropathy. TERAPEVT ARKH 2021; 93:724-728. [DOI: 10.26442/00403660.2021.06.200868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 07/10/2021] [Indexed: 11/22/2022]
Abstract
Modern view on pathogenesis of immunoglobulin (Ig)A-nephropathy and possible relation to intestinal MALT-system activity is presented in the article. Aberrant glycosylation of IgA and increased association of IgA-nephropathy with intestinal diseases or abnormal intestinal permeability are discussed in details. Based on supposed entero-renal pathogenesis of the disease future treatment modalities are considered. Relevant worlds literature is cited.
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Morelli MC, Rendina M, La Manna G, Alessandria C, Pasulo L, Lenci I, Bhoori S, Messa P, Biancone L, Gesualdo L, Russo FP, Petta S, Burra P. Position paper on liver and kidney diseases from the Italian Association for the Study of Liver (AISF), in collaboration with the Italian Society of Nephrology (SIN). Dig Liver Dis 2021; 53 Suppl 2:S49-S86. [PMID: 34074490 DOI: 10.1016/j.dld.2021.03.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023]
Abstract
Liver and kidney are strictly connected in a reciprocal manner, in both the physiological and pathological condition. The Italian Association for the Study of Liver, in collaboration with the Italian Society of Nephrology, with this position paper aims to provide an up-to-date overview on the principal relationships between these two important organs. A panel of well-recognized international expert hepatologists and nephrologists identified five relevant topics: 1) The diagnosis of kidney damage in patients with chronic liver disease; 2) Acute kidney injury in liver cirrhosis; 3) Association between chronic liver disease and chronic kidney disease; 4) Kidney damage according to different etiology of liver disease; 5) Polycystic kidney and liver disease. The discussion process started with a review of the literature relating to each of the five major topics and clinical questions and related statements were subsequently formulated. The quality of evidence and strength of recommendations were graded according to the GRADE system. The statements presented here highlight the importance of strong collaboration between hepatologists and nephrologists for the management of critically ill patients, such as those with combined liver and kidney impairment.
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Affiliation(s)
- Maria Cristina Morelli
- Internal Medicine Unit for the treatment of Severe Organ Failure, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di S.Orsola, Bologna, Italy, Via Albertoni 15, 40138, Bologna, Italy
| | - Maria Rendina
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University of Bari, Policlinic Hospital, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Gaetano La Manna
- Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, St. Orsola Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Torino, Corso Bramante 88, 10126, Torino, Italy
| | - Luisa Pasulo
- Gastroenterology and Transplant Hepatology, "Papa Giovanni XXIII" Hospital, Piazza OMS 1, 24127, Bergamo, Italy
| | - Ilaria Lenci
- Department of Internal Medicine, Hepatology Unit, Tor Vergata University, Rome Viale Oxford 81, 00133, Rome, Italy
| | - Sherrie Bhoori
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori, Via Giacomo Venezian, 1, 20133, Milan, Italy
| | - Piergiorgio Messa
- Unit of Nephrology, Università degli Studi di Milano, Via Commenda 15, 20122, Milano, Italy; Nephrology, Dialysis and Renal Transplant Unit-Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Via Commenda 15, 20122 Milano, Italy
| | - Luigi Biancone
- Division of Nephrology Dialysis and Transplantation, Department of Medical Sciences, Città Della Salute e della Scienza Hospital, University of Turin, Corso Bramante, 88-10126, Turin, Italy
| | - Loreto Gesualdo
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, Università degli Studi di Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Via Giustiniani 2, 35128, Padua, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Piazza delle Cliniche, 2 90127, Palermo, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padua, Via Giustiniani 2, 35128, Padua, Italy.
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Jhee JH, Nam BY, Park JT, Kim HW, Chang TI, Kang EW, Lim BJ, Yoo TH, Kang SW, Jeong HJ, Han SH. CD71 mesangial IgA1 receptor and the progression of IgA nephropathy. Transl Res 2021; 230:34-43. [PMID: 33122053 DOI: 10.1016/j.trsl.2020.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/12/2020] [Accepted: 10/21/2020] [Indexed: 10/23/2022]
Abstract
The transferrin receptor (CD71) is known as a receptor for IgA1 on mesangial cells, but the role of CD71 in IgA nephropathy (IgAN) is unknown. We studied clinical implication of mesangial CD71 in 282 patients with biopsy-proven IgAN (2005-2018). The transcript and protein expression of glomerular CD71 was determined by real-time polymerase chain reaction and immunohistochemistry. Ten subjects with microscopic hematuria only and no evidence of histologic abnormalities on kidney biopsy were considered as controls. Human mesangial cells (HMCs) were treated with sera from IgAN patients and expression levels of CD71 and inflammatory cytokine markers were compared according to disease status. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate from the baseline value. During a mean follow up of 53.5 (18.3-75.9) months, 80 (28.4%) patients developed disease progression. The mRNA expression of CD71 was significantly higher in progressors than in nonprogressors (P = 0.001). Among the Oxford classification scores, patients with M1 had significantly higher CD71 expression levels than those with M0. In a multivariable Cox model, elevated transcript levels of CD71 were significantly associated with 4.32-fold higher risk of disease progression (P = 0.009). Furthermore, CD71 expression levels independently predicted the increase in proteinuria of ≥50% from the baseline (P = 0.03). Finally, HMCs treated with sera from IgAN patients with the higher Oxford score (M1E1S1T0) more increased the mRNA expression of CD71 and inflammatory markers than those with sera from negative score (M0E0S0T0). However, silencing CD71 significantly reduced expression levels of the inflammatory cytokine genes. Our results show that mesangial CD71 is significantly associated with disease progression and may play a biologic role in IgAN.
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Affiliation(s)
- Jong Hyun Jhee
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Bo Young Nam
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, South Korea
| | - Jung Tak Park
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, South Korea
| | - Hyung Woo Kim
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, South Korea
| | - Tae Ik Chang
- Division of Nephrology, Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital, Goyang, Gyeonggi-do, South Korea
| | - Ea Wha Kang
- Division of Nephrology, Department of Internal Medicine, National Health Insurance Service Medical Center, Ilsan Hospital, Goyang, Gyeonggi-do, South Korea
| | - Beom Jin Lim
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, South Korea
| | - Shin-Wook Kang
- Department of Internal Medicine, College of Medicine, Severance Biomedical Science Institute, Brain Korea 21 PLUS, Yonsei University, Seoul, South Korea; Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, South Korea
| | - Hyeon Joo Jeong
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
| | - Seung Hyeok Han
- Department of Internal Medicine, College of Medicine, Institute of Kidney Disease Research, Yonsei University, Seoul, South Korea.
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14
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Scurt FG, Bose K, Canbay A, Mertens PR, Chatzikyrkou C. [Chronic kidney injury in patients with liver diseases - Reappraising pathophysiology and treatment options]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:560-579. [PMID: 33728618 DOI: 10.1055/a-1402-1502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Acute and chronic kidney disease concurs commonly with liver disease and is associated with a wide array of complications including dialysis dependency and increased mortality. Patients with liver disease or liver cirrhosis show a higher prevalence of chronic kidney disease. This is attributed to concomitant comorbidities, such as metabolic syndrome, chronic inflammation, hypercoagulability, hyperfibrinolysis, diabetes mellitus and dyslipidaemias. But chronic progressive kidney disease is not always due to hepatorenal syndrome. Beyond that, other diseases or disease entities should be considered. Among them are diabetic nephropathy, secondary IgA nephropathy, hepatitis C -associated membranoproliferative Glomerulonephritis (MPGN) and hepatitis B-associated membranous nephropathy.Coexisting diseases, similar underlying pathophysiologic mechanisms, or simultaneously concurring pathophysiological processes and overlapping clinical manifestations, impede the etiologic diagnosis and corresponding treatment of chronic kidney disease in the setting of chronic liver disease. In this review, we focus on common and rare pathologies, which can lead to chronic kidney disease in this particular patient group and try to summarize the most recent therapeutic modalities.
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Affiliation(s)
- Florian Gunnar Scurt
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany
| | - Katrin Bose
- Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany.,Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland
| | - Ali Canbay
- Ruhr-Universität Bochum, Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Deutschland
| | - Peter R Mertens
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany
| | - Christos Chatzikyrkou
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany
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15
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Acharya R, Zeng X, Clapp WL, Upadhyay K. IgA vasculitis with nephritis in cirrhotic Wilson disease: Is there an association? Clin Nephrol Case Stud 2020; 8:80-84. [PMID: 33062584 PMCID: PMC7552349 DOI: 10.5414/cncs110268] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/17/2020] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION IgA vasculitis (IgA-V) predominantly involves skin, gastrointestinal (GI) tract, joints, and kidneys. Wilson disease (WD) is a hepatolenticular degenerative disease caused by ATP7B gene mutation. CASE REPORT Here we describe an unusual association of IgA-V with nephritis (IgA-VN) in an 11-year-old child with WD. He presented with palpable purpura without arthritis and GI involvement. Renal function was normal. Urinalysis showed microscopic hematuria and tubular proteinuria. Evaluation showed transaminitis, hypoalbuminemia, IgA hyperglobulinemia, and coagulation abnormalities. Serum ceruloplasmin and copper were low and 24-hour urine copper was extremely elevated. Liver biopsy showed stage IV cirrhosis with increased quantitative liver copper content. Skin and renal biopsy showed IgA-positive leukocytoclastic vasculitis and mesangial hyperplasia with IgA deposition, respectively. Quantitative renal copper content was normal. Homozygous pathogenic variant c.3207C>A (p.His1069Gln) of ATP7B was detected. There were no Kayser-Fleischer rings in the eyes, and neuropsychiatric examination was normal. Treatment with zinc and trientine led to normalization of hepatic function and serum IgA level with resolution of the rash and maintenance of renal function. CONCLUSION Defective hepatic processing and/or clearance of IgA/IgA immune complexes probably led to the IgA-mediated skin and renal injury. Further such reports will help augment our understanding on the pathophysiology of IgA-VN in WD.
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Affiliation(s)
| | - Xu Zeng
- Division of Anatomic Pathology, Department of Pathology, and
| | | | - Kiran Upadhyay
- Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL, USA
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16
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Elhani I, Pillebout E, Terrier B, Hankard A, Vrtovsnik F, Jourde-Chiche N, Greillier S, Groh M, Belfeki N, Bigot A, de Boysson H, Pageaux GP, Raffray L, Urbanski G, Ollivier I, Maillot F, Aouba A, Audemard-Verger A. IgA Vasculitis With Underlying Liver Cirrhosis: A French Nationwide Case Series of 20 Patients. J Rheumatol 2020; 48:735-740. [PMID: 32801133 DOI: 10.3899/jrheum.200293] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/06/2020] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Immunoglobulin A vasculitis (IgAV) and nephropathy (IgAN) share common immunological mechanisms. Liver cirrhosis is well known to be associated with IgAN. Here, we aimed to describe the presentation and outcome of IgAV patients with underlying cirrhosis. METHODS We conducted a French nationwide retrospective study of adult patients presenting with both IgAV and cirrhosis. Baseline characteristics were compared to those of the 260 patients included in the French nationwide IgAV registry (IGAVAS). RESULTS Twenty patients were included, and 7 (35%) were female. The mean ± SD age was 62.7 ± 11 years. At baseline, compared with IGAVAS patients, patients with underlying cirrhosis were older (62.7 ± 11 vs 50.1 ± 18, P < 0.01) and displayed more constitutional symptoms (weight loss 25% vs 8%, P = 0.03). Patients with underlying cirrhosis were also more likely to exhibit elevated serum IgA levels (5.6 g/L vs 3.6 g/L, P = 0.02). Cirrhosis and IgAV were diagnosed simultaneously in 12 patients (60%). Cirrhosis was mainly related to alcohol intake (n = 15, 75%), followed by nonalcoholic steato-hepatitis (n = 2), chronic viral hepatitis (n = 1), hemochromatosis (n = 1), and autoimmune hepatitis (n = 1). During follow-up with a median of 17 months (IQR 12-84), 10/13 (77%) exhibited IgAV remission at Month 3. One patient presented a minor relapse. Six patients died, but no deaths were related to IgAV. CONCLUSION We report the first case series of IgAV patients with underlining cirrhosis, to our knowledge, which was mainly alcohol related. The liver disease did not seem to affect baseline vasculitis characteristics. Physicians should investigate the existence of liver cirrhosis at IgAV diagnosis, especially in the context of alcohol abuse.
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Affiliation(s)
- Ines Elhani
- I. Elhani, MD, A. Hankard, MD, H. de Boysson, MD, A. Aouba, MD, Department of Internal Medicine, Caen, Normandie Université, UNICAEN, CHU de Caen Normandie
| | | | - Benjamin Terrier
- B. Terrier, MD, Université Paris Descartes, and Department of Internal Medicine, Hôpital Cochin, and National Referral Center for Systemic and Autoimmune Diseases, Hôpital Cochin, Paris
| | - Antoine Hankard
- I. Elhani, MD, A. Hankard, MD, H. de Boysson, MD, A. Aouba, MD, Department of Internal Medicine, Caen, Normandie Université, UNICAEN, CHU de Caen Normandie
| | - François Vrtovsnik
- F. Vrtovsnik, MD, Department of Nephrology, Bichat-Claude Bernard Hospital, AP-HP, and Inserm U1149 - CRI, University of Paris, Paris
| | - Noémie Jourde-Chiche
- N. Jourde-Chiche, MD, S. Greillier, MD, Aix-Marseille Univ, C2VN, INSERM, INRA, Centre de Néphrologie et Transplantation Rénale, CHU de la Conception, AP-HM, Marseille
| | - Sophie Greillier
- N. Jourde-Chiche, MD, S. Greillier, MD, Aix-Marseille Univ, C2VN, INSERM, INRA, Centre de Néphrologie et Transplantation Rénale, CHU de la Conception, AP-HM, Marseille
| | - Matthieu Groh
- M. Groh, MD, Department of Internal Medicine, National Referral Center for Hypereosinophilic Syndrome (CEREO), Suresnes
| | - Nabil Belfeki
- N. Belfeki, MD, Department of Internal Medicine, Groupe Hospitalier Sud Ile de France, Melun
| | - Adrien Bigot
- A. Bigot, MD, F. Maillot, MD, A. Audemard-Verger, MD, PhD, Department of Internal Medicine and Clinical Immunology, CHRU Tours, and University of Tours, Tours
| | - Hubert de Boysson
- I. Elhani, MD, A. Hankard, MD, H. de Boysson, MD, A. Aouba, MD, Department of Internal Medicine, Caen, Normandie Université, UNICAEN, CHU de Caen Normandie
| | - Georges-Philippe Pageaux
- G.P. Pageaux, MD, Liver Transplantation Unit, Digestive Department, Saint Eloi University Hospital, University of Montpellier, Montpellier
| | - Loïc Raffray
- L. Raffray, MD, Department of Internal Medicine, Centre Hospitalier Universitaire de la Réunion, Réunion
| | - Geoffrey Urbanski
- G. Urbanski, MD, Department of Internal Medicine, Centre Hospitalier Universitaire d'Angers, Angers
| | - Isabelle Ollivier
- I. Ollivier, MD, Department of Hepato-Gastroenterology and Nutrition, Caen University Hospital, Caen, France
| | - Francois Maillot
- A. Bigot, MD, F. Maillot, MD, A. Audemard-Verger, MD, PhD, Department of Internal Medicine and Clinical Immunology, CHRU Tours, and University of Tours, Tours
| | - Achille Aouba
- I. Elhani, MD, A. Hankard, MD, H. de Boysson, MD, A. Aouba, MD, Department of Internal Medicine, Caen, Normandie Université, UNICAEN, CHU de Caen Normandie
| | - Alexandra Audemard-Verger
- A. Bigot, MD, F. Maillot, MD, A. Audemard-Verger, MD, PhD, Department of Internal Medicine and Clinical Immunology, CHRU Tours, and University of Tours, Tours;
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17
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Zachova K, Kosztyu P, Zadrazil J, Matousovic K, Vondrak K, Hubacek P, Julian BA, Moldoveanu Z, Novak Z, Kostovcikova K, Raska M, Mestecky J. Role of Epstein-Barr Virus in Pathogenesis and Racial Distribution of IgA Nephropathy. Front Immunol 2020; 11:267. [PMID: 32184780 PMCID: PMC7058636 DOI: 10.3389/fimmu.2020.00267] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/03/2020] [Indexed: 02/04/2023] Open
Abstract
IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences. Because human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers. We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract. Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls. Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells. Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth. At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells. Consequently, EBV infects cells secreting immunoglobulins other than IgA. Our novel data implicate Epstein-Barr virus infected IgA+ cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors. Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.
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Affiliation(s)
- Katerina Zachova
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Petr Kosztyu
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Josef Zadrazil
- Department of Internal Medicine III Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Karel Matousovic
- Department of Medicine, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czechia
| | - Karel Vondrak
- Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Petr Hubacek
- Department of Medical Microbiology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czechia
| | - Bruce A Julian
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zina Moldoveanu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zdenek Novak
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Klara Kostovcikova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jiri Mestecky
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.,Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
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18
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Carrion AF, Radhakrishnan R, Martin P. Diagnosis and management of renal dysfunction in patients with cirrhosis. Expert Rev Gastroenterol Hepatol 2020; 14:1-7. [PMID: 31868027 DOI: 10.1080/17474124.2020.1708190] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 12/19/2019] [Indexed: 02/06/2023]
Abstract
Introduction: Renal dysfunction commonly occurs in patients with cirrhosis and is typically associated with poor prognosis. Several pathophysiologic mechanisms are responsible for renal disease in these patients, prompt identification permits individualized management.Areas covered: Pathophysiology, evaluation and differential diagnosis, management and prognosis of renal disease in patients with cirrhosis. Special focus on management of hepatorenal syndrome and indications for simultaneous liver-kidney transplantation.Literature search methodology: a detailed literature search was performed using PubMed without date restrictions. Published guidelines and position papers were also used and cross-referenced to identify additional studies.Expert opinion: The prognostic significance of renal dysfunction in patients with cirrhosis is highlighted by the inclusion of serum creatinine in the model for end-stage liver disease (MELD). Both acute and chronic renal dysfunction result in increased mortality in patients with cirrhosis, although there are marked differences related to the etiology of renal disease. Early recognition and prompt intervention determined by the most likely etiology are key in the management of these patients. Simultaneous liver-kidney transplantation improves patient survival compared to isolated liver transplantation in patients with cirrhosis and persistent renal impairment; however, selection of candidates must be judicious and individualized due to the ongoing shortage of donor kidneys.
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Affiliation(s)
- Andres F Carrion
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Paul Martin
- Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA
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19
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Wang M, Lv J, Zhang X, Chen P, Zhao M, Zhang H. Secondary IgA Nephropathy Shares the Same Immune Features With Primary IgA Nephropathy. Kidney Int Rep 2019; 5:165-172. [PMID: 32043030 PMCID: PMC7000803 DOI: 10.1016/j.ekir.2019.10.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 10/24/2019] [Accepted: 10/28/2019] [Indexed: 01/26/2023] Open
Abstract
Introduction Galactose-deficient IgA1 (Gd-IgA1) and related IgA/IgG immune complexes have been identified as the key drivers in the pathogenesis of IgA nephropathy (IgAN). However, their roles in the development of secondary IgAN are still unknown. Methods In this study, we measured the plasma Gd-IgA1 level, IgA/IgG complex, and Gd-IgA1 glomerular deposits in 100 patients with various kinds of secondary IgAN. Plasma Gd-IgA1 was measured using a lectin-based enzyme-linked immunosorbent assay, and Gd-IgA1 in glomerular deposits was examined by double immunofluorescent staining using its specific monoclonal antibody KM55. Results Patients with secondary IgAN presented with higher plasma Gd-IgA1 levels compared to healthy controls (median, 354.61 U/ml; interquartile range [IQR], 323.93, 395.57 U/ml vs. median, 303.17 U/ml; IQR, 282.24, 337.92 U/ml, P < 0.001) or patients with other kidney diseases (median, 314.61 U/ml; IQR, 278.97, 343.55 U/ml, P < 0.001). A similar trend was observed in plasma IgA/IgG immune complexes or IgA1. There were no differences between secondary and primary IgAN in plasma Gd-IgA1 levels (median, 378.54 U/ml; IQR, 315.96, 398.33 U/ml, P = 0.700) and IgA1-IgG complex levels (median, 18.76 U/ml; IQR, 14.51, 22.83 U/ml vs. median, 19.11 U/ml; IQR, 13.21, 22.37 U/ml, P = 0.888). Co-localized IgA1 and Gd-IgA1 of both secondary and primary IgAN indicated that they both share the feature of Gd-IgA1 deposits on the glomerular mesangium. Conclusion Our study strongly suggests that secondary IgAN shares a similar galactose-deficient IgA1-oriented pathogenesis with primary IgAN.
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Affiliation(s)
- Manliu Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Jicheng Lv
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Xue Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Pei Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
| | - Minghui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China.,Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.,Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Hong Zhang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.,Peking University Institute of Nephrology, Beijing, China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.,Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
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20
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Berthelot L, Jamin A, Viglietti D, Chemouny JM, Ayari H, Pierre M, Housset P, Sauvaget V, Hurtado-Nedelec M, Vrtovsnik F, Daugas E, Monteiro RC, Pillebout E. Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort. Nephrol Dial Transplant 2019; 33:1579-1590. [PMID: 29126311 DOI: 10.1093/ndt/gfx300] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 09/11/2017] [Indexed: 11/12/2022] Open
Abstract
Background Henoch-Schönlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P < 0.005 for all comparisons). After follow-up (1 year), 22 patients showed a poor outcome. Among the tested markers, urine IgA at disease onset adequately reclassified the risk of poor outcome over conventional clinical factors, including estimated glomerular filtration rate, proteinuria and age (continuous net reclassification improvement = 0.72, P = 0.001; integrated discrimination improvement = 0.13, P = 0.009) in IgAV patients. Conclusions Taken together, these results showed that serum Gd-IgA1 and urinary IgA, IgG, IgM, NGAL, IL-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were associated with nephritis in IgAV patients. Urinary IgA level may improve patient risk stratification for poor outcome.
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Affiliation(s)
- Laureline Berthelot
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France
| | - Agnès Jamin
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France
| | - Denis Viglietti
- Department of Nephrology, Saint-Louis Hospital, AP-HP, Paris, France
| | - Jonathan M Chemouny
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France.,Department of Nephrology, Bichat Hospital, DHU Fire, AP-HP, Paris, France
| | - Hamza Ayari
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France
| | - Melissa Pierre
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France
| | - Pierre Housset
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France
| | - Virginia Sauvaget
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France
| | - Margarita Hurtado-Nedelec
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France.,Department of Immunology, Bichat Hospital, AP-HP, Paris, France
| | - François Vrtovsnik
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France.,Department of Nephrology, Bichat Hospital, DHU Fire, AP-HP, Paris, France
| | - Eric Daugas
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France.,Department of Nephrology, Bichat Hospital, DHU Fire, AP-HP, Paris, France
| | | | - Renato C Monteiro
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France.,Department of Immunology, Bichat Hospital, AP-HP, Paris, France
| | - Evangeline Pillebout
- INSERM 1149, Center of Research on Inflammation, Paris, France.,Inflamex, Laboratory of Excellence, Bichat Medical Faculty, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Paris, France.,CNRS ERL8252, Paris, France.,Department of Nephrology, Saint-Louis Hospital, AP-HP, Paris, France
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21
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Monteiro RC. Recent advances in the physiopathology of IgA nephropathy. Nephrol Ther 2018; 14 Suppl 1:S1-S8. [PMID: 29606255 DOI: 10.1016/j.nephro.2018.02.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 02/01/2018] [Indexed: 01/01/2023]
Abstract
Immunoglobulin A nephropathy or Berger's disease is the most common type of primary glomerulonephritis, which is characterized by IgA1-containing immune-deposits in the glomerular mesangium. Microscopic haematuria and proteinuria are the most common presentations. Mesangial cell proliferation with IgA deposition is found on renal biopsy. Mechanims of the disease implicate at least four key molecules have been implicated in immune complex formation: galactose-deficient IgA1, autoantibodies anti-galactose-deficient-IgA1, soluble CD89 (Fc receptor for IgA) and the CD71 mesangial IgA receptor (transferrin receptor). These factors associated with environmental factors (antigens, food and microbiota) are correlated with disease progression and recurrence after transplantation. This review exploits recent data on the role of these molecular players of the disease, which may improve future therapeutic management of immunoglobulin A nephropathy.
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Affiliation(s)
- Renato C Monteiro
- Inserm U1149 centre de recherche sur l'inflammation, 16, rue Henri-Huchard, 75018 Paris, France; CNRS ERL8252, 16, rue Henri-Huchard, 75018 Paris, France; Laboratoire d'excellence Inflamex, faculté de médecine Bichat, université Paris-Diderot, 16, rue Henri-Huchard, 75018 Paris, France; Service d'immunologie, DHU Fire, hôpital Bichat, 16, rue Henri-Huchard, 75018 Paris, France.
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22
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Mohd Hanafiah K, Garcia ML, Barnes NC, Anderson DA. Detection of virus-specific polymeric immunoglobulin A in acute hepatitis A, C, E virus serum samples using novel chimeric secretory component. BMC Res Notes 2018; 11:688. [PMID: 30285838 PMCID: PMC6167832 DOI: 10.1186/s13104-018-3799-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 09/27/2018] [Indexed: 01/23/2023] Open
Abstract
Objective To conduct a proof-of-concept study on preferential binding of polymeric IgA (pIgA) using a novel recombinant rabbit/human chimeric secretory component (cSC) and preliminary assessment of the diagnostic potential of virus-specific pIgA in discriminating acute hepatitis A, E, and C (HAV, HEV, HCV) patients and uninfected controls using an indirect enzyme-linked immunoassay. Results cSC binds > 0.06 μg/ml of purified human and mouse pIgA with negligible cross-reactivity against IgM and IgA. Virus-specific pIgA was significantly higher in serum of acute HAV (n = 6) and HEV (n = 12) patients than uninfected samples (HEV: p < 0.001; HAV: p = 0.001), and had low correlation with virus-specific IgM (HEV r: − 0.25, 95% CI − 0.88 to 0.71, p = 0.636; HAV r: 0.05, 95% CI − 0.54 to 0.60, p: 0.885). Anti-HCV pIgA peaked early in HCV seroconversion panels (n = 14), and was undetectable after 4 weeks post-primary bleed, even in ongoing infections, while serum anti-HCV IgA, IgG and IgM persisted. Patients with early acute HCV infection had significantly higher levels of anti-HCV pIgA compared to those with chronic infections (p < 0.01). The use of novel cSC demonstrates the presence of virus-specific pIgA in sera of patients with acute HAV, HEV, and HCV infection, and posits its potential utility as a diagnostic biomarker that warrants further validation on larger sample populations.
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Affiliation(s)
- Khayriyyah Mohd Hanafiah
- Life Sciences, Macfarlane Burnet Institute, 85 Commercial Rd, Melbourne, VIC, 3004, Australia. .,Department of Immunology, Monash University, 86 Commercial Road, Melbourne, VIC, 3004, Australia. .,School of Biological Sciences, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia.
| | - Mary L Garcia
- Life Sciences, Macfarlane Burnet Institute, 85 Commercial Rd, Melbourne, VIC, 3004, Australia
| | - Nadine C Barnes
- Life Sciences, Macfarlane Burnet Institute, 85 Commercial Rd, Melbourne, VIC, 3004, Australia
| | - David A Anderson
- Life Sciences, Macfarlane Burnet Institute, 85 Commercial Rd, Melbourne, VIC, 3004, Australia.,Department of Microbiology and Immunology, University of Melbourne, 792 Elizabeth Street, Melbourne, VIC, 3000, Australia
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23
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Saha MK, Julian BA, Novak J, Rizk DV. Secondary IgA nephropathy. Kidney Int 2018; 94:674-681. [PMID: 29804660 PMCID: PMC6981247 DOI: 10.1016/j.kint.2018.02.030] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 01/24/2018] [Accepted: 02/06/2018] [Indexed: 12/14/2022]
Abstract
IgA nephropathy is the most common primary glomerulonephritis worldwide. Its frequent coexistence with inflammatory, infectious, or malignant processes raises the possibility of a pathologic rather than coincidental association. Major strides have been made to elucidate the underlying pathophysiologic events that culminate in the development of primary IgA nephropathy. Whether secondary forms of the disease share common pathways triggered by underlying disorders or different mechanisms leading to similar pathologic findings remains to be determined. In this article we describe the most frequent etiologies for secondary IgA nephropathy and review the available literature for the pathophysiology.
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Affiliation(s)
- Manish K Saha
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA; Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Bruce A Julian
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Dana V Rizk
- Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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24
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Carrier P, Debette-Gratien M, Essig M, Loustaud-Ratti V. Beyond serum creatinine: which tools to evaluate renal function in cirrhotic patients? Hepatol Res 2018; 48:771-779. [PMID: 29954046 DOI: 10.1111/hepr.13224] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 06/06/2018] [Accepted: 06/23/2018] [Indexed: 02/08/2023]
Abstract
In cirrhotic patients, a high serum creatinine value is an independent mortality factor. Similarly, it is predictive of renal insufficiency after liver transplantation. In these cases, chronic kidney disease is also an independent mortality factor. A relevant evaluation of glomerular filtration rate is crucial, particularly in cases of end-stage liver disease or liver transplantation, and is key for the decision to undertake dual liver-kidney transplantation. Serum creatinine or creatinine-based equations are the most used tools in clinical practice but they significantly overestimate renal function. Equilibrium inulin renal clearance remains the gold standard but is time consuming and expensive. Cystatin C and cystatin C-based equations are less influenced by muscle mass or bilirubin value, but their dosage is not standardized and they are expensive. Pharmacological models using exogenous markers, new kidney biomarkers, Doppler coupled with ultrasounds, and kidney histology could be interesting tools but their indications need to be specified.
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Affiliation(s)
- Paul Carrier
- Hepatology Federation, Hepatology and Gastroenterology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France.,INSERM U-1248, Medicine and Pharmacy Faculty, Limoges University, Tours, Poitiers, Limoges, France.,Nephrology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France
| | - Marilyne Debette-Gratien
- Hepatology Federation, Hepatology and Gastroenterology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France.,INSERM U-1248, Medicine and Pharmacy Faculty, Limoges University, Tours, Poitiers, Limoges, France.,Nephrology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France
| | - Marie Essig
- INSERM U-1248, Medicine and Pharmacy Faculty, Limoges University, Tours, Poitiers, Limoges, France.,Nephrology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France.,FHU SUPORT (SUrvival oPtimization in Organ Transplantation), Transplantation Federation, Tours, Poitiers, Limoges, France
| | - Véronique Loustaud-Ratti
- Hepatology Federation, Hepatology and Gastroenterology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France.,INSERM U-1248, Medicine and Pharmacy Faculty, Limoges University, Tours, Poitiers, Limoges, France.,Nephrology Unit, Teaching Hospital Limoges, Tours, Poitiers, Limoges, France
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25
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Takada D, Sumida K, Sekine A, Hazue R, Yamanouchi M, Suwabe T, Hayami N, Hoshino J, Sawa N, Takaichi K, Fujii T, Ohashi K, Ubara Y. IgA nephropathy featuring massive wire loop-like deposits in two patients with alcoholic cirrhosis. BMC Nephrol 2017; 18:362. [PMID: 29237409 PMCID: PMC5729455 DOI: 10.1186/s12882-017-0769-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Accepted: 11/20/2017] [Indexed: 12/22/2022] Open
Abstract
Background Various renal manifestations are known to develop in patients with liver disease, including chronic hepatitis and cirrhosis. Case presentation We evaluated renal disease in two 47-year-old Japanese men with liver cirrhosis and chronic alcoholism for 34 years and 27 years, respectively. Renal biopsy demonstrated massive wire loop-like deposits in the subendothelial space of the glomerular basement membrane and in the mesangium. However, immunofluorescence was only positive for IgA and C3, and electron microscopy did not reveal any organized structures in the electron-dense deposits. IgA nephropathy was diagnosed, although the features were different from primary IgA nephropathy. Both patients had portosystemic shunts associated with liver cirrhosis. Their renal deposits and proteinuria resolved completely after 1 year of steroid therapy. Conclusion Alcohol abuse may have contributed to development of secondary IgA nephropathy in these two patients, probably via their portosystemic shunts.
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Affiliation(s)
- Daisuke Takada
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Keiichi Sumida
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Akinari Sekine
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan.
| | - Ryo Hazue
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Masayuki Yamanouchi
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Tatsuya Suwabe
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Noriko Hayami
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Junichi Hoshino
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Naoki Sawa
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan
| | - Kenmei Takaichi
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan.,The Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Takeshi Fujii
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Tokyo, Japan.,Department of Pathology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan
| | - Yoshifumi Ubara
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Kanagawa, 213-8587, Japan. .,The Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan.
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26
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Heineke MH, Ballering AV, Jamin A, Ben Mkaddem S, Monteiro RC, Van Egmond M. New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schönlein purpura). Autoimmun Rev 2017; 16:1246-1253. [PMID: 29037908 DOI: 10.1016/j.autrev.2017.10.009] [Citation(s) in RCA: 211] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 08/29/2017] [Indexed: 12/16/2022]
Abstract
Immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, is the most common form of childhood vasculitis. The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. Symptoms can resolve without intervention, but some patients develop glomerulonephritis with features similar to IgA nephropathy that include hematuria, proteinuria and IgA deposition in the glomerulus. Ultimately, this can lead to end-stage renal disease. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Although Gd-IgA1 complexes are also present in patients with IgAV with nephritis, their role in IgAV is disputed. Alternatively, it has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells. We anticipate that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV. In this Review, we discuss the putative role of IgA, IgA receptors, neutrophils and other factors such as infections, genetics and the complement system in the pathogenesis of IgA vasculitis.
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Affiliation(s)
- Marieke H Heineke
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, De Boelelaan 1109, 1081 HZ Amsterdam, The Netherlands; Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Aranka V Ballering
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, De Boelelaan 1109, 1081 HZ Amsterdam, The Netherlands; Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands
| | - Agnès Jamin
- National French Institute of Health and Medical Research (INSERM) U1149, Centre de Recherche Sur l'Inflammation, 16 Rue Henri Huchard, Paris 75018, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, 16 Rue Henri Huchard, Paris 75018, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France
| | - Sanae Ben Mkaddem
- National French Institute of Health and Medical Research (INSERM) U1149, Centre de Recherche Sur l'Inflammation, 16 Rue Henri Huchard, Paris 75018, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, 16 Rue Henri Huchard, Paris 75018, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France
| | - Renato C Monteiro
- National French Institute of Health and Medical Research (INSERM) U1149, Centre de Recherche Sur l'Inflammation, 16 Rue Henri Huchard, Paris 75018, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, 16 Rue Henri Huchard, Paris 75018, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France
| | - Marjolein Van Egmond
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, De Boelelaan 1109, 1081 HZ Amsterdam, The Netherlands; Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands; Department of Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
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27
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Protein energy malnutrition alters mucosal IgA responses and reduces mucosal vaccine efficacy in mice. Immunol Lett 2017; 190:247-256. [PMID: 28860040 DOI: 10.1016/j.imlet.2017.08.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 05/26/2017] [Accepted: 08/24/2017] [Indexed: 01/27/2023]
Abstract
Oral vaccine responsiveness is often lower in children from less developed countries. Childhood malnutrition may be associated with poor immune response to oral vaccines. The present study was designed to investigate whether protein energy malnutrition (PEM) impairs B cell immunity and ultimately reduces oral vaccine efficacy in a mouse model. Purified isocaloric diets containing low protein (1/10 the protein of the control diet) were used to determine the effect of PEM. PEM increased both nonspecific total IgA and oral antigen-specific IgA in serum without alteration of gut permeability. However, PEM decreased oral antigen-specific IgA in feces, which is consistent with decreased expression of polymeric Immunoglobulin receptor (pIgR) in the small intestine. Of note, polymeric IgA was predominant in serum under PEM. In addition, PEM altered B cell development status in the bone marrow and increased the frequency of IgA-secreting B cells, as well as IgA secretion by long-lived plasma cells in the small intestinal lamina propria. Moreover, PEM reduced the protective efficacy of the mucosally administered cholera vaccine and recombinant attenuated Salmonella enterica serovar Typhimurium vaccine in a mouse model. Our results suggest that PEM can impair mucosal immunity where IgA plays an important role in host protection and may partly explain the reduced efficacy of oral vaccines in malnourished subjects.
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28
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Renal Outcomes in Patients With IgA Nephropathy Undergoing Liver Transplant: A Retrospective Cohort Study. Transplant Direct 2017; 3:e193. [PMID: 28795144 PMCID: PMC5540631 DOI: 10.1097/txd.0000000000000708] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 06/09/2017] [Indexed: 01/09/2023] Open
Abstract
Background End-stage liver disease (ESLD) is the most common cause of secondary immunoglobulin A nephropathy (IgAN). Multiple mechanisms have been proposed to explain the association between liver disease and IgAN. Although some mechanisms are expected to reverse in patients after liver transplant, the long-term renal prognosis is unclear for these patients. Methods This observational retrospective cohort study examined the renal outcomes of 14 patients who had IgAN with end-stage liver disease and subsequently underwent either liver transplant alone or combined liver and kidney transplant at a single tertiary care center. Results Of the 7 patients who underwent liver transplant alone, hematuria persisted in 2, 4 had progressive loss of kidney function with worsening proteinuria in 3 but only 1 reached end-stage renal disease 5 years posttransplant. Among 7 combined liver and kidney transplant recipients, 1 had histologic and 1 had histologic and clinical recurrence of IgAN without kidney allograft loss. Conclusions IgAN in patients with advanced liver disease does not necessarily resolve after liver transplant but has overall favorable renal outcomes.
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29
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Lee KY. A unified pathogenesis for kidney diseases, including genetic diseases and cancers, by the protein-homeostasis-system hypothesis. Kidney Res Clin Pract 2017; 36:132-144. [PMID: 28680821 PMCID: PMC5491160 DOI: 10.23876/j.krcp.2017.36.2.132] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/20/2016] [Accepted: 02/02/2017] [Indexed: 12/14/2022] Open
Abstract
Every cell of an organism is separated and protected by a cell membrane. It is proposed that harmony between intercellular communication and the health of an organism is controlled by a system, designated the protein-homeostasis-system (PHS). Kidneys consist of a variety of types of renal cells, each with its own characteristic cell-receptor interactions and producing characteristic proteins. A functional union of these renal cells can be determined by various renal function tests, and harmonious intercellular communication is essential for the healthy state of the host. Injury to a kind of renal cells can impair renal function and induce an imbalance in total body health. Every acute or chronic renal disease has unknown etiologic substances that are responsible for renal cell injury at the molecular level. The immune/repair system of the host should control the etiologic substances acting against renal cells; if this system fails, the disease progresses to end stage renal disease. Each renal disease has its characteristic pathologic lesions where immune cells and immune proteins, such as immunoglobulins and complements, are infiltrated. These immune cells and immune proteins may control the etiologic substances involved in renal pathologic lesions. Also, genetic renal diseases and cancers may originate from a protein deficiency or malfunctioning protein under the PHS. A unified pathogenesis for renal diseases, including acute glomerulonephritis, idiopathic nephrotic syndrome, immunoglobulin A nephropathy, genetic renal diseases such as Alport syndrome, and malignancies such as Wilms tumor and renal cell carcinoma, is proposed using the PHS hypothesis.
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Affiliation(s)
- Kyung-Yil Lee
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Pediatrics, The Catholic University of Korea, Daejeon St. Mary's Hospital, Daejeon, Korea
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30
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Jhee JH, Kang HY, Wu M, Nam BY, Chang TI, Jung SY, Park S, Kim H, Yun HR, Kee YK, Yoon CY, Park JT, Yoo TH, Kang SW, Han SH. Circulating CD89-IgA complex does not predict deterioration of kidney function in Korean patients with IgA nephropathy. ACTA ACUST UNITED AC 2017; 56:75-85. [DOI: 10.1515/cclm-2017-0090] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 04/17/2017] [Indexed: 12/15/2022]
Abstract
Abstract
Background:
Soluble CD89 (sCD89)-IgA complex plays a key role in the pathogenesis of IgA nephropathy (IgAN). However, there is a lack of evidence supporting this complex as a good biomarker for disease progression. This study aimed to evaluate the usefulness of sCD89-IgA complex for risk stratification of IgAN.
Methods:
A total of 326 patients with biopsy-proven IgAN were included. sCD89-IgA complex was measured by sandwich-enzyme-linked immunosorbent assay. The study endpoints were a 30% decline in estimated glomerular filtration rate (eGFR).
Results:
sCD89-IgA complex levels were inversely and weakly associated with eGFR at the time of biopsy (r=−0.12, p=0.03). However, the significance between the two factors was lost in the multivariate linear regression after adjustment of clinical factors (β=0.35, p=0.75). In a multivariate Cox model, the highest (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.35–1.61; p=0.45) and middle (HR, 0.93; 95% CI, 0.46–1.89; p=0.84) tertiles of sCD89-IgA complex levels were not associated with an increased risk of developing a 30% decrease in eGFR. Furthermore, the decline rates in eGFR did not differ between groups and C-statistics revealed that the sCD89-IgA complex were not superior to clinical factors in predicting disease progression.
Conclusions:
This study found no association between sCD89-IgA complex levels and disease progression in IgAN. Although sCD89 can contribute to the formation of immune complexes, our findings suggest that the sCD89-IgA level is not a good predictor of adverse outcomes and has limited clinical utility as a biomarker for risk stratification in IgAN.
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Affiliation(s)
- Jong Hyun Jhee
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Hye-Young Kang
- Severance Biomedical Science Institute, Brain Korea 21 PLUS , Yonsei University , Seoul , Republic of Korea
| | - Meiyan Wu
- Severance Biomedical Science Institute, Brain Korea 21 PLUS , Yonsei University , Seoul , Republic of Korea
- Department of Nephrology , The First Hospital of Jilin University , Changchun , P.R. China
| | - Bo Young Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS , Yonsei University , Seoul , Republic of Korea
| | - Tae-Ik Chang
- Department of Internal Medicine , National Health Insurance Service Medical Center, Ilsan Hospital , Gyeonggi-do , Republic of Korea
| | - Su-Young Jung
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Seohyun Park
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Hyoungnae Kim
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Hae-Ryong Yun
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Youn Kyung Kee
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Chang-Yun Yoon
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Jung Tak Park
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Tae-Hyun Yoo
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
| | - Shin-Wook Kang
- Department of Internal Medicine , College of Medicine, Institute of Kidney Disease Research , Yonsei University , Seoul , Republic of Korea
- Severance Biomedical Science Institute, Brain Korea 21 PLUS , Yonsei University , Seoul , Republic of Korea
| | - Seung Hyeok Han
- Department of Internal Medicine , Severance Hospital , Yonsei University College of Medicine , 50-1 Yonsei-ro, Seodaemun-gu , Seoul , 120-752, Korea
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Harvey DJ. Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: An update for 2011-2012. MASS SPECTROMETRY REVIEWS 2017; 36:255-422. [PMID: 26270629 DOI: 10.1002/mas.21471] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 01/15/2015] [Indexed: 06/04/2023]
Abstract
This review is the seventh update of the original article published in 1999 on the application of MALDI mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2012. General aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, and fragmentation are covered in the first part of the review and applications to various structural types constitute the remainder. The main groups of compound are oligo- and poly-saccharides, glycoproteins, glycolipids, glycosides, and biopharmaceuticals. Much of this material is presented in tabular form. Also discussed are medical and industrial applications of the technique, studies of enzyme reactions, and applications to chemical synthesis. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:255-422, 2017.
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Affiliation(s)
- David J Harvey
- Department of Biochemistry, Oxford Glycobiology Institute, University of Oxford, Oxford, OX1 3QU, UK
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32
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Cheong J, Galanko JA, Arora S, Cabezas J, Ndugga NJ, Lucey MR, Hayashi PH, Barritt AS, Bataller R. Reduced impact of renal failure on the outcome of patients with alcoholic liver disease undergoing liver transplantation. Liver Int 2017; 37:290-298. [PMID: 27258535 PMCID: PMC5136341 DOI: 10.1111/liv.13182] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 06/02/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Pretransplant renal failure is commonly reported to be a poor prognostic indicator affecting survival after liver transplantation (LT). However, whether the impact of renal failure on patient outcome varies according to the aetiology of the underlying liver disease is largely unknown. METHODS We investigated the association between renal failure at the time of LT and patient outcome in patients with alcoholic liver disease (ALD) (n = 6920), non-alcoholic steatohepatitis (NASH) (n = 2956) and hepatitis C (HCV) (n = 14 922) using the United Network for Organ Sharing (UNOS) database between February 2002 and December 2013. A total of 24 798 transplant recipients were included. RESULTS The presence of renal failure was more frequently seen in patients with ALD (23.95%) and NASH (23.27%) compared to patients with HCV (19.38%) (P < 0.001). In multivariate analysis, renal failure was an independent predictor of poor survival. Renal failure showed detrimental effect on patient survival in the overall series (HR = 1.466, P < 0.0001). Importantly, the impact of renal failure was less marked in patients with ALD (HR = 1.31, P < 0.0001) than in patients with NASH (HR = 1.73, P < 0.0001) or HCV (HR = 1.52, P < 0.0001). Despite a higher model for end-stage liver disease (MELD) score at the time of LT, ALD patients with renal failure had better long-term prognosis than non-ALD patients. CONCLUSIONS Renal failure at the time of LT conferred a lower patient and graft survival post-LT. However, renal failure has less impact on the outcome of patients with ALD than that of patients with non-alcoholic liver disease after LT.
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Affiliation(s)
- Jaeyoun Cheong
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC,Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Joseph A. Galanko
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Sumant Arora
- Department of Medicine, University of Alabama at Birmingham, Montgomery, AL
| | - Joaquin Cabezas
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC,Department of Gastroenterology and Hepatology, University Hospital Marques de Valdecilla, Santander, Spain
| | - Nambi J. Ndugga
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Michael R. Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin, Madison, WI
| | - Paul H. Hayashi
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - A. Sidney Barritt
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Kim SM, Song IH. [Acute Kidney Injury in Cirrhotic Patients with Portal Hypertension]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2016; 68:237-244. [PMID: 27871159 DOI: 10.4166/kjg.2016.68.5.237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Acute kidney injury (AKI) is one of the most common manifestations encountered in clinical practice. It is associated with high morbidity and mortality in cirrhotic pre- and post-transplantation patients. Hepatorenal syndrome (HRS), a special form of AKI in cirrhotic patients, was recognized as a consequence of renal vasoconstriction from systemic/renal hemodynamic alterations developed in advanced cirrhosis with portal hypertension. Recently, multiple factors-such as infection/inflammation, underlying glomerulonephritis, bile cast, or increased abdominal pressure-have been considered to contribute to renal dysfunction in cirrhotic patients, which were presumed to induce HRS. Moreover, in addition to changing the definition of AKI in the nephrologic guidelines, the new AKI definition for early diagnosis and intervention based on characteristics of liver cirrhosis has been proposed in an international meeting. This article provides a comprehensive and recent review of AKI definition, laying out the topics in accordance with the pathophysiologic mechanisms and therapeutic interventions of AKI in cirrhotic patients with portal hypertension.
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Affiliation(s)
- So Mi Kim
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Il Han Song
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
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Moresco RN, Speeckaert MM, Zmonarski SC, Krajewska M, Komuda-Leszek E, Perkowska-Ptasinska A, Gesualdo L, Rocchetti MT, Delanghe SE, Vanholder R, Van Biesen W, Delanghe JR. Urinary myeloid IgA Fc alpha receptor (CD89) and transglutaminase-2 as new biomarkers for active IgA nephropathy and henoch-Schönlein purpura nephritis. BBA CLINICAL 2016; 5:79-84. [PMID: 27051593 PMCID: PMC4802400 DOI: 10.1016/j.bbacli.2016.02.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 02/06/2016] [Accepted: 02/16/2016] [Indexed: 10/25/2022]
Abstract
BACKGROUND IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) are glomerular diseases that share a common and central pathogenic mechanism. The formation of immune complexes containing IgA1, myeloid IgA Fc alpha receptor (FcαRI/CD89) and transglutaminase-2 (TG2) is observed in both conditions. Therefore, urinary CD89 and TG2 could be potential biomarkers to identify active IgAN/HSPN. METHODS In this multicenter study, 160 patients with IgAN or HSPN were enrolled. Urinary concentrations of CD89 and TG2, as well as some other biochemical parameters, were measured. RESULTS Urinary CD89 and TG2 were lower in patients with active IgAN/HSPN compared to IgAN/HSPN patients in complete remission (P < 0.001). The CD89xTG2 formula had a high ability to discriminate active from inactive IgAN/HSPN in both situations: CD89xTG2/proteinuria ratio (AUC: 0.84, P < 0.001, sensitivity: 76%, specificity: 74%) and CD89xTG2/urinary creatinine ratio (AUC: 0.82, P < 0.001, sensitivity: 75%, specificity: 74%). Significant correlations between urinary CD89 and TG2 (r = 0.711, P < 0.001), proteinuria and urinary CD89 (r = - 0.585, P < 0.001), and proteinuria and urinary TG2 (r = - 0.620, P < 0.001) were observed. CONCLUSIONS Determination of CD89 and TG2 in urine samples can be useful to identify patients with active IgAN/HSPN.
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Affiliation(s)
- Rafael N. Moresco
- Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, Brazil
- Department of Clinical Chemistry, Ghent University Hospital, Gent, Belgium
| | | | - Slawomir C. Zmonarski
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - Ewa Komuda-Leszek
- Department of Transplantation Medicine and Nephrology, Medical University of Warsaw, Warsaw, Poland
| | | | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Section of Nephrology, University of Bari “Aldo Moro”, Bari, Italy
| | - Maria T. Rocchetti
- Department of Emergency and Organ Transplantation, Section of Nephrology, University of Bari “Aldo Moro”, Bari, Italy
| | | | | | - Wim Van Biesen
- Department of Nephrology, Ghent University Hospital, Gent, Belgium
| | - Joris R. Delanghe
- Department of Clinical Chemistry, Ghent University Hospital, Gent, Belgium
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35
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Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestecky J, Raska M, Renfrow MB, Julian BA, Novak J. The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy. Front Immunol 2016; 7:117. [PMID: 27148252 PMCID: PMC4828451 DOI: 10.3389/fimmu.2016.00117] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 03/15/2016] [Indexed: 12/12/2022] Open
Abstract
IgA nephropathy (IgAN) is the most common primary glomerulonephritis, frequently leading to end-stage renal disease, as there is no disease-specific therapy. IgAN is diagnosed from pathological assessment of a renal biopsy specimen based on predominant or codominant IgA-containing immunodeposits, usually with complement C3 co-deposits and with variable presence of IgG and/or IgM. The IgA in these renal deposits is galactose-deficient IgA1, with less than a full complement of galactose residues on the O-glycans in the hinge region of the heavy chains. Research from the past decade led to the definition of IgAN as an autoimmune disease with a multi-hit pathogenetic process with contributing genetic and environmental components. In this process, circulating galactose-deficient IgA1 (autoantigen) is bound by antiglycan IgG or IgA (autoantibodies) to form immune complexes. Some of these circulating complexes deposit in glomeruli, and thereby activate mesangial cells and induce renal injury through cellular proliferation and overproduction of extracellular matrix components and cytokines/chemokines. Glycosylation pathways associated with production of the autoantigen and the unique characteristics of the corresponding autoantibodies in patients with IgAN have been uncovered. Complement likely plays a significant role in the formation and the nephritogenic activities of these complexes. Complement activation is mediated through the alternative and lectin pathways and probably occurs systemically on IgA1-containing circulating immune complexes as well as locally in glomeruli. Incidence of IgAN varies greatly by geographical location; the disease is rare in central Africa but accounts for up to 40% of native-kidney biopsies in eastern Asia. Some of this variation may be explained by genetically determined influences on the pathogenesis of the disease. Genome-wide association studies to date have identified several loci associated with IgAN. Some of these loci are associated with the increased prevalence of IgAN, whereas others, such as deletion of complement factor H-related genes 1 and 3, are protective against the disease. Understanding the molecular mechanisms and genetic and biochemical factors involved in formation and activities of pathogenic IgA1-containing immune complexes will enable the development of future disease-specific therapies as well as identification of non-invasive disease-specific biomarkers.
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Affiliation(s)
- Barbora Knoppova
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic
| | - Colin Reily
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nicolas Maillard
- Université Jean Monnet, Saint Etienne, France
- PRES Université de Lyon, Lyon, France
| | - Dana V. Rizk
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zina Moldoveanu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jiri Mestecky
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Milan Raska
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, Olomouc, Czech Republic
| | - Matthew B. Renfrow
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Bruce A. Julian
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jan Novak
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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36
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Molecular Insights into the Pathogenesis of IgA Nephropathy. Trends Mol Med 2015; 21:762-775. [DOI: 10.1016/j.molmed.2015.10.003] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 10/17/2015] [Accepted: 10/19/2015] [Indexed: 01/04/2023]
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Bissonnette MLZ, Henriksen KJ, Delaney K, Stankus N, Chang A. Medullary Microvascular Thrombosis and Injury in Sickle Hemoglobin C Disease. J Am Soc Nephrol 2015; 27:1300-4. [PMID: 26546258 DOI: 10.1681/asn.2015040399] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Sickle cell nephropathy is a common complication in patients with sickle cell hemoglobinopathies. In these disorders, polymerization of mutated hemoglobin S results in deformation of red blood cells, which can cause endothelial cell injury in the kidney that may lead to thrombus formation when severe or manifest by multilayering of the basement membranes (glomerular and/or peritubular capillaries) in milder forms of injury. As the injury progresses, the subsequent ischemia, tubular dysfunction, and glomerular scarring can result in CKD or ESRD. Sickle cell nephropathy can occur in patients with homozygous hemoglobin SS or heterozygous hemoglobin S (hemoglobin SC, hemoglobin S/β(0)-thalassemia, and hemoglobin S/β(+)-thalassemia). Clinical manifestations resulting from hemoglobin S polymerization are often milder in patients with heterozygous hemoglobin S. These patients may not present with clinically apparent acute sickle cell crises, but these milder forms can provide a unique view of the kidney injury in sickle cell disease. Here, we report a patient with hemoglobin SC disease who showed peritubular capillary and vasa recta thrombi and capillary basement membrane alterations primarily involving the renal medulla. This patient highlights the vascular occlusion and endothelial cell injury in the medulla that contribute to sickle cell nephropathy.
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38
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Aleyd E, Heineke MH, van Egmond M. The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease. Immunol Rev 2015; 268:123-38. [DOI: 10.1111/imr.12337] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Esil Aleyd
- Department of Molecular Cell Biology and Immunology; VU University Medical Center; Amsterdam The Netherlands
| | - Marieke H. Heineke
- Department of Molecular Cell Biology and Immunology; VU University Medical Center; Amsterdam The Netherlands
| | - Marjolein van Egmond
- Department of Molecular Cell Biology and Immunology; VU University Medical Center; Amsterdam The Netherlands
- Department of Surgery; VU University Medical Center; Amsterdam The Netherlands
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39
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Almeida J, Polvorosa MA, Gonzalez-Quintela A, Madruga I, Marcos M, Pérez-Nieto MA, Hernandez-Cerceño ML, Orfao A, Laso FJ. Altered Distribution of Peripheral Blood Maturation-Associated B-Cell Subsets in Chronic Alcoholism. Alcohol Clin Exp Res 2015; 39:1476-84. [PMID: 26146763 DOI: 10.1111/acer.12783] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 05/14/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although decreased counts of peripheral blood (PB) B cells-associated with an apparently contradictory polyclonal hypergammaglobulinemia-have been reported in chronic alcoholism, no information exists about the specific subsets of circulating B cells altered and their relationship with antibody production. Here, we analyzed for the first time the distribution of multiple maturation-associated subpopulations of PB B cells in alcoholism and its potential relationship with the onset of liver disease. METHODS PB samples from 35 male patients-20 had alcoholic hepatitis (AH) and 15 chronic alcoholism without liver disease (AWLD)-were studied, in parallel to 19 male healthy donors (controls). The distribution of PB B-cell subsets (immature/regulatory, naïve, CD27(-) and CD27(+) memory B lymphocytes, and circulating plasmablasts of distinct immunoglobulin-Ig-isotypes) was analyzed by flow cytometry. RESULTS Patients with AH showed significantly decreased numbers of total PB B lymphocytes (vs. controls and AWLD), at the expense of immature, memory, and, to a lesser extent, also naïve B cells. AWLD showed reduced numbers of immature and naïve B cells (vs. controls), but higher PB counts of plasmablasts (vs. the other 2 groups). Although PB memory B cells were reduced among the patients, the percentage of surface (s)IgA(+) cells (particularly CD27(-) /sIgA(+) cells) was increased in AH, whereas both sIgG(+) and sIgA(+) memory B cells were significantly overrepresented in AWLD versus healthy donors. Regarding circulating plasmablasts, patients with AH only showed significantly reduced counts of sIgG(+) cells versus controls. In contrast, the proportion of both sIgA(+) and sIgG(+) plasmablasts-from all plasmablasts-was reduced in AH and increased in AWLD (vs. the other 2 groups). CONCLUSIONS AH and AWLD patients display a significantly reduced PB B-cell count, at the expense of decreased numbers of recently produced immature/regulatory B cells and naïve B cells, together with an increase in Ig-switched memory B lymphocytes and plasmablasts, particularly of IgA(+) cells.
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Affiliation(s)
- Julia Almeida
- Instituto de Biologia Molecular y Celular del Cancer, Centro de Investigacion del Cancer/IBMCC (CSIC-USAL), Institute of Biomedical Research of Salamanca (IBSAL), Cytometry Service, Salamanca, Spain.,Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Maria Angeles Polvorosa
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain.,Department of Medicine, IBSAL, University of Salamanca, Salamanca, Spain
| | - Arturo Gonzalez-Quintela
- Department of Internal Medicine, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Ignacio Madruga
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain.,Department of Medicine, IBSAL, University of Salamanca, Salamanca, Spain
| | - Miguel Marcos
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain.,Department of Medicine, IBSAL, University of Salamanca, Salamanca, Spain
| | - Maria Angeles Pérez-Nieto
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain.,Department of Medicine, IBSAL, University of Salamanca, Salamanca, Spain
| | | | - Alberto Orfao
- Instituto de Biologia Molecular y Celular del Cancer, Centro de Investigacion del Cancer/IBMCC (CSIC-USAL), Institute of Biomedical Research of Salamanca (IBSAL), Cytometry Service, Salamanca, Spain.,Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Francisco Javier Laso
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain.,Department of Medicine, IBSAL, University of Salamanca, Salamanca, Spain
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Berthelot L, Robert T, Vuiblet V, Tabary T, Braconnier A, Dramé M, Toupance O, Rieu P, Monteiro RC, Touré F. Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes. Kidney Int 2015; 88:815-22. [PMID: 26061544 DOI: 10.1038/ki.2015.158] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Revised: 03/24/2015] [Accepted: 04/09/2015] [Indexed: 12/22/2022]
Abstract
IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently leads to end-stage renal disease and kidney transplantation. However, disease recurrence often occurs after transplantation. Here we evaluated the predictive value of three markers for IgAN recurrence: the presence of galactose-deficient IgA1, IgG anti-IgA autoantibodies, and IgA-soluble (s) CD89 complexes. This was analyzed in 38 kidney transplant recipients with IgAN recurrence and compared with 22 patients transplanted for IgAN but without recurrence and with 17 healthy controls. Pre-transplantation galactose-deficient IgA1 serum levels were significantly higher in the recurrence compared with the no recurrence or control groups. IgA-IgG complexes were significantly elevated in the recurrence group. Both the recurrence and no recurrence groups had increased values of IgA-sCD89 complexes compared with healthy controls, but values were significantly lower in patients with recurrence compared with no recurrence. Areas under the receiver operating curve of the markers in pre-transplantation sera were 0.86 for galactose-deficient-IgA, 0.82 for IgA-IgG, and 0.78 for sCD89-IgA; all significant. Disease recurrence was associated with decreased serum galactose-deficient IgA1 and appearance of mesangial-galactose-deficient IgA1 deposits, whereas increased serum IgA-sCD89 complexes were associated with mesangial sCD89 deposits. Thus, galactose-deficient-IgA1, IgG autoantibodies, and IgA-sCD89 complexes are valuable biomarkers to predict disease recurrence, highlighting major pathogenic mechanisms in IgAN.
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Affiliation(s)
- Laureline Berthelot
- INSERM U1149, Faculté Bichat Medical School, ELR8252 CNRS, Center for Research on Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, DHU Fire, France.,Inflamex Laboratory of Excellence, Site Xavier Bichat, France
| | - Thomas Robert
- Department of Nephrology, Hôpital Maison Blanche-CHU Reims, Reims, France
| | - Vincent Vuiblet
- Department of Nephrology, Hôpital Maison Blanche-CHU Reims, Reims, France.,CNRS URCA UMR 7369, Reims, France
| | - Thierry Tabary
- Laboratory of Immunology, EA3798 CHU Reims, IFR53 URCA, Reims, France
| | - Antoine Braconnier
- Department of Nephrology, Hôpital Maison Blanche-CHU Reims, Reims, France
| | - Moustapha Dramé
- Department of Research and Innovation, CHU Reims, Reims, France
| | - Olivier Toupance
- Department of Nephrology, Hôpital Maison Blanche-CHU Reims, Reims, France
| | - Philippe Rieu
- Department of Nephrology, Hôpital Maison Blanche-CHU Reims, Reims, France.,CNRS URCA UMR 7369, Reims, France
| | - Renato C Monteiro
- INSERM U1149, Faculté Bichat Medical School, ELR8252 CNRS, Center for Research on Inflammation, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, DHU Fire, France.,Inflamex Laboratory of Excellence, Site Xavier Bichat, France.,Service d'Immunologie, Assistance Publique de Paris, Hôpital Bichat-Claude Bernard, DHU Fire, Paris, France
| | - Fatouma Touré
- Department of Nephrology, Hôpital Maison Blanche-CHU Reims, Reims, France.,CNRS URCA UMR 7369, Reims, France
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41
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Moresco RN, Speeckaert MM, Delanghe JR. Diagnosis and monitoring of IgA nephropathy: the role of biomarkers as an alternative to renal biopsy. Autoimmun Rev 2015; 14:847-53. [PMID: 26026694 DOI: 10.1016/j.autrev.2015.05.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 05/20/2015] [Indexed: 12/13/2022]
Abstract
IgA nephropathy (IgAN) is the most prevalent form of chronic glomerulonephritis in the world. The underlying pathogenesis of this autoimmune disease comprises the formation of immune complexes, including glycan-specific IgA1 or IgG antibodies and an aberrant glycosylation of IgA1. Until now, anatomopathological analysis of renal biopsies is essential for the diagnosis of IgAN and different histological classification systems have been proposed, e.g. the Oxford classification. However, a percutaneous renal biopsy is frequently not performed for several reasons and the Oxford classification system has some limitations. Since the poor prognosis of IgAN patients is partly the result of a delayed diagnosis, there is an urgent need for reliable noninvasive biomarkers that might be applicable in routine clinical practice. This article reviews the advances on the understanding of the underlying pathophysiological mechanisms of IgAN and discusses in depth the recent development of new biomarkers, including the use of proteomics and microRNAs.
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Affiliation(s)
- Rafael N Moresco
- Department of Clinical Chemistry, Ghent University Hospital, Gent, Belgium; Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, Brazil
| | | | - Joris R Delanghe
- Department of Clinical Chemistry, Ghent University Hospital, Gent, Belgium.
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42
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Association Between Post-transplantation Immunoglobulin A Deposition and Reduced Allograft Function. Transplant Proc 2015; 47:332-6. [DOI: 10.1016/j.transproceed.2015.01.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 01/14/2015] [Indexed: 12/14/2022]
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Quantitative analysis of immunoglobulin subclasses and subclass specific glycosylation by LC-MS-MRM in liver disease. J Proteomics 2015; 116:24-33. [PMID: 25582524 DOI: 10.1016/j.jprot.2014.12.020] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Revised: 11/13/2014] [Accepted: 12/09/2014] [Indexed: 12/23/2022]
Abstract
UNLABELLED Aberrant glycosylation of IgGs has been linked to human diseases, including liver disease. In this study, we have quantified plasma immunoglobulins in cirrhosis (CIR) and hepatocellular carcinoma (HCC) and employed a novel LC-MS-MRM assay to quantify glycoforms of IgG subclasses 1-4. Glycan oxonium ions and peptide-GlcNAc fragment ions were utilized to quantify the IgG glycoforms purified by affinity chromatography with normalization to the unique peptide for each IgG subclass. Our results indicate that HCC patients have increased circulating IgG1, IgG3, IgA1, and IgM compared to healthy controls; comparison of HCC and CIR patients shows that HCC patients have significantly higher concentration of IgG1 and IgM but lower concentration of IgG2. An increase in galactose-deficient core fucosylated glycoforms was consistently observed in CIR and HCC patients. The FA2G0 and FA2BG0 glycoforms increase approximately 2-fold in all IgG subclasses accompanied by a decrease in the FA2G2 glycoform. Fucosylation changes are less pronounced but we have detected increased degree of fucosylation in the IgG1 and IgG3 glycoforms. In conclusion, we have optimized a sensitive and selective LC-MS-MRM method for the quantification of immunoglobulin subclasses and their site specific glycoforms, demonstrating that both quantities and glycoforms of immunoglobulins change significantly in liver disease progression to HCC. BIOLOGICAL SIGNIFICANCE We have demonstrated that both quantities and glycoforms of immunoglobulin subclasses change significantly in liver disease progression to HCC through quantitative study of immunoglobulin subclasses and their site specific glycoforms using a sensitive and selective LC-MS-MRM method. Redistribution of the glycoforms of specific immunoglobulin subclasses could have important implications for receptor mediated responses affecting the progression of liver disease.
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Abstract
Renal impairment is common in liver disease and may occur as a consequence of the pathophysiological changes that underpin cirrhosis or secondary to a pre-existing unrelated insult. Nevertheless, the onset of renal impairment often portends a worsening prognosis. Hepatorenal syndrome remains one of the most recognized and reported causes of renal impairment in cirrhosis. However, other causes of renal impairment occur and can be classified into prerenal, intrinsic or postrenal, which are the subjects of the present review.
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Novak J, Raska M, Mestecky J, Julian BA. IgA Nephropathy and Related Diseases. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00105-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Goulabchand R, Vincent T, Batteux F, Eliaou JF, Guilpain P. Impact of autoantibody glycosylation in autoimmune diseases. Autoimmun Rev 2014; 13:742-50. [DOI: 10.1016/j.autrev.2014.02.005] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 02/01/2014] [Indexed: 12/12/2022]
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Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 60:1055-62. [PMID: 24445215 DOI: 10.1016/j.jhep.2014.01.010] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 12/11/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS A third of the population are estimated to have NAFLD of varying severity. Serum immunoglobulins are frequently elevated in patients with chronic liver disease, but little is known about serum immunoglobulin levels in patients with NAFLD. Aim of this study was to evaluate serum immunoglobulin levels (IgA, IgG, and IgM) in a large cohort of patients with biopsy-proven NAFLD and determine if immunoglobulin levels are associated with clinical or histological features. METHODS Patients seen in a tertiary fatty liver clinic between 1999 and 2009 were included. Liver biopsies were assessed using the Kleiner score. Immunoglobulin levels and other blood tests were taken at time of biopsy. RESULTS 285 patients (110 simple steatosis and 175 NASH) had serum immunoglobulins measured within 6months of liver biopsy. 130 (46%) patients had elevated (>1× upper limit of normal) serum IgA levels, 28 (10%) patients had elevated IgG and 22 (8%) raised IgM. Serum IgA levels were elevated more frequently in patients with NASH compared with subjects with simple steatosis (55% vs. 31%, p<0.001). Overall, 55 (19%) patients had advanced liver fibrosis (Kleiner stage 3-4). There was a significant positive association between serum IgA levels and the stage of fibrosis (p<0.001). Serum IgA, age, platelets, AST/ALT ratio and BMI were all independently with advanced fibrosis following multivariate analysis. A model constructed from these independent predictors accurately predicted advanced fibrosis (AUROC 0.87). CONCLUSIONS The serum IgA level was frequently elevated in patients with NAFLD and was an independent predictor of advanced fibrosis.
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New insights into the pathogenesis of IgA nephropathy. Semin Immunopathol 2014; 36:431-42. [PMID: 24442210 DOI: 10.1007/s00281-013-0411-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 11/26/2013] [Indexed: 01/10/2023]
Abstract
IgA nephropathy (IgAN) is the most common diagnosis amongst primary glomerular diseases in most countries where renal biopsies are regularly performed. Only a fraction of these patients is at high risk of losing glomerular filtration rate (GFR) in particular those with high grade proteinuria, uncontrolled hypertension or already impaired GFR at diagnosis, and those with renal scars in the renal biopsy. Genetic modifiers of IgAN onset and/or course are emerging. Spontaneous animal models of IgAN are problematic given considerable species differences between the rodent and human IgA system. However, new transgenic models help to better understand the pathogenesis. A key pathogenetic role appears to be played by underglycated IgA1 as well as autoantibodies to these IgA glycoforms and IgA receptors such as CD89 and transferrin receptor 1. Once IgA and/or IgA-containing immune complexes are deposited or formed in the mesangium, secondary effector mechanisms become important including complement activation, release of mesangial growth factors (in particular platelet-derived growth factor), and finally non-IgAN-specific events that culminate in glomerular and subsequently renal tubulointerstitial scaring. Here, we review these processes and describe potential novel therapeutic targets in IgAN.
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Glycosylation des autoanticorps au cours des maladies auto-immunes. Rev Med Interne 2013; 34:746-53. [DOI: 10.1016/j.revmed.2013.09.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 07/01/2013] [Accepted: 09/14/2013] [Indexed: 01/13/2023]
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Papp M, Sipeki N, Vitalis Z, Tornai T, Altorjay I, Tornai I, Udvardy M, Fechner K, Jacobsen S, Teegen B, Sumegi A, Veres G, Lakatos PL, Kappelmayer J, Antal-Szalmas P. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol 2013; 59:457-66. [PMID: 23639483 DOI: 10.1016/j.jhep.2013.04.018] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2012] [Revised: 04/12/2013] [Accepted: 04/16/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Anti-neutrophil cytoplasmic antibodies (ANCA) are a non-uniform family of antibodies recognizing diverse components of neutrophil granulocytes. ANCA formation might be induced by protracted bacterial infections or probably reflect an abnormal immune response to commensal microorganisms. Bacterial infections are common complications in cirrhosis with high incidence of episodes caused by enteric organisms, therefore, we sought to study the presence and clinical importance of ANCA in cirrhosis. METHODS Sera of 385 patients with cirrhosis of different etiologies were assayed for ANCA of IgG, IgA, IgA1, IgA2, and secretory IgA subtypes by indirect immunofluorescence and ELISAs. The control group comprised 202 patients with chronic liver diseases without cirrhosis and 100 healthy subjects. In cirrhosis, a 2-year follow-up, observational study was conducted to assess a possible association between the presence of ANCA and clinically significant bacterial infections. RESULTS Prevalence of ANCA IgA was significantly higher in cirrhosis (52.2%) compared to chronic liver diseases (18.6%) or healthy controls (0%, p<0.001 for both). ANCA IgA subtyping assays revealed marked increase in the proportion of IgA2 subtype (46% of total ANCA IgA) and presence of the secretory component concurrently. Presence of ANCA IgA was associated with disease-specific clinical characteristics (Child-Pugh stage and presence of ascites, p<0.001). During a 2-year follow-up period, risk of infections was higher among patients with ANCA IgA compared to those without (41.8% vs. 23.4%, p<0.001). ANCA IgA positivity was associated with a shorter time to the first infectious complication (pLogRank <0.001) in Kaplan-Meier analysis and was identified as an independent predictor in multivariate Cox-regression analysis (HR:1.74, 95% CI: 1.18-2.56, p=0.006). CONCLUSIONS Presence of IgA type ANCA is common in cirrhosis. Involvement of gut mucosal immune system is in center of their formation and probably reflects sustained exposure to bacterial constituents.
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Affiliation(s)
- Maria Papp
- 2nd Department of Medicine, Division of Gastroenterology, University of Debrecen, Debrecen, Hungary.
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