A Panel of Serum Biomarkers Differentiates IgA Nephropathy from Other Renal Diseases

Yanagawa, Hiroyuki; Suzuki, Hitoshi; Suzuki, Yusuke; Krzemieniecki, Krzysztof; Gharavi, Ali G.; Matsuoka, Kiyoshi; Makita, Yuko; Julian, Bruce A.; Novák, Jan; Tomino, Yasuhiko

doi:10.1371/journal.pone.0098081

Cited by 110 publications

(104 citation statements)

References 33 publications

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“…Anti-Gd-IgA1 IgG, or IgA antibodies, were found to be associated with a risk for progression, dialysis or death [30] and this was confirmed in an international study [16]. Notably, IgG anti-Gd-IgA1 can be detected in patients with or without high levels of Gd-IgA1.…”

Section: Biomarkers Specific To Iganmentioning

confidence: 74%

“…In patients with IgAN there is a high frequency of O-glycans consisting of GalNAc alone due to defective galactosylation (Gd-IgA1) [1,2]. Although Gd-IgA1 is a rather sensitive and specific marker for IgAN, as reported by most studies (with a sensitivity of 56-76 % and a specificity of 89-94 %) [14][15][16], discrepancies exist likely because of the technical pitfalls for detecting Gd-IgA1 based on lectin binding assays [17]. The development of a monoclonal antibody specific to Gd-IgA1 could offer a new appropriate biomarker [18]; however, using this specific test, only one third of IgAN patients had values higher than those of other diseases.…”

Section: Biomarkers Specific To Iganmentioning

confidence: 99%

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Biomarkers and targeted new therapies for IgA nephropathy

Coppo

2016

Pediatr Nephrol

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IgA nephropathy (IgAN) has variable clinical presentation and outcome. There is a need to identify children who have the potential to progress to end stage renal disease (ESRD). Biomarkers related to the pathogenetic process of IgAN can detect risk factors and identify targets for new therapies. Galactose-deficient IgA1 (Gd-IgA1) is a specific biomarker of IgAN and could be the first treatment target. In experimental mice, reduction of IgA1 deposits and hematuria was observed after treatment with a bacterial protease that selectively cleaves human IgA1. Glycan-targeted drugs that may act to neutralize Gd-IgA1 inhibit abnormal enzymatic glycosylation of IgA1 or deplete cells producing Gd-IgA1. The autoimmune response to Gd-IgA1 produces autoantibodies that are sensitive and specific biomarkers of IgAN development and progression and suggests the possible benefits of anti-B cell therapies directed against CD20, B-cell activating factor (BAFF), or B cell receptor, and also proteasome inhibitors. The activation of complement in IgAN offers new biomarkers and the rationale for using complement inhibitors, including eculizumab. Renal pathological features represent sensitive biomarkers of added value over clinical data and may drive steroid therapy in selected cases. Finally, the hypothesis of the involvement of intestinal mucosal immunity in the pathogenesis of IgAN suggests the possibility of avoiding the systemic effect of steroid. Enteric budesonide targeting Peyer's patches at the ileocecal junction is an interesting option that has provided some preliminary favorable results in IgAN. In conclusion, the identification of new biomarkers is a promising area for therapies targeting IgAN in patients at risk of progression.

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Section: Biomarkers Specific To Iganmentioning

confidence: 74%

Section: Biomarkers Specific To Iganmentioning

confidence: 99%

Biomarkers and targeted new therapies for IgA nephropathy

Coppo

2016

Pediatr Nephrol

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“…The glycosylation deficiency of IgA1 is O-glycosylation, which is characterized by a decrease in the degree of galactose modification at the end of GalNAc but direct sialylation by ST6GalNAc-II [18]. Therefore, the smooth docking and correct localization of glycosyltransferase in Golgi is one of the crucial factors for the IgA1 glycosylation.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Golgi Matrix Protein 130 Cause Aberrant IgA1 Glycosylation in IgA Nephropathy

Wang

Zhao

et al. 2019

Am J Nephrol

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Background: Aberrant O-glycosylation IgA1 production is a major factor in the pathogenesis of IgA nephropathy, but the underlying mechanism is still unclear. IgA1 glycosylation modification is in Golgi, and downregulation of the Golgi peripheral membrane protein Golgi matrix protein 130 (GM130) could lead to glycosylation deficiency. In this study, we aimed to explore the role of GM130 in glycosylate deficiency IgA1 (Gd-IgA1) production. Methods: We enrolled 27 IgA nephropathy patients, 12 patients with chronic tonsillitis, 15 non-IgAN chronic kidney disease patients, and 15 healthy volunteers as healthy control. We explored GM130 expression in Tonsillar tissue by immunofluorescence staining and Western blotting and expression in peripheral blood mononuclear cells (PBMCs) by flow cytometry. The concentration of IgA1 and level of O-glycosylation were determined by ELISA and Vicia Villosa lectin-binding assay. Real-time PCR and Western blot were used to analyze the levels of β1,3-Gal transferase (C1GALT1) and ST6GalNAC2, respectively. To explore the contribution of GM130 in IgA1 O-glycosylation modification, cells were subjected to experiments for evaluation of GM130 silencing by GM130-siRNA transfection. Results: GM130 expression was significantly decreased in tonsil tissues and PBMC of IgAN patients; the expression of C1GALT1 decreased and Gd-IgA1 level increased significantly in patients with IgAN patients. The expression of GM130 was negatively related to Gd-IgA1 production. By siRNA transfection, our results clearly indicated that the downregulation of GM130 can increase IgA1 O-glycosylation deficiency, which is thought to reduce C1GALT1 expression but not affect the expression of ST6GalNAC2. Conclusion: We identified and demonstrated that GM130 plays an important role in IgA1 O-glycans deficiency in IgAN patients, by negatively regulating C1GALT1 expression. We believe that this finding will provide theoretical foundations for a new mechanism of Gd-IgA1 production in IgAN patients.

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“…My colleagues Yanagawa and Suzuki et al [33] compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgA nephropathy patients, 79 patients with non-IgA nephropathy CKD and 106 healthy controls. Serum was collected at the time of renal biopsy from all IgA nephropathy and CKD patients.…”

Section: Iga Nephropathymentioning

confidence: 99%

“…Therefore, it can be concluded that serum levels of Gd-IgA1-specific antibodies are elevated in most IgA nephropathy patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgA nephropathy from other glomerular diseases [33]. …”

Section: Iga Nephropathymentioning

confidence: 99%

Pathogenesis and Treatment of Chronic Kidney Disease: A Review of Our Recent Basic and Clinical Data

Tomino

2014

Kidney Blood Press Res

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439

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Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of people from all racial and ethnic groups. At end of 2013, over 300,000 Japanese patients had maintenance dialysis therapy (JSDT). In Japan, the major causes of end stage kidney disease (ESKD) are chronic glomerulonephritis (particularly IgA nephropathy), type 2 diabetic nephropathy, and hypertensive nephrosclerosis. Hypertension is a major factor driving the progression of CKD to ESKD. Since many features of the pathogenesis of IgA nephropathy are still obscure, specific treatment is not yet available. However, efforts by investigators around the world have gradually clarified different aspects of the pathogenesis and treatment of IgA nephropathy. Today, around half of all diabetic patients in Japan receive medical treatment. Type 2 diabetic nephropathy is one of the major long-term microvascular complications occurring in nearly 40% of Japanese diabetic patients. The pathogenesis of diabetic nephropathy involves both genetic and environmental factors. However, the candidate genes related to the initiation and progression of the disorder are still obscure in patients with diabetic nephropathy. Regarding environmental factors, the toxicity of persistent hyperglycemia, reactive oxygen species, systemic and/or glomerular hypertension, dyslipidemia and complement are considered to play an important role. The first part of this review covers the pathogenesis of IgA nephropathy and type 2 diabetic nephropathy, and combines the clinicopathological findings in patients with our research on the ddY and KKA-y mouse models (spontaneous animal models for IgA nephropathy and diabetic nephropathy, respectively). In Japan, the major renal replacement therapies (RRT) are peritoneal dialysis (PD) and hemodialysis (HD). The second part of this review focuses on PD and HD. Based on our research findings from patients and as well as from animal models, we discuss strategies for the management of patients on PD and HD. i 2015 S. Karger AG, Basel

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A Panel of Serum Biomarkers Differentiates IgA Nephropathy from Other Renal Diseases

Cited by 110 publications

References 33 publications

Biomarkers and targeted new therapies for IgA nephropathy

Biomarkers and targeted new therapies for IgA nephropathy

Loss of the Golgi Matrix Protein 130 Cause Aberrant IgA1 Glycosylation in IgA Nephropathy

Pathogenesis and Treatment of Chronic Kidney Disease: A Review of Our Recent Basic and Clinical Data

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