Comment on: Clinical significance of IgG deposition in the glomerular mesangial area in patients with IgA nephropathy

Background: Aberrant galactose-deficient IgA1 molecules (Gd-IgA1) are important causal factors in IgA nephropathy (IgAN); however, the detection of Gd-IgA1 in IgAN is complicated and instable. A monoclonal antibody, KM55, which specifically recognizes Gd-IgA1 has been developed. In the present study, we further explored the clinical significance of Gd-IgA1 using KM55. Methods: In this study, we enrolled 75 patients with IgAN and 80 healthy controls and detected the plasma Gd-IgA1 levels using the KM55 ELISA method. We also stained mesangial Gd-IgA1 deposition using KM55. Results: We observed that the levels of plasma Gd-IgA1 in IgAN patients were elevated compared to the corresponding levels of healthy controls. Patients were divided into 2 groups based on the median of Gd-IgA1. Patients with high Gd-IgA1 levels had significantly higher levels of uric acid (UA) and IgA. The other clinical manifestations demonstrated that there were no differences in age, sex, blood pressure, initial proteinuria, hematuria, estimated glomerular filtration rate and Oxford pathological classification between the 2 groups of patients. In addition, positive correlations were observed between Gd-IgA1 and Bb, C3a, C4d and MAC. Mesangial Gd-IgA1 was positive in IgAN but negative in the normal renal tissue adjacent to neoplasm. We next analyzed the correlation between plasma Gd-IgA1 and mesangial Gd-IgA1 deposition. The results showed that a high level of plasma Gd-IgA1 was related to the deposition of mesangial Gd-IgA1, although the difference was not significant. Conclusion: We verified the elevated level of plasma and mesangial Gd-IgA1 in patients with IgAN by KM55, which provided an alternative, easy, and reliable tool for diagnosis and activity assessment of IgAN. The level of plasma Gd-IgA1 positively correlated with levels of UA, total IgA levels, and complement activation products.

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Clinical significance of histological grading and staging for predicting the effectiveness of steroid therapy in IgA nephropathy

Clinical and Experimental Nephrology ◽

10.1007/s101570070029 ◽

2000 ◽

Vol 4 (3) ◽

pp. 241-250 ◽

Cited By ~ 5

Author(s):

Kazuho Honda ◽

Kosaku Nitta ◽

Hideo Kobayashi ◽

Keiko Uchida ◽

Akira Kawashima ◽

...

Keyword(s):

Iga Nephropathy ◽

Clinical Significance ◽

Steroid Therapy ◽

Histological Grading

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microRNA-630 Regulates Underglycosylated IgA1 Production in the Tonsils by Targeting TLR4 in IgA Nephropathy

Frontiers in Immunology ◽

10.3389/fimmu.2020.563699 ◽

2020 ◽

Vol 11 ◽

Author(s):

Chan Liu ◽

Mu-Yao Ye ◽

Wen-Zhe Yan ◽

Xiao-Fei Peng ◽

Li-Yu He ◽

...

Keyword(s):

Iga Nephropathy ◽

Molecular Mechanisms ◽

Mononuclear Cells ◽

Immunohistochemical Analysis ◽

Bioinformatic Analysis ◽

Cell Culture Supernatant ◽

Mechanism Study ◽

Complement Components ◽

Mesangial Area ◽

Primary Glomerular Disease

IgA nephropathy (IgAN) is the most common primary glomerular disease. The characteristic pathology involves immune complexes formed by the deposition of IgA1 and underglycosylated IgA1 aggregates in the mesangial area, which may be accompanied by the deposition of IgG and/or IgM and complement components. However, the molecular mechanisms of IgAN remain unclear. In the present study, microarray analysis showed that the expression of microRNA-630 (miR-630) was significantly reduced in palatal tonsils from IgAN patients compared with chronic tonsillitis. Additionally, bioinformatic analysis showed that Toll-like receptor 4 (TLR4) was the predicted target gene of miR-630 and was regulated by miR-630. When miR-630 was overexpressed in palatal tonsil mononuclear cells from IgAN patients, the expression of TLR4 was reduced and the content of IgA1 in the cell culture supernatant was decreased, and the level of galactosylation in the IgA1 hinge region was increased. Moreover, immunohistochemical analysis showed that the expression of TLR4 in IgAN patients was significantly increased. After knocking down the expression of TLR4, both the concentration of IgA1 and the binding force of IgA1 with broad bean lectin were significantly reduced in IgAN. Furthermore, the mechanism study demonstrated that TLR4 might regulate the expression of IL-1β and IL-8 through NF-κB signaling pathway to modulate the concentration of IgA1 and the glycosylation level of IgA1. This interesting finding may offer new insight into the molecular mechanism of IgAN.

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The TLR4-MyD88-NF-κB pathway is involved in sIgA-mediated IgA nephropathy

Journal of Nephrology ◽

10.1007/s40620-020-00722-3 ◽

2020 ◽

Vol 33 (6) ◽

pp. 1251-1261 ◽

Cited By ~ 2

Author(s):

Junjun Zhang ◽

Yiming Mi ◽

Ruwen Zhou ◽

Zhangsuo Liu ◽

Bo Huang ◽

...

Keyword(s):

Iga Nephropathy ◽

Mesangial Cells ◽

Immunofluorescence Assay ◽

Kidney Damage ◽

Secretory Iga ◽

Tnf Α ◽

Mesangial Area ◽

Enhanced Expression ◽

Better Than

AbstractPrevious studies have shown that secretory IgA (sIgA) was critically involved in IgA nephropathy (IgAN) immune responses. Toll-like receptors (TLRs), especially TLR4 which participates in mucosal immunity, may be involved in the pathogenesis of IgAN. The purpose of this study was to investigate whether sIgA and TLR4 interact to mediate kidney damage in IgAN patients. IgAN patients with positive sIgA deposition in renal tissues were screened by immunofluorescence assay. Patient salivary sIgA (P-sIgA) was collected and purified by jacalin affinity chromatography. Salivary sIgA from healthy volunteers was used as a control (N-sIgA). Expression of TLR4, MyD88, NF-κB, TNF-α, IL-6, and MCP-1 were detected in the mesangial area of IgAN patients by immunohistochemistry, the expression levels in patients with positive sIgA deposition were higher than that with negative sIgA deposition. Human renal mesangial cells (HRMCs) were cultured in vitro, flow cytometry showed that P-sIgA bound HRMCs significantly better than N-sIgA. HRMCs were cultured in the presence of sIgA (400 μg/mL) for 24 h, compared with cells cultured with N-sIgA, HRMCs cultured in vitro with P-sIgA showed enhanced expression of TLR4, increased secretion of TNF-α, IL-6, and MCP-1, and increased expression of MyD88/NF-κB. TLR4 shRNA silencing and NF-κB inhibition both reduced the ability of HRMCs to synthesize TNF-α, IL-6, and MCP-1. Our results indicate that sIgA may induce high expression of TLR4 in HRMCs and further activate downstream signalling pathways, prompting HRMCs to secrete multiple cytokines and thereby mediating kidney damage in IgAN patients.

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IgA Nephropathy in Cirrhosis; Incidence, Pathogenesis, and Clinical Significance: Literature Review

The American Journal of Gastroenterology ◽

10.14309/00000434-200910003-00369 ◽

2009 ◽

Vol 104 ◽

pp. S139

Author(s):

Hilana Hatoum ◽

Fadi Rzouq

Keyword(s):

Literature Review ◽

Iga Nephropathy ◽

Clinical Significance

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The origin and the clinical significance of urinary angiotensinogen in proteinuric IgA nephropathy patients

Annals of Medicine ◽

10.3109/07853890.2011.558518 ◽

2011 ◽

Vol 44 (5) ◽

pp. 448-457 ◽

Cited By ~ 14

Author(s):

Hye Ryoun Jang ◽

Soo Min Kim ◽

Yu-Ji Lee ◽

Jung Eun Lee ◽

Wooseong Huh ◽

...

Keyword(s):

Iga Nephropathy ◽

Clinical Significance ◽

Urinary Angiotensinogen

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Distribution pattern of mesangial C4d deposits as predictor of kidney failure in IgA nephropathy

PLoS ONE ◽

10.1371/journal.pone.0252638 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252638

Author(s):

Suchin Worawichawong ◽

Sirithep Plumworasawat ◽

Wisit Liwlompaisan ◽

Vasant Sumethkul ◽

Bunyong Phakdeekitcharoen ◽

...

Keyword(s):

Iga Nephropathy ◽

Kidney Failure ◽

Interstitial Fibrosis ◽

Univariate Analysis ◽

Clinicopathological Parameters ◽

Positive Staining ◽

Global Pattern ◽

Mesangial Area ◽

Lower Egfr ◽

C4d Staining

Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high proportion of stained glomeruli was often required for the classification of C4d positive (C4d+ve). Positive staining in lower proportion of staining would be classified as C4d-ve. This retrospective study evaluated the prognostic value of C4d+ve using a less stringent definition (one C4d+ve glomerulus) in Thai patients with IgAN (n = 120). Baseline findings and outcomes were compared between those with more extensive C4d staining patterns and those with more restricted staining. Clinico-pathologic parameters and risk for kidney outcomes (kidney failure or decline GFR50%) were compared between C4d+ve versus C4d-ve, and between different patterns: Focal (< 50%) versus Diffuse (≥ 50% of glomeruli); or Global (≥ 50) versus Segmental (< 50% of mesangial area). The hazard ratios were estimated using Cox proportional hazard models for Model 1 (Oxford score+ C4d) and Model 2 (Model 1+ clinical factors). C4d+ve (n = 81) had lower eGFR, more global sclerosis, and interstitial fibrosis than C4d-ve at baseline. The 5-year kidney survival for C4d+ve was lower (53.7%) than C4d-ve (89.7%); P = 0.0255. By univariate analysis, T1, T2, C4d+ve, eGFR<60, proteinuria were predictors of kidney outcome. By multivariate analysis, proteinuria, T1, T2 and C4d+ve were independent predictors (Model 2 HR (95% CI) C4d+ve: 3.24 (1.09–9.58), p = 0.034). Segmental had lower eGFR, higher tubulointerstitial fibrosis, and segmental sclerosis compared to Global pattern. Clinicopathological parameters were not different between Focal and Diffuse patterns. Outcomes were similar between staining patterns. In conclusion, C4d staining may be a valuable marker of poor prognosis in Asian patients with IgAN. Less stringent criteria for C4d+ve should be considered as no differences in outcomes were observed between more extensive staining with less extensive patterns. More studies are needed to identify the optimum criteria for C4d+ve.

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Intravenous administration of Streptococcus mutans induces IgA nephropathy-like lesions

Clinical and Experimental Nephrology ◽

10.1007/s10157-020-01961-1 ◽

2020 ◽

Vol 24 (12) ◽

pp. 1122-1131

Author(s):

Shuhei Naka ◽

Kaoruko Wato ◽

Taro Misaki ◽

Seigo Ito ◽

Yasuyuki Nagasawa ◽

...

Keyword(s):

Iga Nephropathy ◽

Streptococcus Mutans ◽

Intravenous Administration ◽

Mesangial Cells ◽

Late Phase ◽

Control Group ◽

Chronic Glomerulonephritis ◽

Sprague Dawley ◽

Mesangial Area ◽

Specific Pathogen

Abstract Background IgA nephropathy (IgAN) is one of the most frequently occurring types of chronic glomerulonephritis. Previous analyses have revealed that a major pathogen of dental caries, Streptococcus mutans [which expresses collagen-binding protein (Cnm) on its surface], is involved in the pathogenesis of IgAN. Methods Cnm-positive S. mutans isolated from a patient with IgAN was intravenously administered to specific pathogen-free Sprague–Dawley rats to evaluate their kidney conditions. Results The urinary protein level of the S. mutans group reached a plateau at 30 days, with increased numbers of mesangial cells and an increased mesangial matrix. The numbers of rats with IgA-positive and/or C3-positive glomeruli were significantly greater in the S. mutans group than in the control group at 45 days (P < 0.05). Electron microscopy analyses revealed electron-dense depositions in the mesangial area among rats in the S. mutans group. There were significantly more CD68-positive cells (macrophages) in the glomeruli of the S. mutans group than in the glomeruli of the control group during the late phase (P < 0.05), similar to the findings in patients with IgAN. Conclusion Our results suggested that intravenous administration of Cnm-positive S. mutans caused transient induction of IgAN-like lesions in rats.

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