Complement activation is associated with crescent formation in IgA nephropathy

Itami, Hiroe; Hara, Shigeo; Samejima, Ken-ichi; Tsushima, Hideo; Morimoto, Katsuhiko; Okamoto, Ken‐ichi; Kosugi, Takaaki; Kawano, Tomikazu; Fujiki, Kengo; Kitada, Hiromichi; Hatakeyama, Kinta; Tsuruya, Kazuhiko; Ohbayashi, Chiho

doi:10.1007/s00428-020-02800-0

Cited by 23 publications

(29 citation statements)

References 36 publications

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“…Mostly small descriptive studies found C5b-9 as coarse granules in the glomerulus ( 57 , 58 , 72 , 76 , 81 , 137 , 139 , 143 , 158 , 160 , 161 )—always in the mesangium, sometimes also along the capillary wall ( 19 , 44 , 52 , 67 , 75 , 96 , 97 , 110 , 115 , 124 , 128 , 162 – 166 ), in one case report only along the capillary wall ( 159 ) —, along Bowman’s capsule ( 52 , 162 , 163 ), as coarse granules ( 19 , 44 , 52 , 57 , 70 , 72 , 75 , 96 , 97 , 110 , 115 , 163 ) or linearly ( 110 , 115 ) along the tubular basement membrane and occasionally on tubular cells ( 110 ), and in the vascular wall ( 19 , 52 , 57 , 67 , 72 , 96 , 110 , 115 , 137 , 162 ). Deposits along the capillary wall were localized in the subepithelial space ( 97 , 164 ).…”

Section: Kidney Diseases Due To Immune Complex Depositionmentioning

confidence: 99%

“…Individual components of C5b-9 were two times more abundant in patients with than without global mesangial hypercellularity, endocapillary hypercellularity, or moderate to extensive interstitial fibrosis or tubular atrophy but equally abundant in patients with or without glomerulosclerosis ( 124 ). Glomerular deposits were more frequent when capsular adhesion and crescents were present ( 76 ), while those with cellular or fibrocellular crescents had more intense staining ( 166 ). Deposits seemed also more frequent in the glomerulus (27 vs. 12%, p = 0.06) and vascular wall (68 vs. 46%, p = 0.06) when thrombotic microangiopathy was present ( 167 ).…”

Section: Kidney Diseases Due To Immune Complex Depositionmentioning

confidence: 99%

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Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys

et al. 2021

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The membrane attack complex—also known as C5b-9—is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.

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Section: Kidney Diseases Due To Immune Complex Depositionmentioning

confidence: 99%

Section: Kidney Diseases Due To Immune Complex Depositionmentioning

confidence: 99%

Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys

et al. 2021

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“…This may point to different pathways involved in the pathogenesis of crescentic IgAN, where the level of underglycosylation might be of secondary importance. Previous studies have described differences in the pathogenesis, histology, and presentation between IgAN and IgA vasculitis; regarding the pattern of glomerular deposits, the impact of systemic inflammation, role of complement activation, and disease outcome supporting the above suggestion [ 26 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 53%

Serum Levels of miR-148b and Let-7b at Diagnosis May Have Important Impact in the Response to Treatment and Long-Term Outcome in IgA Nephropathy

Kouri

Stangou

Lioulios

et al. 2021

JCM

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Background/aims: Previous studies showed that two microRNAs, let-7b and miR-148, which regulate the O-glycosylation process of IgA1, may predict diagnosis of primary IgA nephropathy (IgAN). The combined analysis of their serum levels in calculated statistical models may act as serum biomarkers for the diagnosis of primary IgAN. In the present study, we aimed to assess their impact not only on clinical and histological findings at onset but also on renal function after a long-term follow-up. Patients and methods: We enrolled 61 Caucasian patients with biopsy-proven IgAN. Serum levels of miR-148b, let-7b, and galactose-deficient IgA1 (Gd-IgA1) at the time of diagnosis were measured using real-time quantitative PCR and enzyme-linked immunosorbent assay using the monoclonal antibody KM55, respectively. Their values along with calculated Models 1 and 2 were correlated with histologic scoring system (Oxford classification system) and with renal function at diagnosis and after 11.9 ± 6.6 years. Fifty-five healthy volunteers were enrolled as controls. Results: No significant correlation was found between miRNA and Gd-IgA1 levels and eGFR and proteinuria at diagnosis. A significant negative association was detected between the presence of crescents and serum levels of let-7b (p = 0.002), miR-148b (p = 0.01), and Models 1 and 2 (p = 0.02 and p = 0.007, respectively). At the end of follow-up, eGFR correlated with let-7b levels (p = 0.01), Model 1 (p = 0.002), and Model 2 (p = 0.004). Patients with fast progression of the renal damage had significantly increased levels of let-7b (p = 0.01), Model 1 (p = 0.003), and Model 2 (p = 0.005) compared to slow progressors, as did those who reached ESKD (p = 0.002, p = 0.001, and p = 0.001, respectively). Results were most prominent in those treated with corticosteroids. Finally, cut off levels in Models 1 and 2 could also predict the renal function outcome after long-term follow-up. Conclusions: Serum levels of let-7b and miR-148b and their combination, may serve as predictors for long-term renal function outcomes, particularly in patients treated with corticosteroids.

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“…In fact, many studies have previously suggested that the local complement system in the glomeruli is activated via the alternative or the mannose-binding lectin (MBL) pathway in IgAN patients. 14,15 In particular, Roos et al reported that activation of the lectin pathway was associated with more severe renal damage in IgAN patients. 14 In their study, complement activation occurred via the alternative pathway in 75% of patients, whereas glomerular deposition of MBL, Lficolin, and C4d, which is indicative of activation of complement via the lectin pathway, was observed in 25% of patients.…”

Section: Introductionmentioning

confidence: 99%

“…Although renal biopsy remains the gold standard for diagnosis, recent efforts have been made to find new biomarkers that might predict the progression and prognosis of IgAN. In fact, many studies have previously suggested that the local complement system in the glomeruli is activated via the alternative or the mannose‐binding lectin (MBL) pathway in IgAN patients 14,15 . In particular, Roos et al .…”

Section: Introductionmentioning

confidence: 99%

Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy

Wang

et al. 2021

Histopathology

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Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy Aims: Glomerular complement 3 (C3) deposition is often observed in renal biopsies of patients with IgA nephropathy (IgAN); however, the relationship between the intensity of C3 deposition and the long-term prognosis of IgAN has rarely been reported. In this retrospective study, we aimed to evaluate the prognostic value of glomerular C3 deposition for IgAN progression. Methods and results: From June 2009 to June 2010, a total of 136 adult patients with IgAN were enrolled in the study. According to the intensity of glomerular C3 deposition, patients were divided into a glomerular C3 high group (34 patients) and a glomerular C3 low group (102 patients). The levels of clinical parameters, glomerular immune complexes, histopathological features, and serum cytokines of the two groups were compared. On the basis of an average of 105 months of follow-up, the predictive value of glomerular C3 deposition for IgAN progression was also investigated. Patients in the C3 high group had more severe glomerular IgA, IgG, IgM, and complement factor H deposition, a higher percentage of mesangial hypercellularity (M1), and higher levels of segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T2), and crescents (C2) than those in the C3 low group. Renal biopsies in the C3 high group showed higher densities of interstitial inflammatory cells and higher levels of serum interferon-c than those in the C3 low group. Multivariate Cox regression analysis revealed that a higher intensity of glomerular C3 deposition remained as an independent predictor of serum creatinine doubling and end-stage renal disease. Conclusions: A high intensity of glomerular C3 deposition is associated with the severity of renal lesions, and predicts long-term poor renal survival for IgAN patients.

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Complement activation is associated with crescent formation in IgA nephropathy

Cited by 23 publications

References 36 publications

Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys

Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys

Serum Levels of miR-148b and Let-7b at Diagnosis May Have Important Impact in the Response to Treatment and Long-Term Outcome in IgA Nephropathy

Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy

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