Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy

Paunas, Theodora Ioana Flavia; Finne, Kenneth; Leh, Sabine; Marti, Hans-Peter; Mollnes, Tom Eirik; Berven, Frode S.; Vikse, Bjørn Egil

doi:10.1186/s12014-017-9165-x

Cited by 41 publications

(58 citation statements)

References 27 publications

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“…In our study, we found that microangiopathy was associated with C4d, C1q, and C5b-9 deposits; in contrast, MBL deposits were not detected in most patients, even after we repeated the experiment using different anti-MBL antibodies or using fresh-frozen tissue samples (data not shown). Proteomics-based analyses of laser-captured microdissected glomeruli revealed that the classical pathway components C1q, C1r, and C1s were significantly higher in patients with progressive IgA nephropathy compared to patients with non-progressive IgA nephropathy [48]. These data suggest that C4d may reflect activation of both the lectin and classical pathways in IgA nephropathy.…”

Section: Discussionmentioning

confidence: 81%

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

et al. 2019

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Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.

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Section: Discussionmentioning

confidence: 81%

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

et al. 2019

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“… 53 In a proteomic analysis, glomerular FHR5 was 1.79 times more abundant in patients with progressive versus stable IgAN. 54 FHR5 antagonizes the ability of fH to negatively regulate C3 activation. 55 , 56 Consequently, it was interesting that patients with progressive disease had more cases of glomerular FHR5 staining in the absence of fH.…”

Section: Discussionmentioning

confidence: 99%

Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition

Medjeral-Thomas

Troldborg

Constantinou

et al. 2018

Kidney International Reports

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IntroductionIgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.MethodsTo elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.ResultsM-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.ConclusionOur data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.

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“…Application of this novel technique to the diagnosis of glomerulonephritis has just begun. To date, IgA nephropathy (IgAN) has been analysed in a few studies, with a focus mainly on deposited immunoglobulin and complements . In our study, we analysed the glomerular proteomics of IgAN and membranous nephropathy (MN) by LMD and LC‐MS/MS and we compared our findings with those for normal glomeruli obtained at biopsies from kidney transplant donors.…”

Section: Introductionmentioning

confidence: 99%

“…To date, IgA nephropathy (IgAN) has been analysed in a few studies, with a focus mainly on deposited immunoglobulin and complements. 6,7 In our study, we analysed the glomerular proteomics of IgAN and membranous nephropathy (MN) by LMD and LC-MS/MS and we compared our findings with those for normal glomeruli obtained at biopsies from kidney transplant donors. Moreover, we investigated the significance of the detected molecules with regard to the diagnosis and pathogenesis of glomerular diseases.…”

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confidence: 99%

Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography‐tandem mass spectrometry

et al. 2019

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Aim Laser microdissection (LMD) and liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) enable clinicians to analyse proteins from tissue sections. In nephrology, these methods are used to diagnose diseases of abnormal protein deposition, such as amyloidosis, but they are seldom applied to the diagnosis and pathophysiological understanding of human glomerular diseases. Methods Renal biopsy specimens were obtained from five patients with IgA nephropathy (IgAN), five patients with membranous nephropathy (MN) and five kidney transplant donors (as controls). From 10‐μm‐thick sections of formalin‐fixed, paraffin‐embedded specimens, 0.3‐mm2 samples of glomerular tissue were subjected to LMD. The samples were analysed by LC‐MS/MS and investigated clinically and histologically. Results From the control glomeruli, we identified more than 300 types of proteins. In patients with IgAN, we detected significant increases not only in IgA1 and in C3, but also in the factors related to oxidative stress and cell proliferation in comparison to the controls. In patients with MN, levels of IgG1, IgG4, C3, C4a and phospholipase‐A2‐receptor were significantly elevated in comparison to the controls, as were the aforementioned factors related to oxidative stress and cell proliferations detected in IgAN. Conclusion Application of LMD and LC‐MS/MS to renal biopsy specimens enabled us to identify not only pathognomonic proteins for the diagnosis, but also several factors possibly involved in the pathogenesis of human glomerular diseases.

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Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy

Cited by 41 publications

References 27 publications

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis

Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition

Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography‐tandem mass spectrometry

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