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

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Abstract

Background

The clinical course of IgA nephropathy (IgAN) is variable and complement activation may predict prognosis. The present study investigated whether glomerular abundance of complement proteins associates with progression to end-stage renal disease (ESRD) in patients for whom prognosis could not be predicted based on clinical variables.

Methods

Based on data from the Norwegian Kidney Biopsy Registry and the Norwegian Renal Registry, three groups were included: IgAN patients with (n = 9) or without (n = 16) progression to ESRD during 10 years, and controls (n = 15) with a normal kidney biopsy. IgAN patients had eGFR > 45 ml/min/1.73 m ² and non-nephrotic proteinuria at time of biopsy. Using stored formalin-fixed paraffin embedded kidney biopsy tissue, about 100 glomerular cross sections were microdissected for each patient. Samples were analyzed by liquid chromatography–tandem mass spectrometry and relative abundances of complement proteins were compared between groups.

Results

Proteomic analyses quantified 2018 proteins, of which 28 proteins belong to the complement system. As compared to IgAN patients without progressive disease, glomeruli from patients with progressive IgAN had significantly higher abundance of components of the classical and the terminal complement pathways, and inhibitory factors such as Factor H and factor H related proteins. Abundance of complement proteins classified progressors from non-progressors with an area under ROC curve of 0.91 ( p = 0.001). Clinical and morphological data were similar between the two patient groups and could not predict progressive IgAN.

Conclusions

In conclusion, higher glomerular abundance of complement proteins was associated with a progressive clinical course in IgAN and are candidate biomarkers to predict prognosis.

Electronic supplementary material

The online version of this article (doi:10.1186/s12014-017-9165-x) contains supplementary material, which is available to authorized users.

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Most cited references 22

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Complement. Second of two parts.

M J Walport (2001)

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The complement system

J. Sarma, Peter Ward (2010)

The complement system consists of a tightly regulated network of proteins that play an important role in host defense and inflammation. Complement activation results in opsonization of pathogens and their removal by phagocytes, as well as cell lysis. Inappropriate complement activation and complement deficiencies are the underlying cause of the pathophysiology of many diseases such as systemic lupus erythematosus and asthma. This review represents an overview of the complement system in an effort to understand the beneficial as well as harmful roles it plays during inflammatory responses.

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Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease.

Anja Roos, Beatrijs D Oortwijn, Maria Rastaldi … (2006)

IgA nephropathy (IgAN) is characterized by glomerular co-deposition of IgA and complement components. Earlier studies showed that IgA activates the alternative pathway of complement, whereas more recent data also indicate activation of the lectin pathway. The lectin pathway can be activated by binding of mannose-binding lectin (MBL) and ficolins to carbohydrate ligands, followed by activation of MBL-associated serine proteases and C4. This study examined the potential role of the lectin pathway in IgAN. Renal biopsies of patients with IgAN (n=60) showed mesangial deposition of IgA1 but not IgA2. Glomerular deposition of MBL was observed in 15 (25%) of 60 cases with IgAN and showed a mesangial pattern. All MBL-positive case, but none of the MBL-negative cases showed glomerular co-deposition of L-ficolin, MBL-associated serine proteases, and C4d. Glomerular deposition of MBL and L-ficolin was associated with more pronounced histologic damage, as evidenced by increased mesangial proliferation, extracapillary proliferation, glomerular sclerosis, and interstitial infiltration, as well as with significantly more proteinuria. Patients who had IgAN with or without glomerular MBL deposition did not show significant differences in serum levels of MBL, L-ficolin, or IgA or in the size distribution of circulating IgA. Furthermore, in vitro experiments showed clear binding of MBL to polymeric but not monomeric patient IgA, without a significant difference between both groups. Together, these findings strongly point to a role for the lectin pathway of complement in glomerular complement activation in IgAN and suggest a contribution for both MBL and L-ficolin in the progression of the disease.

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Author and article information

Contributors

Teodora Ioana Flavia Paunas: +47- 45006480 , flavia.teodora.ioana.paunas@helse-fonna.no , flavia_paunas@yahoo.com

Kenneth Finne: Kenneth.Finne@uib.no

Sabine Leh: sabine.leh@helse-bergen.no

Hans-Peter Marti: Hans-Peter.Marti@uib.no

Tom Eirik Mollnes: t.e.mollnes@medisin.uio.no

Frode Berven: Frode.Berven@uib.no

Bjørn Egil Vikse: bjorn.egil.vikse@helse-fonna.no

Journal

Journal ID (nlm-ta): Clin Proteomics

Journal ID (iso-abbrev): Clin Proteomics

Title: Clinical Proteomics

Publisher: BioMed Central (London )

ISSN (Print): 1542-6416

ISSN (Electronic): 1559-0275

Publication date (Electronic): 14 August 2017

Publication date PMC-release: 14 August 2017

Publication date Collection: 2017

Volume: 14

Electronic Location Identifier: 30

Affiliations

[1 ]GRID grid.413782.b, Department of Medicine, , Haugesund Hospital, ; Postbox 2170, 5504 Haugesund, Norway

[2 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Clinical Medicine, , University of Bergen, ; Bergen, Norway

[3 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Department of Pathology, , Haukeland University Hospital, ; Bergen, Norway

[4 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Department of Medicine, , Haukeland University Hospital, ; Bergen, Norway

[5 ]ISNI 0000 0004 1936 8921, GRID grid.5510.1, Department of Immunology, Oslo University Hospital, Rikshospitalet, K. G. Jebsen Inflammation Research Center, , University of Oslo, ; Oslo, Norway

[6 ]ISNI 0000000122595234, GRID grid.10919.30, Research Laboratory Nordland Hospital, K. G. Jebsen Thrombosis Research and Expertise Center, , University of Tromsø, ; Bodø, Norway

[7 ]ISNI 0000 0001 1516 2393, GRID grid.5947.f, Centre of Molecular Inflammation Research, , Norwegian University of Science and Technology, ; Trondheim, Norway

[8 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Biomedicine, , University of Bergen, ; Bergen, Norway

Article

Publisher ID: 9165

DOI: 10.1186/s12014-017-9165-x

PMC ID: 5557313

PubMed ID: 28814945

SO-VID: a535bf02-a4ae-41a2-9bf9-bc2f5a652b2c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 6 March 2017

Date accepted : 19 July 2017

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: iga nephropathy,complement,esrd,formalin-fixed paraffin embedded kidney biopsy tissue,liquid chromatography–tandem mass spectrometry,proteomic analyses

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ScienceOpen disciplines: Molecular medicine

Keywords: iga nephropathy, complement, esrd, formalin-fixed paraffin embedded kidney biopsy tissue, liquid chromatography–tandem mass spectrometry, proteomic analyses

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

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Abstract

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Conclusions

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Biomarkers for Inflammatory Lung Disease

Most cited references 22

Complement. Second of two parts.

The complement system

Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease.

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