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

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

doi:10.1186/s12014-017-9165-x

Abstract

BackgroundThe 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.MethodsBased 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 m2 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.ResultsProteomic 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.ConclusionsIn conclusion, higher glomerular abundance of complement proteins was associated with a progressive clinical course in IgAN and are candidate biomarkers to predict prognosis.

Highlights

The clinical course of IgA nephropathy (IgAN) is variable and complement activation may predict prognosis
By using the 11-digit national identity number, data from the Norwegian Kidney Biopsy Registry were linked with the Norwegian Renal Registry which has registed all cases with end-stage renal disease (ESRD) in Norway since 1980
Three groups were included and kidney biopsy tissue could be retrieved and enough glomeruli microdissected for 16 patients with non-progressive IgAN, 9 patients with progressive IgAN and 15 controls with normal biopsies

Summary

Introduction

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 clini‐ cal variables. The clinical course of IgA nephropathy (IgAN) is highly variable and difficult to predict, some patients have a stable clinical course, while others progress to end-stage renal disease (ESRD). Several clinical and histological factors at time of diagnosis have been shown to indicate worse prognosis. These include low estimated glomerular filtration rate (eGFR), hypertension, proteinuria, mesangial hypercellularity, segmental glomerulosclerosis or adhesion, tubular atrophy and interstitial fibrosis [1,2,3]. Previous studies have shown that the lectin pathway [12, 13] and the alternative pathway [14] likely are involved in the pathophysiology of IgAN

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