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. 2019 Nov 8;14(1):247.
doi: 10.1186/s13023-019-1237-8.

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

Nóra Garam  1 , Zoltán Prohászka  2 , Ágnes Szilágyi  1 , Christof Aigner  3 , Alice Schmidt  3 , Martina Gaggl  3 , Gere Sunder-Plassmann  3 , Dóra Bajcsi  4 , Jürgen Brunner  5 , Alexandra Dumfarth  6 , Daniel Cejka  6 , Stefan Flaschberger  7 , Hana Flögelova  8 , Ágnes Haris  9 , Ágnes Hartmann  10 , Andreas Heilos  11 , Thomas Mueller  11 , Krisztina Rusai  11 , Klaus Arbeiter  11 , Johannes Hofer  5   12   13 , Dániel Jakab  14 , Mária Sinkó  14 , Erika Szigeti  14 , Csaba Bereczki  14 , Viktor Janko  15 , Kata Kelen  16 , György S Reusz  16 , Attila J Szabó  16 , Nóra Klenk  17 , Krisztina Kóbor  17 , Nika Kojc  18 , Maarten Knechtelsdorfer  19 , Mario Laganovic  20 , Adrian Catalin Lungu  21 , Anamarija Meglic  22 , Rina Rus  22 , Tanja Kersnik-Levart  22 , Ernesta Macioniene  23 , Marius Miglinas  23 , Anna Pawłowska  24 , Tomasz Stompór  24 , Ludmila Podracka  25 , Michael Rudnicki  26 , Gert Mayer  26 , Romana Rysava  27 , Jana Reiterova  27 , Marijan Saraga  28 , Tomáš Seeman  29 , Jakub Zieg  29 , Eva Sládková  30 , Tamás Szabó  31 , Andrei Capitanescu  32 , Simona Stancu  32 , Miroslav Tisljar  33 , Kresimir Galesic  33 , András Tislér  34 , Inga Vainumäe  35 , Martin Windpessl  36 , Tomas Zaoral  37 , Galia Zlatanova  38 , Dorottya Csuka  1
Affiliations

C4 nephritic factor in patients with immune-complex-mediated membranoproliferative glomerulonephritis and C3-glomerulopathy

Nóra Garam et al. Orphanet J Rare Dis. .

Abstract

Background: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors.

Results: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF.

Conclusions: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; C3 nephritic factor; C4 nephritic factor; Dense deposit disease; Membranoproliferative glomerulonephritis.

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Conflict of interest statement

The authors declare that they have no competing interests as defined by Nature Research, or other interests that might be perceived to influence the results and/or discussion reported in this paper.

Figures

Fig. 1
Fig. 1
Distribution of genes affected by LPVs among the autoantibody negative and autoantibody positive groups of patients. * C3NeF, C4NeF, anti-C1q, anti-FH, anti-FB, anti-C3. ** CD46, CFH, C3, CFI, THBD, CFB. *** ‘combined’ stands for LPVs in the following genes: C3 and CFH n = 2; CFI and THBD n = 1; CD46 and THBD n = 1; CD46 and CFB n = 1; CD46 and heterozygous deletion of entire CFH n = 1. P-value was obtained by chi-square test
Fig. 2
Fig. 2
Kaplan-Meier analysis of IC-MPGN/C3G patients’ renal survival in the groups with or without C4NeF (a) and in groups with positivity for C3NeF and/or C4NeF, and double-negative patients (b). P-value was obtained by log-rank test. (Curve for C4NeF positive and double positive patients run together)
Fig. 3
Fig. 3
Membership of C4NeF positive patients in the different clusters generated by unsupervised data-driven cluster analysis based on clinical, genetic and laboratory data [29]. Complete dataset to generate the clusters was available for 92 patients, whereas for 26 patients cluster membership was predicted by decision-tree analysis based algorithm [29]. Figure: Dotted line represents threshold of positivity for C4NeF (18%), ANOVA p = 0.0287. Table: P-value was obtained by chi-square test. Cluster membership of patients not included in the cluster analysis were predicted based on decision tree analysis [30]
Fig. 4
Fig. 4
Flow chart of the enrolled patients
Fig. 5
Fig. 5
Schematic representation of the complement pathways with steps of action of C3NeF and C4NeF, highlighting all complement investigations performed in this study. Complement parameters investigated in this study are underlined. Complement regulators are shown in red triangles. Complement autoantibodies are shown in blue. Complement activation products are shown by asterisks. Abbreviations: DAF - decay-accelerating factor; CR1 - complement receptor type 1; C4BP - C4b-binding protein; MCP - membrane cofactor protein
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