Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis

Dominique S Genest; Arnaud Bonnefoy; Myriam Khalili; Clémence Merlen; Geneviève Genest; Anne-Laure Lapeyraque; Natacha Patey; Nassima Smail; Virginie Royal; Stéphan Troyanov

doi:10.1016/j.ekir.2022.02.002

Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis

Kidney Int Rep. 2022 Feb 14;7(5):1027-1036. doi: 10.1016/j.ekir.2022.02.002. eCollection 2022 May.

Authors

Dominique S Genest¹, Arnaud Bonnefoy^{2

3}, Myriam Khalili¹, Clémence Merlen^{2

3}, Geneviève Genest⁴, Anne-Laure Lapeyraque⁵, Natacha Patey⁶, Nassima Smail⁷, Virginie Royal⁸, Stéphan Troyanov^{1

3

7}

Affiliations

¹ Division of Nephrology, Hôpital du Sacré-Coeur de Montréal, Quebec, Canada.
² Division of Hematology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Quebec, Canada.
³ Research Center, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Quebec, Canada.
⁴ Department of Allergy and Immunology, McGill University, Quebec, Canada.
⁵ Division of Nephrology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Quebec, Canada.
⁶ Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Quebec, Canada.
⁷ Division of Nephrology, Hôtel-Dieu de St-Jérôme, St-Jerome, Quebec, Canada.
⁸ Department of Pathology, Hôpital Maisonneuve-Rosemont, University of Montreal, Quebec, Canada.

Abstract

Introduction: Studies on complement activation have implicated a combination of the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) in triggering the terminal pathway (TP) for each common autoimmune glomerulonephritis (GN). Evaluating different pathways simultaneously may help identify whether one is preferentially activated and, consequently, which is best to target for each disease.

Methods: We followed 112 patients with focal segmental glomerular sclerosis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), lupus nephritis (LN), and antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) for a median duration of 22 (12-52) months. At the time of greatest clinical activity, we simultaneously evaluated urinary C3a (C3 convertase activity), C5a and sC5b-9 (TP), MASP-1 and MASP-2 (LP), C1q (CP), C4a (CP/LP), and Ba and Bb (AP). We evaluated the relation between activation fragments of the AP and CP/LP with the TP.

Results: Urinary complement biomarkers for each pathway were associated with the severity of proteinuria. Fragments of the TP were higher among patients with FSGS and MN compared with patients with IgAN, LN, and AAV. For the AP, urinary Ba level was lower in those with IgAN and LN compared with those with FSGS. For the CP/LP, urinary C4a, MASP-1, and MASP-2 levels were similar between diseases whereas urinary C1q levels were lower in those with LN. For each GN, independent associations existed between the activation markers of the AP and CP/LP with the degree of TP activation, except for the AP in AAV, although perhaps underpowered.

Conclusion: The AP and CP/LP contribute individually to the TP activation in autoimmune GN, and both seem to be valid potential therapeutic targets.

Keywords: autoimmune glomerulonephritis; complement pathway activation; monocyte chemoattractant protein-1; proteinuria; transforming growth factor β1.