Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis

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.

Graphical abstract

Figure 1

Terminal pathway activation urinary fragments in autoimmune GN. Urinary terminal pathway fragments, expressed as a creatinine ratio. Median differences were evaluated with the Kruskal–Wallis test, whereas subgroup analyses were performed using the Mann-Whitney U test and Bonferroni P value thresholds. AAV, antineutrophil cytoplasmic autoantibody-associated vasculitis; FSGS, focal segmental glomerular sclerosis; IgAN, IgA nephropathy; LN, lupus nephritis; MN, membranous nephropathy; creat, creatinine; GN, glomerulonephritis; DB, diabetes; CKD, chronic kidney disease.

Figure 2

Urinary Ba, C4a, and C1q in autoimmune GN. Expressed as a creatinine ratio. Median differences were evaluated with the Kruskal–Wallis test, whereas subgroup analyses were performed using the Mann-Whitney U test and Bonferroni P value thresholds. Although the Kruskal–Wallis tests were statistically significant for C4a, all subanalyses using the Bonferroni P value thresholds were not. AAV, antineutrophil cytoplasmic autoantibody-associated vasculitis; FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; LN, lupus nephritis; MN, membranous nephropathy; creat, creatinine; GN, glomerulonephritis.

Figure 3

Linear relationship between urinary C4a and Ba with C5a. AAV, antineutrophil cytoplasmic autoantibody-associated vasculitis; IgAN, IgA nephropathy; LN, lupus nephritis; MN, membranous nephropathy.