Unraveling the Role of Complement in Focal Segmental Glomerulosclerosis Pathogenesis: Insights and Challenges

We thank Dr Zagorec and collaborators for their interest in our study and for adding additional patient data supporting a plausible role for complement activation in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Immunofluorescence (IF) and immunohistochemistry (IHC) are invaluable in assessing complement in glomerulonephritis (GN). C4d deposition in non-sclerotic glomeruli segments in 55/58 of their FSGS subjects indicates classical or lectin pathway activation. This, coupled with the lack of C1q deposition, supports lectin initiation. However, the absence of C1q has been described in GN known to activate the classical pathway, and other studies have found greater C1q in FSGS biopsies with little mannose-binding lectin1van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. Sep 2019; 96: 738-749https://doi.org/10.1016/j.kint.2019.04.028Abstract Full Text Full Text PDF Scopus (12) Google Scholar. Additionally, we previously found a greater relationship between the terminal pathway and urinary Ba, a marker of alternative pathway activity, compared to urinary C4a2Genest D.S. Bonnefoy A. Khalili M. et al.Comparison of Complement Pathway Activation in Autoimmune Glomerulonephritis.Kidney Int Rep. May 2022; 7: 1027-1036https://doi.org/10.1016/j.ekir.2022.02.002Abstract Full Text Full Text PDF Scopus (10) Google Scholar. While overlapping pathway activation in GN is expected, many questions remain. Why isn't C3 found by IF in non-sclerotic glomeruli segments? What triggers the cascade, and where is it initiated? Anti-nephrin antibodies targeting podocytes support local activation3Shirai Y. Miura K. Ishizuka K. et al.A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.Kidney Int. Mar 2024; 105: 608-617https://doi.org/10.1016/j.kint.2023.11.022Abstract Full Text Full Text PDF Scopus (1) Google Scholar, but plasma Bb and C4a levels, significantly higher in FSGS than in lupus nephritis, support a systemic trigger4Thurman J.M. Wong M. Renner B. et al.Complement Activation in Patients with Focal Segmental Glomerulosclerosis.PLoS One. 2015; 10e0136558https://doi.org/10.1371/journal.pone.0136558Crossref Scopus (54) Google Scholar. The lack of activation in minimal change disease (MCD) is also remarkable. In contrast to the absent urinary complement fragments in MCD in our cohort, a recent study found C4d in glomeruli by IHC in 46/47 FSGS biopsies but also in 6/15 MCD5Abedi M. Nili F. Dehkhoda F. Abdollahi A. Salarvand S. Evaluation of C4d expression and staining patterns by immunohistochemistry in renal biopsy samples with focal segmental glomerulosclerosis and minimal change disease.Ann Diagn Pathol. Feb 13 2024; 70152281https://doi.org/10.1016/j.anndiagpath.2024.152281Crossref Scopus (0) Google Scholar. In addition, background C4d was found in some controls without glomerular disease. Similarly, C4d was found by IHC in 73%, 21% and 10% of FSGS, MCD and controls in another cohort1van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. Sep 2019; 96: 738-749https://doi.org/10.1016/j.kint.2019.04.028Abstract Full Text Full Text PDF Scopus (12) Google Scholar. While C4d deposition in MCD could reflect unsampled FSGS, the value of faint staining is uncertain and could represent passive trapping rather than ongoing complement activation. Contrary to the above group and the findings from Abedi5Abedi M. Nili F. Dehkhoda F. Abdollahi A. Salarvand S. Evaluation of C4d expression and staining patterns by immunohistochemistry in renal biopsy samples with focal segmental glomerulosclerosis and minimal change disease.Ann Diagn Pathol. Feb 13 2024; 70152281https://doi.org/10.1016/j.anndiagpath.2024.152281Crossref Scopus (0) Google Scholar, our study and three others found strong associations between complement activation and proteinuria1van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. Sep 2019; 96: 738-749https://doi.org/10.1016/j.kint.2019.04.028Abstract Full Text Full Text PDF Scopus (12) Google Scholar,3Shirai Y. Miura K. Ishizuka K. et al.A multi-institutional study found a possible role of anti-nephrin antibodies in post-transplant focal segmental glomerulosclerosis recurrence.Kidney Int. Mar 2024; 105: 608-617https://doi.org/10.1016/j.kint.2023.11.022Abstract Full Text Full Text PDF Scopus (1) Google Scholar,4Thurman J.M. Wong M. Renner B. et al.Complement Activation in Patients with Focal Segmental Glomerulosclerosis.PLoS One. 2015; 10e0136558https://doi.org/10.1371/journal.pone.0136558Crossref Scopus (54) Google Scholar. With the lack of a unified FSGS pathogenesis and the variable findings using plasma, tissue or urinary markers of complement activation, future studies are warranted to determine how the complement system can influence the podocyte pattern of injury.