The Lectin Pathway–A Dominant Pattern of the Complement System Activation in Primary Focal Segmental Glomerulosclerosis?

We read with a big interest article by Cambier et al. reporting significantly elevated urine levels of C5b-C9 and C5a in individuals with focal segmental glomerulosclerosis (FSGS) indicating role of the complement system activation in disease pathogenesis (1Cambier A. Patey N. Royal V. et al.A Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change Disease.Kidney Int Rep. 2024; (In press)Abstract Full Text Full Text PDF Scopus (1) Google Scholar). We can not only confirm the role of complement system activation in pathogenesis of primary FSGS (pFSGS), but also show prognostic significance of C4d, long-term tissue "fingerprint" of complement activation, and role of lectin pathway activation. In our cohort of 58 strictly selected patients with pFSGS treated with immunosuppressive therapy (relevant data shown in Fig.A), additional immunohistochemistry (IHC) for C4d on paraffin-embedded biopsy samples was performed. At least one non-globally sclerosed glomerulus (nGSG) was C4d+ in segmental distribution in 55 IHC samples. All segmental sclerosis were C4d+ and around 40% of all glomeruli were nonsclerotic C4d+ glomeruli (Fig.B). C1q was negative in all biopsy samples. Percentage of segmentally sclerosed glomeruli (%SSG) was positively correlated with %C4d+nGSG (ρ=0.36, P=0.007)(Fig.C). In contrast to study above where there was positive correlation between proteinuria and complement components level found, in our study there was not significant correlation between baseline 24-hour proteinuria and %C4d+nGSG (ρ=0.217, P=0.111)(Fig.D) what is consistent with previous report (3van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. 2019; 96: 738-749Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). In the univariate logistic regression models, IgM positivity (69% samples) and C3 positivity (17% samples) were not associated with treatment failure (TF), defined as non-achievement of at least partial remission at the last follow-up, (OR 2.35, 0.95CI 0.71-7.87, P=0.164 and OR 1.53, 0.95CI 0.39-5.99, P=0.545, respectively), %SSG was marginally significant (OR 1.03, 0.95CI 0.99-1.07, P=0.088), whereas percentages of IFTA and %C4d+nGSG were independent predictors of TF, and remain significant after the adjustment to the 24-h proteinuria and %SSG in the multivariate model (OR per 1% =1.06, 0.95CI 1.003-1.11, P=0.038 and OR per 1% =1.03, 0.95CI 1.007-1.054, P=0.008, respectively). C4d positivity in all SSG and association between percentage of SSG and C4d are consistent with previous reports (2Drachenberg C.B. Papadimitriou J.C. Chandra P. et al.Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies.Kidney Int Rep. 2019; 4: 1555-1567Abstract Full Text Full Text PDF PubMed Google Scholar,3van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. 2019; 96: 738-749Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Although prognostic significance of C4d was not investigated in the pivotal study by de Lest et al., it was shown that C4d could precede the development of segmental sclerosis in FSGS (3van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. 2019; 96: 738-749Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). This is possible explanation why around 60% of C4d+ glomeruli in our analysis were without sclerosis. Of note, around 20% of individuals with minimal change disease (MCD) were also C4d+, so role of complement activation can not be ruled out in pathogenesis of MCD (3van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. 2019; 96: 738-749Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Although previous studies indicated possible role of IgM and C3 in pathogenesis of FSGS, apparently they do not influence on disease outcome (4Strassheim D. Renner B. Panzer S. et al.IgM contributes to glomerular injury in FSGS.J Am Soc Nephrol. 2013; 24: 393-406Crossref PubMed Scopus (78) Google Scholar). Taken together, complement components are not only trapped by chance in sclerotic areas, but might play a role in development of sclerosis and indicate worse renal prognosis. Previous studies speculate on classic or alternative complement pathway activation in FSGS (2Drachenberg C.B. Papadimitriou J.C. Chandra P. et al.Epidemiology and Pathophysiology of Glomerular C4d Staining in Native Kidney Biopsies.Kidney Int Rep. 2019; 4: 1555-1567Abstract Full Text Full Text PDF PubMed Google Scholar, 3van de Lest N.A. Zandbergen M. Wolterbeek R. et al.Glomerular C4d deposition can precede the development of focal segmental glomerulosclerosis.Kidney Int. 2019; 96: 738-749Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 4Strassheim D. Renner B. Panzer S. et al.IgM contributes to glomerular injury in FSGS.J Am Soc Nephrol. 2013; 24: 393-406Crossref PubMed Scopus (78) Google Scholar, 5Chandra P. C4d in Native Glomerular Diseases.Am J Nephrol. 2019; 49: 81-92Crossref PubMed Scopus (22) Google Scholar). Since almost all renal samples were C4d+ in absence of C1q and rare C3 deposits, lectin pathway might play the main role in the pathogenesis of pFSGS. Further studies are needed to elucidate the role of lectin pathway in pFSGS as well as prognostic significance of C4d deposits and possible treatment implications in context of therapeutic agents interfering with complement cascade. Funding: none Conflict of interest: All authors declare no conflict of interest. Unravelling the Role of Complement in Focal Segmental Glomerulosclerosis Pathogenesis: Insights and ChallengesKidney International ReportsPreviewWe 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. Full-Text PDF Open AccessA Prospective Study on Complement Activation Distinguishes Focal Segmental Glomerulosclerosis from Minimal Change DiseaseKidney International ReportsVol. 9Issue 3PreviewMinimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are related podocytopathies with distinct kidney outcomes. Surprisingly, elevated urinary activation fragments have been found in FSGS despite little complement deposition on immunofluorescence (IF) staining. Whether complement activation distinguishes FSGS from MCD, participating in the development of segmental lesions, remains unknown.