Complement activity influences glomerular inflammation and clinical severity in IgA nephropathy and C3 glomerulopathy

The mechanisms that link complement activation and glomerular injury are not understood. Recently, novel mechanisms of complement dysregulation mediated by factor H related protein (FHR)1 and FHR5 have been described. IgA nephropathy (IgAN) is important and poorly understood. Exciting recent evidence suggests FHR proteins and lectin complement pathways contribute to IgAN pathogenesis. C3 glomerulopathy (C3G) demonstrates the potential for alternative complement pathway dysregulation to drive glomerular injury. However, in the majority of C3G cases, precise pathogenesis is not understood. I hypothesised IgAN and C3G pathogenesis were dependent on imbalances of FHR1, FHR5 and lectin complement pathway proteins. I demonstrated circulating FHR1 levels and the ratio of FHR1 to factor H (FH) were increased in patients with IgAN compared to healthy controls and in patients with progressive compared to stable IgAN. I found IgAN patients had higher circulating FHR5 levels than healthy controls and higher circulating FHR5 levels associated with histology markers of IgAN severity. Glomerular FHR5 deposition associated with both clinical and histologic markers of IgAN severity and immunohistolgical markers of complement activation. Glomerular FHR5 deposition also associated with clinical and histology markers of C3G severity and co-localised with glomerular complement (C)3 deposits in C3G. Glomerular FHR5 deposition co-localised with markers of both ongoing (C3b/iC3b/C3c) and previous (C3dg) alternative complement activation in C3G and IgAN. I detected FHR5 in Immunoglobulin (Ig)A containing immune complexes. With regards to the lectin complement pathway, I found IgAN patients had higher circulating levels of M-ficolin, L-ficolin, mannan binding lectin (MBL) associated serine protease (MASP)-1 and MBL associated protein (MAp)19 than healthy controls, and lower circulating levels of MASP-3 than healthy controls. Lower circulating MASP-3 levels also associated with markers of IgAN severity. My research addresses fundamental gaps in our understanding of glomerular complement activation and IgAN pathogenesis. The results are limited by a number of important confounding factors that need to be addressed. However, they justify researching the mechanisms by which FHR5 contributes to complement activation and disease severity in IgAN and C3G and could contribute to novel and exciting diagnostic tools and therapeutic targets for IgAN, C3G and other complement dependent glomerulopathies.Open Acces

Longitudinal proteomic profiling of dialysis patients with COVID-19 reveals markers of severity and predictors of death

Funder: The Sidharth Burman endowmentEnd-stage kidney disease (ESKD) patients are at high risk of severe COVID-19. We measured 436 circulating proteins in serial blood samples from hospitalised and non-hospitalised ESKD patients with COVID-19 (n = 256 samples from 55 patients). Comparison to 51 non-infected patients revealed 221 differentially expressed proteins, with consistent results in a separate subcohort of 46 COVID-19 patients. Two hundred and three proteins were associated with clinical severity, including IL6, markers of monocyte recruitment (e.g. CCL2, CCL7), neutrophil activation (e.g. proteinase-3), and epithelial injury (e.g. KRT19). Machine-learning identified predictors of severity including IL18BP, CTSD, GDF15, and KRT19. Survival analysis with joint models revealed 69 predictors of death. Longitudinal modelling with linear mixed models uncovered 32 proteins displaying different temporal profiles in severe versus non-severe disease, including integrins and adhesion molecules. These data implicate epithelial damage, innate immune activation, and leucocyte–endothelial interactions in the pathology of severe COVID-19 and provide a resource for identifying drug targets

Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis.

Background. Current guidelines advise that rituximab or cyclophosphamide should be used for the treatment of organthreatening disease in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), although few studies have examined the efficacy and safety of these agents in combination. Methods. We conducted a single-centre cohort study of 66 patients treated with a combination of oral corticosteroids, rituximab and low-dose pulsed intravenous cyclophosphamide followed by a maintenance regimen of azathioprine and tapered steroid for the treatment of biopsy-proven renal involvement in AAV. Patients were followed for a median of 56 months. Case– control analysis with 198 propensity-matched cases from European Vasculitis Study Group (EUVAS) trials compared long-term differences in relapse-free, renal and patient survival. Results. At entry, the median Birmingham Vasculitis Activity Score (BVAS) was 19 and estimated glomerular filtration rate was 25 mL/min. Cumulative doses of rituximab, cyclophosphamide and corticosteroids were 2, 3 and 4.2 g, respectively, at 6 months. A total of 94% of patients achieved disease remission by 6 months (BVAS < 0) and patient and renal survival were 84 and 95%, respectively, at 5 years. A total of 84% achieved ANCA-negative status and 57% remained B cell deplete at 2 years, which was associated with low rates of major relapse (15% at 5 years). The serious infection rate during long-term follow-up was 1.24 per 10 patient-years. Treatment with this regimen was associated with a reduced risk of death {hazard ratio [HR] 0.29 [95% confidence interval (CI) 0.125–0.675], P ¼ 0.004}, progression to end-stage renal disease (ESRD) [HR 0.20 (95% CI 0.06–0.65), P ¼ 0.007] and relapse [HR 0.49 (95% CI 0.25–0.97), P ¼ 0.04] compared with propensity-matched patients enrolled in EUVAS trials. Conclusions. This regimen is potentially superior to current standards of care, and controlled studies are warranted to establish the u

Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin–Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H–Related Protein-5 (FHR5) Deposition

IgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury. Methods: To elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN. Results: M-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN. Conclusion: Our data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity