Urinary complement proteins are increased in children with IgA vasculitis (Henoch-Schönlein purpura) nephritis.

BACKGROUND: Children with immunoglobulin A vasculitis (IgAV Henoch-Schönlein purpura) frequently encounter nephritis (IgAV-N) with 1-2% risk of kidney failure. The pathophysiology of IgAV-N is not fully understood with speculation that complement may contribute. The aim of this study was to identify whether urinary complement proteins are increased in children with IgAV-N. METHODS: A cross-sectional prospective cohort of children with IgAV were recruited together with controls including healthy children and children with systemic lupus erythematosus (SLE). Patients were subdivided according to the presence of nephritis. Urinary C3, C4, C5, and C5a were measured by enzyme-linked immunosorbent assay (ELISA) and corrected for urinary creatinine. RESULTS: The study included 103 children; 47 with IgAV (37 IgAV without nephritis, IgAVwoN; 10 IgAV-N), 30 SLE and 26 healthy children. Urinary complement C3, C4, and C5 were all statistically significantly increased in all children with IgAV compared to SLE patients (all p < 0.05). In patients with IgAV-N, urinary complement C3, C4, C5, C5a were all statistically significantly increased compared to IgAVwoN (C3 14.65 µg/mmol [2.26-20.21] vs. 2.26 µg/mmol [0.15-3.14], p = 0.007; C4 6.52 µg/mmol [1.30-9.72] vs. 1.37 µg/mmol [0.38-2.43], p = 0.04; C5 1.36 µg/mmol [0.65-2.85] vs. 0.38 µg/mmol [0.03-0.72], p = 0.005; C5a 101.9 ng/mmol [15.36-230.0] vs. 18.33 ng/mmol [4.27-33.30], p = 0.01). Using logistic regression, the urinary complement components produced an outstanding ability to discriminate between patients with and without nephritis in IgAV (AUC 0.92, p < 0.001). CONCLUSIONS: Children with IgAV-N have evidence of increased complement proteins present in their urine that may indicate a pathological role and may allow treatment stratification. A higher resolution version of the Graphical abstract is available as Supplementary information.

Urinary markers of the alternative and lectin complement pathway are increased in IgA vasculitis nephritis.

Background: IgA vasculitis (IgAV) is the most common form of childhood vasculitis. Nephritis (IgAVN) occurs in 50% of patients and 1-2% progress to chronic kidney disease stage 5. The pathophysiology of nephritis remains largely unknown, but recent evidence suggests that the complement system may be involved. The aim of this cross-sectional study was to explore whether there is evidence of alternative and/or lectin complement pathway activation in children with IgAVN. Methods: Children with IgAV were recruited and grouped according to proteinuria: IgAVN or IgAV without nephritis (IgAVwoN). Age and sex-matched healthy controls (HCs) were also recruited. Cross-sectional urine and plasma concentrations of complement factor D (CFD), factor B (CFB), and MBL-associated protease 1 (MASP-1) were performed using commercially available enzyme-linked immunoassays. Results: A total of 50 children were included (IgAVN, n = 15; IgAVwoN, n = 20, HCs, n = 15). The mean age was 8.5 ± 3.7 years old, male:female ratio was 1:1. Urinary CFD and CFB concentrations were statistically significantly increased in children with IgAVN (3.5 ± 5.4 µg/mmol; 25.9 ± 26.5 µg/mmol, respectively) compared to both IgAVwoN (0.4 ± 0.4 µg/mmol, P = 0.002; 9.2 ± 11.5 µg/mmol, P = 0.004) and HCs (0.3 ± 0.2 µg/mmol, P < 0.001; 5.1 ± 6.0 µg/mmol, P < 0.001). No statistically significant difference was reported for the plasma concentrations of CFD and CFB. Urinary MASP-1 concentrations were statistically significantly increased in IgAVN (116.9 ± 116.7 ng/mmol) compared to HCs (41.4 ± 56.1 ng/mmol, P = 0.006) and plasma MASP-1 concentrations were increased in IgAVwoN (254.2 ± 23.3 ng/mL) compared to HCs (233.4 ± 6.6 ng/mL, P = 0.046). Conclusion: There is evidence of complement pathway products in the urine of children with IgAVN that warrants further investigation.

Mesangial cells are key contributors to the fibrotic damage seen in the lupus nephritis glomerulus.

BACKGROUND: Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus patients. Mesangial cells (MCs) comprise a third of the glomerular cells and are key contributors to fibrotic changes within the kidney. This project aims to identify the roles of MCs in an in vitro model of LN. METHODS: Conditionally immortalised MCs were treated with pro-inflammatory cytokines or with patient sera in an in vitro model of LN and assessed for their roles in inflammation and fibrosis. RESULTS: MCs were shown to produce pro-inflammatory cytokines in response to a model of the inflammatory environment in LN. Further the cells expressed increased levels of mRNA for extracellular matrix (ECM) proteins (COL1A1, COL1A2, COL4A1 and LAMB1), matrix metalloproteinase enzymes (MMP9) and tissue inhibitors of matrix metalloproteinases (TIMP1). Treatment of MCs with serum from patients with active LN was able to induce a similar, albeit milder phenotype. Treatment of MCs with cytokines or patient sera was able to induce secretion of TGF-ß1, a known inducer of fibrotic changes. Inhibition of TGF-ß1 actions through SB-431542 (an activin A receptor type II-like kinase (ALK5) inhibitor) was able to reduce these responses suggesting that the release of TGF-ß1 plays a role in these changes. CONCLUSIONS: MCs contribute to the inflammatory environment in LN by producing cytokines involved in leukocyte recruitment, activation and maturation. Further the cells remodel the ECM via protein deposition and enzymatic degradation. This occurs through the actions of TGF-ß1 on its receptor, ALK5. This may represent a potential therapeutic target for treatment of LN-associated fibrosis.