Multimodal Profiling of Complement Expression and Association With Outcomes in ANCA-Associated Vasculitis With Glomerulonephritis
In brief
Low serum C3 linked to double the kidney failure and death risk in vasculitis
Among 369 patients with ANCA-associated vasculitis affecting the kidneys, low serum C3 was linked to about twice the risk of kidney failure and death. Kidney tissue also showed increased complement-related gene activity that was only weakly reflected in blood tests or routine staining. The retrospective findings need prospective validation before tissue profiling can guide care.
- Journal
- Kidney international reports (Q1)
- Published
- 26 August 2026
- Study design
- Prospective / inception cohort
- Evidence level
- Level 2, Moderate (CEBM 2b)
- Authors
- Benoît Brilland, Victor Milon, Cyrille Vandenbussche, Nathalie Merillon, Eleonore Ourouda, Andrea Boizard-Moracchini, et al.
- PMID
- 42866688
- DOI
- 10.1016/j.ekir.2026.107056
Why clinicians should know about it
- Picked for Pathology and Forensic Medicine (top studies of the week, 18 October 2026): ANCA vasculitis renal pathology, complement expression analysis
Abstract
INTRODUCTION: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) is classically considered pauci-immune, yet complement activation is a central pathogenic mechanism. Whether intrarenal complement-related transcriptional programs are reflected by conventional serum or immunofluorescence markers, and whether they are clinically informative, remains unclear. METHODS: In 369 patients with AAV-GN from 2 independent retrospective cohorts, complement was assessed across circulating, histopathologic, and transcriptomic layers (serum C3/C4, glomerular C1q/C3 deposition, and targeted kidney transcriptomics). Predefined classical and alternative pathway-related expression scores were derived from intrarenal gene expression. Associations with severity and outcomes were evaluated using multivariable Cox models. Public spatial transcriptomic data sets provided validation and localization. RESULTS: Below-normal serum C3/C4 levels were uncommon. Low serum C3, but not C4, was associated with more severe kidney involvement, kidney failure (adjusted hazard ratio [aHR]: 2.0 [1.1-3.7]), and mortality (aHR: 2.3 [1.3-4.0]). Both glomerular C3 (47%) and C1q (11%) deposition identified more severe pathology and adverse outcomes. Compared with controls, AAV-GN kidneys showed increased complement-related expression-including classical pathway components, proximal alternative pathway genes (C3, C5AR1), and regulatory transcripts-that was only weakly concordant with serum or deposition markers. Low alternative pathway-related expression was independently associated with better kidney (aHR: 0.3 [0.1-0.7]) and overall (aHR: 0.4 [0.2-0.9]) survival. Spatial transcriptomics validated these signatures and suggested contributions from both immune and resident kidney compartments. CONCLUSION: AAV-GN displays a reproducible intrarenal complement-related transcriptional program, only weakly captured by serum levels or routine immunofluorescence, associated with renal severity and outcomes. These findings support prospective studies integrating tissue complement transcriptomics for stratification and therapeutic hypothesis generation.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.