Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France.
Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom.
J Am Soc Nephrol. 2024 Aug 1;35(8):1034-1044. doi: 10.1681/ASN.0000000000000373. Epub 2024 May 6.
We evidenced terminal pathway activation (C5b-9 deposits) in most of the glomeruli on kidney biopsy of C3 glomerulopathy. The amount of C5b-9 deposits correlated with disease prognosis in C3 glomerulopathy. Increased terminal pathway activation was found predominantly in a subgroup exhibiting an immuno-fibroblastic signature.
C3 glomerulopathy is a rare disease resulting from an overactivation of the complement alternative pathway. Although there is also evidence of terminal pathway activation, its occurrence and consequences on the disease have been poorly studied.
We retrospectively studied a cohort of 42 patients diagnosed with C3 glomerulopathy. We performed centralized extensive characterization of histological parameters. Kidney C5b-9 staining was performed as a marker of terminal pathway activation; intrarenal immune response was characterized through transcriptomic analysis.
Eighty-eight percent of biopsies showed C5b-9 deposits in glomeruli. Biopsies were grouped according to the amount of C5b-9 deposits (no or low =15/42, 36%; intermediate =15/42, 36%; and high =12/42, 28%). Patients with high C5b-9 deposits significantly differed from the two other groups of patients and were characterized by a significant higher histological chronicity score ( = 0.005) and lower outcome-free survival ( = 0.001). In multivariable analysis, higher glomerular C5b-9 remained associated with poor kidney prognosis after adjustment. One third of the 847 studied immune genes were upregulated in C3 glomerulopathy biopsies compared with controls. Unsupervised clustering on differentially expressed genes identified a group of kidney biopsies enriched in high glomerular C5b-9 with high immune and fibroblastic signature and showed high chronicity scores on histological examination.
In a cohort of patients with C3 glomerulopathy, intrarenal terminal pathway activation was associated with specific histological phenotype and disease prognosis.
我们在 C3 肾小球病患者的肾活检中发现大多数肾小球都存在终末途径激活（C5b-9 沉积）。C3 肾小球病患者的 C5b-9 沉积量与疾病预后相关。在表现出免疫纤维母细胞特征的亚组中，主要发现了终末途径的过度激活。
C3 肾小球病是一种由补体替代途径过度激活引起的罕见疾病。尽管也有证据表明存在终末途径激活，但它在疾病中的发生和后果尚未得到充分研究。
我们回顾性研究了一组 42 例诊断为 C3 肾小球病的患者。我们对组织学参数进行了集中的广泛特征分析。通过肾 C5b-9 染色作为终末途径激活的标志物；通过转录组分析来描述肾内免疫反应。
88%的活检显示肾小球有 C5b-9 沉积。根据 C5b-9 沉积量（无或低=15/42，36%；中=15/42，36%；高=12/42，28%）将活检分为三组。高 C5b-9 沉积的患者与另外两组患者显著不同，表现为显著更高的组织学慢性评分（=0.005）和更低的无结局生存（=0.001）。多变量分析显示，调整后肾小球 C5b-9 升高与肾脏预后不良相关。与对照组相比，847 个研究免疫基因中有三分之一在 C3 肾小球病活检中上调。差异表达基因的无监督聚类鉴定了一组肾活检，这些活检在肾小球 C5b-9 高、免疫和纤维母细胞特征丰富，组织学检查显示高慢性评分。
在 C3 肾小球病患者队列中，肾内终末途径激活与特定的组织学表型和疾病预后相关。
