Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment
Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment
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DOI：
10.1016/j.ekir.2019.06.008
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发表时间：
2019-10-01
影响因子：
6
通讯作者：
Pickering, Matthew C.
中科院分区：
文献类型：
--
作者：
Medjeral-Thomas, Nicholas R.;Moffitt, Hilary;Pickering, Matthew C.
引言：靶向补体的治疗药物越来越多地用于肾小球疾病。然而，肾小球补体沉积与炎症和损伤的机制还不完全清楚。补体因子H相关蛋白5（FHR 5）与补体C3相互作用，并被认为是促进激活。循环和肾小球FHR 5与伊加肾病相关，异常FHR 5与家族性C3肾小球病（C3 G）相关。我们的特点是肾小球FHR 5染色在C3 G和评估其与肾小球损伤和clinical outcome.Methods的组织学特征的关系：我们开发了FHR 5染色协议福尔马林固定石蜡包埋（FFPE）肾组织，并将其应用于剩余的活检切片从C3 G cohol.Results：肾小球FHR 5是非常普遍的本地和移植C3 G和肾小球C3和C5 b-9染色。肾小球FHR 5染色与估计肾小球滤过率（eGFR）呈负相关（P= 0.04，中位数差异为19.7 ml/min/1.73 m2; 95%可信区间[CI] 1.1-43.0），与诊断活检时的膜增生性肾小球肾炎模式呈正相关（比值比18; 95% CI 1.6-201; P = 0.049）。肾小球FHR 5染色强度与肾小球补体C3 b/iC 3b/C3 c呈正相关（Pearson相关系数（R）= 0.59; P = 0.0008），C3 dg（R = 0.47; P = 0.02）和C5 b 9结论：肾小球FHR 5在C3 G中高度流行，与肾小球C3相互作用，并与疾病严重程度的标志物相关。肾小球FHR 5可能加剧补体介导的肾小球损伤C3 G和其与肾小球补体的相互作用可能会被利用为目标补体治疗剂。
Introduction: Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H-related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome.Methods: We developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort.Results: Glomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) (P= 0.04, difference of medians 19.7 ml/min per 1.73 m(2); 95% confidence interval [CI] 1.1-43.0) and positively with a membranoproliferative glomerulonephritis pattern at diagnostic biopsy (odds ratio 18; 95% CI 1.6-201; P = 0.049). Glomerular FHR5 staining intensity positively correlated with glomerular complement C3b/iC3b/C3c (Pearson's correlation coefficient (R) = 0.59; P = 0.0008), C3dg (R = 0.47; P = 0.02) and C5b9 (R = 0.44, P = 0.02).Conclusions: Glomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents.