C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology chara...C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.展开更多
文摘目的:Graves眼病是一种复杂的器官特异性自身免疫性疾病,发病机制尚不明确。补体系统中的核心成分5/5a(component 5/5a,C5/C5a)可能在该疾病的病理过程中发挥重要作用。本研究旨在利用孟德尔随机化(Mendelian randomization,MR)方法探究C5/C5a与Graves眼病的因果关系,以期为Graves眼病的诊断与治疗提供新的理论依据。方法:基于全基因组关联分析(genome-wide association study,GWAS)的汇总数据,以补体C5/C5a作为暴露因素,Graves眼病作为结局因素,分析补体C5/C5a与Graves眼病的因果关系,利用共定位分析得出假设的后验概率(posterior probability of hypothesis,PPH),进一步验证补体C5与Graves眼病的遗传关联。结果:Wald比率法模型显示补体C5与Graves眼病呈显著正相关(OR=4.109,95%CI 1.990~8.486,P<0.001),逆方差加权法(inverse variance weighted,IVW)模型显示C5a与Graves眼病同样呈正相关(OR=2.901,95%CI 1.225~6.869,P=0.015),共定位分析显示补体C5与Graves眼病在给定的遗传窗口内共享同一个单核苷酸多态性(single nucleotide polymorphism,SNP)rs7036980,PPH4为0.81(>0.80为概率高)。结论:补体C5/C5a的高水平显著增加Graves眼病的发生风险,通过靶向补体C5的抑制剂可以有效降低Graves眼病的发生风险。
文摘C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.
