绘制IgA肾病中补体靶向治疗格局：一项系统性综述及结构化描述性综合。
完整摘要 · 中文译文
背景：补体激活是IgA肾病（IgAN）疾病进展的关键驱动因素。既往综述仅限于II期证据，而关键的III期数据——包括APPLAUSE-IgAN试验的24个月结果——近期已发表，因此有必要对补体靶向治疗进行更新评估。 方法：我们在PubMed、Web of Science、Embase和Cochrane中进行了截至2026年4月24日的系统文献检索，纳入针对经活检证实的IgA肾病成人患者使用补体抑制剂的随机对照试验。由于针对不同补体节点的药物之间存在显著的机制异质性，未进行定量荟萃分析。相反，我们采用结构化描述性综合，即一种预先设定的、基于领域的比较方法，重点关注各试验的疗效信号、安全性特征和方法学差异。 结果：共纳入4项随机对照试验，涉及584例患者，覆盖因子B和C5抑制。III期iptacopan试验显示稳健的蛋白尿减少、eGFR斜率衰减以及肾衰竭风险降低，但较高的严重感染发生率和确诊的肺炎球菌感染突出表明，旁路途径抑制可减弱但不能消除荚膜细菌感染风险。ravulizumab、iptacopan和cemdisiran的II期试验提供了早期疗效信号，且未报告荚膜细菌感染事件，但样本量小和随访时间短限制了安全性推断。所有试验均要求预防性接种疫苗，且感染风险相关义务各不相同。 d 由具有最严格 REMS 要求的靶向末端通路抑制剂所致。方法学异质性——尤其是关于活检时机和纤维化排除——成为跨试验比较的主要障碍。在这些随机对照试验之外，ASO、siRNA 和小分子抑制剂的动态研发管线仍在持续发展。 结论：补体抑制剂在各项单独试验中显示出有前景但异质性的信号；然而，分子靶点、试验设计和入选标准的显著差异使得无法推断存在统一的类效应。感染风险缓解措施因补体靶点而异——末端通路抑制剂具有最高的荚膜细菌负担和最严格的监管限制，而旁路途径抑制剂保留了部分疫苗介导的防御能力，但仍需全面接种疫苗和监测。这些观察结果具有假设生成意义，并强调了需要具有硬性肾脏终点的机制特异性 III 期项目和个体患者水平的荟萃分析，以推进 IgA 肾病中的精准补体治疗。 系统综述注册：https://www.crd.york.ac.uk/PROSPERO/view/CRD420261385690.
完整摘要 · 英文原文
BACKGROUND: Complement activation is a key driver of disease progression in IgA nephropathy (IgAN). While previous syntheses were limited to phase II evidence, pivotal phase III data-including the 24-month results of the APPLAUSE-IgAN trial-have recently emerged, necessitating an updated appraisal of complement-targeted therapies. METHODS: We conducted a systematic literature search in PubMed, Web of Science, Embase, and Cochrane up to April 24, 2026, for randomized controlled trials of complement inhibitors in adults with biopsy-proven IgA nephropathy. Due to marked mechanistic heterogeneity across agents targeting distinct complement nodes, a quantitative meta-analysis was not performed. Instead, we performed a structured descriptive synthesis, a predefined, domain-based comparative method, focusing on efficacy signals, safety profiles, and methodological disparities across trials. RESULTS: Four RCTs comprising 584 patients were included, representing factor B and C5 inhibition. The phase III iptacopan trial demonstrated robust proteinuria reduction, eGFR slope attenuation, and a decreased risk of kidney failure, but a higher serious-infection rate and confirmed pneumococcal infections highlighted that alternative-pathway inhibition attenuates rather than abolishes encapsulated-bacteria risk. Phase II trials of ravulizumab, iptacopan, and cemdisiran provided early efficacy signals with no encapsulated-bacterial events reported, though small size and short follow-up limit safety inference. All trials required prophylactic vaccination, and infection-risk obligations differed by target-terminal-pathway inhibitors carrying the strictest REMS requirements. Methodological heterogeneity-particularly regarding biopsy timing and fibrosis exclusion-emerged as a major barrier to cross-trial comparisons. Beyond these RCTs, a dynamic pipeline of ASO, siRNA, and small-molecule inhibitors continues to evolve. CONCLUSION: Complement inhibitors show promising but heterogeneous signals across individual trials; however, marked differences in molecular targets, trial design, and eligibility preclude any inference of a uniform class effect. Infection risk mitigation differs by complement target-terminal-pathway inhibitors carry the highest encapsulated-bacterial burden and strictest regulatory constraints, whereas alternative-pathway inhibitors preserve partial vaccine-mediated defence but still require comprehensive vaccination and surveillance. These observations are hypothesis-generating and underscore the need for mechanism-specific phase III programmes with hard renal endpoints and individual patient-level meta-analyses to advance precision complement therapeutics in IgAN. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261385690.