编者按

美国肾脏病学会年会（ASN Kidney Week 2025）正在美国休斯敦举行。11月6日，免疫性肾病的发病机制与治疗策略成为与会者关注的焦点。该专题会议上，欧洲肾脏协会（ERA）免疫性肾病工作组主席、奥地利因斯布鲁克医科大学肾脏病专家Andreas Kronbichler教授就ANCA相关性血管炎（AAV）中补体激活和肾小球损伤的病理生理学发表了专题演讲。肾医线现场记者特邀Kronbichler教授撰文分享了他的学术见解，并探讨了对未来免疫性肾病治疗策略的深度思考。

奥地利因斯布鲁克医科大学（Medical University Innsbruck）肾脏内科顾问医师、助理教授，曾担任英国剑桥大学临床高级研究员/大学讲师，同时兼任剑桥阿登布鲁克医院（Addenbrooke's Hospital）顾问医师；

发表了 300 余篇同行评审论文，主要研究方向之一为抗中性粒细胞胞浆抗体（ANCA）相关性血管炎及肾病综合征；

《新英格兰医学杂志》（NEJM）、《美国肾脏病学会杂志》（JASN）等多个期刊的评审专家；

现任欧洲肾脏协会（ERA）免疫肾病学工作组主席，同时是ERA杰出会员（Distinguished Fellow of the ERA）；

2013年荣获德国肾脏病学会颁发的Dr Johannes und Hertha Tuba Preis及Nils-Alwall-Preis；荣获2024年度ERA Eberhard Ritz奖。

补体通路：AAV治疗的新兴靶点

Kronbichler教授指出，补体激活主要通过旁路途径（alternativepathway）进行，目前已证实小分子C5a受体拮抗剂avacopan无论在小鼠模型还是在人体中都被证实有效。与此同时，新一代补体抑制剂正在快速推进临床研究，如C3靶向药物伊普可泮（iptacopan，商品名Fabhalta）已进入Ⅱ期试验阶段。

值得注意的是“目前这些药物尚未直接针对补体–中性粒细胞–内皮细胞之间的相互作用，”Kronbichler教授指出，“但来自中国赵明辉团队的研究表明，补体系统亦参与AAV中血小板活化。”他相信现有的补体抑制剂在缓解内皮损伤方面同样能发挥效用。

Nephrology on-line: In your ASN presentation, you discussed the role of complement activation in ANCA-associated vasculitis (AAV). How has our understanding of the complement–neutrophil–endothelium interplay evolved in recent years, and what new therapeutic targets are emerging from this research?

Dr. Kronbichler: Complement activation mainly occurs via the alternative pathway. We know that avacopan is effective, both in men and also mice. There are further therapies currently under investigation, but clearly the Iptacopan (Fabhalta) trial (Phase 2) is progressing very well. To the best of my knowledge, none of these treatments specifically tackle the complement-neutrophil-endothelium interplay. We have, however, evidence from studies from China (Ming-hui Zhao’s group) that complement is involved in platelet activation in AAV, thus, I would believe that available complement inhibitors are also effective related to endothelial damage. 

临床实践中的核心挑战：从诊断到预后评估

近期发表于Nature Reviews Rheumatology的一篇综述系统分析了AAV的诊断、分类与预后挑战，Kronbichler教授是作者之一。他认为，在AAV的诊断、分型和预后预测方面，我们仍有诸多未解之谜。

目前，不同亚型患者的临床终点（例如伯明翰血管炎活动度评分[BVAS]）往往是相同的，但这对于表现为严重肾脏疾病的患者通常并不适用。对于这类患者，治疗后的eGFR（估算肾小球滤过率）改善必须成为最重要的终点指标。

无抗体（ANCA阴性）病例的识别、重叠表型的管理以及组织病理学异质性等问题，都是尚未被满足的重要的临床需求。对组织病理学损伤进行正确评估同样至关重要。但总体而言，几乎所有的患者都需要治疗，即使是那些病理表现非常严重的患者。总之，在这个领域我们还有很多工作要做。

Nephrology on-line: You are one of the authors of a recent Nature Reviews Rheumatology review that systematically analyzed the challenges in diagnosing, classifying, and predicting prognosis in AAV. From your perspective, which aspects remain the most difficult in clinical practice—such as identifying ANCA-negative disease, managing overlapping phenotypes, or addressing histopathologic heterogeneity?

Dr. Kronbichler: Great question! Well, I think that we have many unanswered questions. Endpoints for different subsets are still the same (i.e., Birmingham Vasculitis Activity Score) but this is often not relevant for those presenting with severe kidney disease. For such individuals, the increase in eGFR with treatment must be the most important endpoint. The other mentioned points all are major or have major unmet needs. The correct assessment of histopathologic lesions is also of relevance. But overall, almost all patients will require treatment, even those with very severe histopathology. So, in conclusion, there is a lot to do here. 

2025视角下的免疫性肾病治疗目标再定义

随着免疫介导性肾病的治疗模式快速发展，2025年我们应如何重新定义抗中性粒细胞胞浆抗体相关性血管炎（AAV）和狼疮性肾炎（LN）的治疗目标？临床医生需在疾病早期控制、长期缓解与最大限度降低治疗毒性之间寻求怎样的平衡？

对此，Kronbichler教授指出，我们需要找到能够反映患者“免疫能力（immunocompetence）”的生物标志物，这类标志物既能指导诱导治疗，也能指导维持治疗。移植医学领域已出现相关探索，一项Ⅱ期临床试验正采用细小病毒（torque teno virus）开展研究。我们迫切需要为AAV和狼疮性肾炎（LN）找到类似的标志物。

Kronbichler教授强调：值得注意的是，我们不应对患者治疗不足。在大多数情况下，初始治疗或许应包括强效或更强效的免疫抑制方案。他所观察到的感染问题主要出现在以下情况：患者就诊较晚、已出现大量组织损伤，此时临床医生对治疗存在顾虑。长期缓解通常需要通过长期治疗来实现。

狼疮性肾炎患者中是否可推行重复肾活检策略仍是待解问题——这种做法在患者群体中并不特别受欢迎。

Nephrology on-line: As treatment paradigms for immune-mediated kidney disease rapidly evolve, how should we redefine therapeutic goals in AAV and lupus nephritis in 2025? What balance should clinicians seek between early disease control, long-term remission, and minimization of treatment toxicity?

Dr. Kronbichler: “Immunocompetence” markers need to emerge, that would allow you to guide either induction but also maintenance treatment. We are seeing this in transplant medicine, with a Phase 2 trial using torque teno virus. We need to find similar markers for AAV and LN. It is noteworthy that we should not under treat patients, and likely the initial treatment should include (more) aggressive immunosuppression in most cases. I see the issues around infections mainly if patients present late, have a huge damage accrual already, and then there is hesitancy to treat. Long-term remission is usually achieved by long-term treatment. The question will remain if we can implement for instance a repeat biopsy policy in lupus nephritis, something not particularly popular among patients.

展望未来：ERA免疫性肾病工作组的合作与方向

作为ERA免疫性肾病工作组主席，Kronbichler教授在提到正在开展或计划进行的研究最新进展时指出，ERA免疫性肾病工作组是一个非常注重紧密合作的研究团队。他们近期讨论了一些新的研究项目，但这些项目主要集中于综述类研究。同时，他们将重点比较近期发布的所有狼疮性肾炎推荐/指南，以得出更具体的指导建议。

借此机会，Kronbichler教授对中国的读者和研究者们说：“我们非常欢迎来自中国的咨询与合作！一个很好的研究方向是聚焦IgA肾病，探讨中国与欧洲患者之间的差异。最后，Kronbichler教授再次强调：”我们期待与大家的协作！

Nephrology on-line: Beyond AAV and lupus nephritis, could you share updates on your ongoing or planned studies within the ERA Immunonephrology Working Group? What future research directions do you believe will shape the next decade of glomerular and systemic vasculitis care?

Dr. Kronbichler: The ERA Immunonephrology Working Group is a very collaborative group of investigators. We have recently discussed further research projects, but these are mainly related to reviews. We will also focus on comparisons of all recent lupus nephritis recommendations/guidelines to be more concrete. For your readership: we are open for inquiries also from China! A good example would be a focus on IgAN and differences between patients in China and Europe! We would welcome collaboration!