引言

肾小球疾病作为全球高发的肾脏疾病，其中IgA肾病更是最常见的原发性肾小球疾病类型，长期以来，早期诊断困难、治疗方案缺乏针对性、疗效评估指标有限等问题，始终制约着该领域诊疗水平的提升。随着免疫学研究的深入，B细胞活化与肾小球疾病的关键关联被逐步揭示，靶向B细胞疗法成为肾小球疾病治疗的新兴方向。

本刊有幸特邀国际IgA肾病联盟（IIgANN）主席、英国莱斯特大学Jonathan Barratt教授结合多年临床与科研经验，围绕全球肾小球疾病诊疗挑战、B细胞疗法作用机制、临床研究进展及未来发展方向展开深度解读，为突破现有诊疗瓶颈、推动个体化医疗落地提供了重要思路与方向。

肾医线：作为国际IgA肾病联盟（IIgANN）主席、乔治临床肾脏专家组成员，结合您的丰富经验，您认为当前全球肾小球疾病诊疗面临的最大挑战是什么？哪些领域最有望取得突破性进展？

Jonathan Barratt教授：我认为主要挑战之一是尽早识别患者。IgA肾病等肾小球疾病患者大多没有明显症状，往往是偶然检查才被发现。我们现在有很多效果很好的新型治疗手段，但前提是要尽早诊断患者，才能实现成功治疗，这是目前最核心的挑战之一。另一个关键挑战是为合适的患者匹配最合适的药物，未来我们需要在生物标志物领域开展大量研究，以此推动肾小球疾病的个体化治疗。

Nephrology Online: As the Chairman of the International IgA Nephropathy Network and a member of the George Clinical Renal Expert Team, and drawing on your extensive experience, would you please share with us what you see as the greatest challenges in global glomerular disease care today, and which areas hold the most promise for breakthrough advances?

Dr Barratt: I think one of the major challenges is identifying patients early enough, because, particularly patients with IgA nephropathy, are asymptomatic, and they only come to our attention by chance. We have lots of wonderful new treatments that are great, but we need to find the patients early enough so that we can actually treat them successfully. So, I think that is one of the major challenges. The next challenge is identifying which is the right drug for the right patient. Here, we are going to need to do lots of work on biomarkers to help us personalize the treatment of patients with glomerular disease.

肾医线：在2026年世界肾脏病学大会（WCN 2026）上，您重点介绍了B细胞疗法在肾小球疾病中的应用前景。鉴于B细胞活化与致病性IgA产生密切相关，您认为靶向B细胞治疗IgA肾病的主要机制是什么？与现有疗法相比，靶向B细胞疗法有哪些独特优势，又存在哪些潜在局限？

Jonathan Barratt教授：IgA肾病的发病核心是循环免疫复合物的形成，而这类免疫复合物的生成，依赖于浆细胞（属于B细胞谱系）产生的致病性IgA。因此，通过不同药物联合靶向抑制B细胞的增殖与存活，是十分合理的治疗策略。我们可以通过多种方式实现这一目标，比如用Nefecon靶向黏膜微环境，阻断BAFF和/或APRIL，或是清除CD38+浆细胞，这些方案都展现出令人振奋的潜力。

靶向B细胞疗法优势十分显著，这类疗法能大幅降低循环中致病性IgA的水平，显著减少蛋白尿，早期临床研究还显示其对肾功能有明显的保护作用，整体前景十分可观。但潜在风险也不容忽视，抑制B细胞功能会全面影响抗体反应，不仅会抑制致病抗体，还会削弱人体抗感染的抗体生成。目前我们尚不清楚，对IgA肾病患者持续5~10年抑制抗感染抗体，会带来怎样的长期影响，这是未来需要重点关注的问题。

Nephrology Online: We know at the WCN 2026, you highlighted the future of B-cell therapy in glomerular disease. Given the close link between B-cell activation and pathogenic IgA production, what do you see as the main mechanism by which B-cell targeting could treat IgA nephropathy? Compared with current therapies, for B-cell targeting therapy, what are the unique advantages, and any potential limitations you would like to share with us?

Dr Barratt: I think we know that IgA nephropathy is driven by formation circulating immune complexes, and for those immune complexes to form, there needs to be generation of pathogenic IgA, which is derived from plasma cells, which are B-cell lineage cells. Therefore, targeting B-cell proliferation and survival using different drug classes in combination is a logical treatment. We can do that in a number of different ways. We can target the mucosal microenvironment with a drug like Nefecon. We can block that and/or APRIL. Or we could deplete CD38-positive plasma cells. We have lots of different options available to us, all of which look very exciting.

I think what we have seen with each of these therapies is that they can reduce significantly the levels of pathogenic IgA in the circulation, and we can see substantial reduction in proteinuria. The early phase studies suggest quite a marked protection of kidney function. I think all of those look incredibly promising. The concern, of course, is that if you suppress B-cell function, you are going to suppress antibody responses, not just of antibodies that cause disease, but also suppress antibodies that help us fight infection. That is what is unknown - what is going to be the impact of suppressing antibodies that help fight infections over five or ten years in a patient with IgA nephropathy. That is something we are going to need to think about.

肾医线：IgA肾病是全球最常见的原发性肾小球疾病，靶向B细胞疗法正处于广泛研究阶段。您牵头或参与了ORIGIN 3、VISIONARY等多项国际试验，能否分享这些研究的关键结果或最新进展？

Jonathan Barratt教授：去年我们公布了斯贝利单抗的研究成果，该药物靶向APRIL，可显著降低致病性IgA（Gd-IgA1）水平，减少蛋白尿和血尿，相关结果发表在《新英格兰医学杂志》（NEJM），但VISIONARY试验目前还没有肾小球滤过率（GFR）相关数据。

另外还有两种靶向BAFF/APRIL的药物，一是阿塞西普（atacicept），来自ORIGIN 3试验，同样能降低致病性IgA、改善血尿和蛋白尿，暂未获取GFR数据；二是泰它西普，仅在中国开展临床试验，虽未检测Gd-IgA1，但也能减少血尿和蛋白尿，且Ⅲ期试验首次证实此类药物对肾功能有显著的保护作用，该药物已在中国获批用于狼疮治疗，未来几个月有望公布更多研究数据。

Nephrology Online: IgA nephropathy is the most common primary glomerular disease worldwide, and B-cell targeted therapies are under extensive investigation. We know you have led and participated in several international trials, for example, the ORIGIN 3, VISIONARY.

Would you please share the key findings or recent progress of those studies?

Dr Barratt: Yes. We have had presentations last year on the role of sibeprenlimab. We have seen a publication in the New England Journal  Medicine at ASN last year showing that targeting APRIL with sibeprenlimab significantly reduces the pathogenic form of IgA (Gd-IgA1), and reduces proteinuria and hematuria. But we don't have any GFR data yet from the VISIONARY trial. We will need to wait a little longer for that. Similarly, we have data for two agents that target BAFF and APRIL. One is atacicept from the ORIGIN 3 trial, which again was presented at the ASN with a publication in the New England Journal Medicine, and this showed targeting BAFF and APRIL significantly reduces the pathogenic form of IgA, reduces blood and protein in the urine, but again, we don't have GFR data. And then we have the data from the trial of telitacicept, which is being undertaken exclusively in China. We had data presented at the ASN, which had no Gd-IgA1 investigation, but similarly showing reductions in hematuria and proteinuria, but importantly, for the first time, we saw GFR data showing quite marked protection of kidney function with telitacicept in the phase III trial. Telitacicept is already approved in China for the treatment of lupus. We hope to see more data from that study in the coming months.

肾医线：在WCN 2026上，您做了“肾脏病理与肾功能关联”专题报告。能否阐述这一报告的宗旨是什么？

Jonathan Barratt教授：我在这场报告中想强调，我们目前极度缺乏能精准反映肾脏内部病变的生物标志物。血尿、蛋白尿、肾功能下降这些临床表现，可能对应多种截然不同的肾脏病理改变，而我们无法对患者反复进行肾活检。目前常规使用的血尿、蛋白尿、GFR等指标，精准度远远不够，无法明确肾脏内部的真实病变情况。

而我们现在已有多种作用机制不同的新型疗法，只有精准掌握肾脏病理状态，才能针对特定病理类型开展精准治疗，这对肾小球疾病的诊疗至关重要。

Nephrology Online:  At WCN 2026, you presented a session entitled, “Linking Renal Pathology to Kidney Function”. Could you elaborate on the purpose of this lecture? 

Dr Barratt: Yes. During that lecture I tried to point out that we really don’t have very good biomarkers of what is going on in the kidney, by presenting cases where we had either hematuria or we had proteinuria or we had a decline in kidney function. I went through the different kidney pathologies that could be associated with those clinical findings. And there was a wide range of pathologies. What I was trying to get at is that we need much better biomarkers in the blood and the urine, because we simply can't keep doing kidney biopsies in our patients. At the moment, the things we traditionally use, like blood in the urine, proteinuria, and GFR, are not precise enough to tell us what is happening in the kidneys, and that is really important when you think that we have lots of new therapies, all of which do very different things. It would be much better for us to understand what is going on in the kidneys so we could target specific treatments to specific forms of pathology within the kidney tissue.

肾医线：结合您在WCN 2026的交流，您认为肾小球疾病领域未来的研究重点应是什么？

Jonathan Barratt教授：未来的核心方向是推动肾小球疾病的个体化医疗。我们已经拥有了多种新药，但还不清楚哪类患者适合哪种药物。接下来需要全力研发生物标志物，实现在合适的时间，为合适的患者匹配最合适的治疗方案。简单来说，药物已经就位，我们需要学会用最科学、最优的方式使用它们。

Nephrology Online: From your discussions and exchanges, and we believe you have many at the WCN, what do you think should be the future research priorities in the field of glomerular disease? 

Dr Barratt: Well, to carry on the theme, I think we need to aim for personalized medicine in glomerular disease. We have lots of new drugs, but we don’t know which are the right patients that are going to do best on each of these drugs. We need to look to develop biomarkers that allow us to tailor the right drug to the right patient at the right time. So, now we have the drugs, we need to just learn how to use them in the best possible way.

总结

本次专访清晰呈现了全球肾小球疾病的诊疗现状与未来趋势，早期识别患者与个体化用药匹配是当前面临的核心难题，生物标志物研发则是破解难题的关键。靶向B细胞疗法凭借可降低致病性IgA水平、改善蛋白尿血尿、保护肾功能的显著优势，成为IgA肾病治疗的突破性方向。同时该疗法存在抑制机体抗感染抗体、长期安全性未知的潜在局限。未来肾小球疾病领域将以个体化医疗为核心，依托生物标志物研究的突破，实现新型治疗药物的科学精准应用，推动整个领域诊疗水平实现跨越式发展。

专家简介


Jonathan Barratt 教授

主要研究领域为IgA肾病的发病机制以及肾小球疾病、多个系统相关性肾病以及慢性肾脏病并发症，尤其是肾性贫血。
英国国家罕见肾病登记中心（RaDaR）IgA肾病罕见病组负责人、英国莱斯特大学生命科学部肾脏研究组组长
国际IgA肾病联盟（the International IgA Nephropathy Network，IIGANN）主席，FDA和美国肾脏病学会肾脏健康倡议：确定IgA肾病临床试验替代终点工作组的成员，英国肾小球肾炎临床研究小组联合主席，KDIGO肾小球疾病临床实践指南编写组IgA肾病内容部分负责人
多项IgA肾病国际随机对照Ⅱ期和Ⅲ期临床试验的首席研究员，并作为IgA肾病新疗法的专家证人出席了FDA和EMA。是美国肾脏病学会Kidney International and Clinical Journal编委会成员，英国肾脏研究资助委员会成员