编者按：在第62届欧洲肾脏协会年会（ERA 2025）上，肾医线对欧洲肾脏协会（ERA）前主席、德国维尔茨堡大学及英国牛津大学资深教授Christoph Wanner进行专访，请他围绕心肾轴、慢性肾脏病（CKD）治疗策略及领域未来发展等话题展开深入探讨，为临床医生带来了心肾领域的前沿视角，也为慢性肾脏病的管理与研究指明了方向。

心肾轴新洞察：关注纤维化机制，改善患者生存质量

当被问及在“心肾轴”主题演讲中探索的器官互联病理生理学机制，以及对当代肾脏病临床医生最具意义的新机制见解或治疗启示时，Wanner教授指出，当前对肾脏病医生而言，最关键的认知（且有数据支持）是：许多进展性肾脏病患者在进入透析阶段前，就已死于心血管疾病，仅有部分患者能存活至开始透析。其深层机制在于肾脏和心脏会同时发生纤维化过程。

幸运的是，现代治疗手段已能针对这些纤维化通路，有效减缓肾脏纤维化、慢性肾脏病及心力衰竭的进展。这对临床肾脏病学而言是个振奋人心的消息，因为它能帮助患者在更长时间内维持生活质量，甚至可能延缓乃至避免透析需求。

Nephrology On-line: In your presentation on the heart–kidney axis, you explored the interconnected pathophysiology of these organs. What new mechanistic insights or therapeutic implications do you think are most relevant for practicing nephrologists today?

Dr Wanner:  The most relevant insight for nephrologists today is the recognition, supported by data, that many patients with progressive kidney disease die from cardiovascular disease before reaching dialysis. Only a proportion of patients survive to initiate dialysis. The underlying mechanism involves fibrotic processes occurring simultaneously in both the kidney and the heart. Fortunately, modern therapeutic approaches now enable us to target these fibrotic pathways, effectively slowing the progression of kidney fibrosis, chronic kidney disease, and heart failure. This represents encouraging news for clinical nephrology, as it allows us to maintain patients' quality of life for a longer period, potentially delaying or even avoiding the need for dialysis.

联合用药策略：早期联用非奈利酮与SGLT2抑制剂的证据与实践

Wanner教授主张对慢性肾脏病患者早期联合使用非奈利酮与SGLT2抑制剂。他解释，SGLT2抑制剂与非甾体类盐皮质激素受体拮抗剂（MRAs）具有良好的互补性，二者分别作用于不同的病理生理学机制——前者针对血流动力学通路，后者针对抗纤维化通路，这两种疗法均能为肾脏和心脏提供保护作用。

在临床实践中，他建议先启用SGLT2抑制剂，随后使用非甾体类MRAs，这种用药顺序有助于降低高钾血症风险，且两种药物应紧密衔接使用，以有效控制疾病进展。他强调，早期干预至关重要，因为时间等同于肾单位的保护（即“time is nephron mass”），及时治疗还有助于预防心力衰竭的进展。

Nephrology On-line: You advocate for the early combination of finerenone and SGLT2 inhibitors in CKD patients. Could you share key evidence supporting this approach, and how should clinicians balance the risks and benefits in real-world patients with diabetes and cardiovascular comorbidities?

Dr Wanner: SGLT2 inhibitors and non-steroidal MRAs complement each other well because they address distinct pathophysiological mechanisms—hemodynamic and anti-fibrotic pathways, respectively. Both therapies provide protective effects for the kidney and the heart. Clinically, we recommend initiating an SGLT2 inhibitor first, followed by a non-steroidal MRA, as this sequence helps to minimize the risk of hyperkalemia. These agents should be introduced in close succession to manage disease progression effectively. 

My key message is: early intervention is critical, as time equates to nephron preservation. Timely treatment also helps prevent the progression of heart failure.

脂质管理新方向：超越他汀类药物，PCSK9抑制剂显潜力

关于慢性肾脏病患者的脂质管理，Wanner教授提到，降脂治疗在慢性肾脏病管理中仍不可或缺，KDIGO指南将其列为1A类推荐——所有高危慢性肾脏病患者都应接受他汀类药物治疗。当前KDIGO采用的是“一劳永逸”策略，主张启动治疗时无需常规监测血脂水平，以最大限度覆盖高危人群。

但心脏病学指南正日益采用“3-2目标”概念，而“一劳永逸”策略中的中等强度他汀治疗，往往不足以达到新推荐的低低密度脂蛋白胆固醇（LDL-C）目标。为实现这些目标——尤其是针对特定患者群体——PCSK9抑制剂成为必要选择。这类药物通常每两周皮下注射一次，降脂效果显著，不过价格相对较高。

尽管目前缺乏以肾脏病患者的肾脏或心血管结局为主要终点的特异性试验，但现有数据证实，PCSK9抑制剂能安全且显著地降低LDL-C水平。由于缺乏专门证据，暂时无法形成明确的指南推荐，只能提供临床指导。但对于需要强化降脂以达到治疗目标的患者，应考虑除他汀类药物外的降脂策略，包括PCSK9抑制剂。

Nephrology On-line: In your lecture on lipid management in CKD, you speak about moving beyond the statin era. What novel lipid-lowering strategies show the most promise in this population, and how do you see them integrating with existing CKD care pathways?

Dr Wanner: Lipid-lowering therapy remains essential in the management of chronic kidney disease, and is strongly recommended as a Grade 1A indication by KDIGO guidelines - everybody with chronic kidney disease at high risk should receive statin therapy. The current KDIGO approach follows the "fire-and-forget" strategy, which advocates initiating treatment without routine monitoring of lipid levels, to maximize treatment coverage among high-risk individuals. However, Cardiology guidelines are increasingly adopting the 3-2 target concept. Moderate-intensity statin therapy within the fire-and-forget strategy is often insufficient to achieve the newly recommended low LDL-cholesterol targets. To achieve these goals—particularly in specific subsets of patients— PCSK9 inhibitors are becoming necessary. These agents, typically administered via subcutaneous injection every two weeks, are highly effective in lowering LDL-cholesterol, although they remain relatively expensive.

Despite the absence of kidney-specific outcome trials, existing data confirm that PCSK9 inhibitors safely and significantly reduce LDL-cholesterol levels. Nevertheless, as nephrologists, we would prefer to see trials where kidney or cardiovascular outcomes in CKD patients are designated as primary endpoints. Currently, such dedicated evidence is lacking, which limits our ability to formulate definitive guideline recommendations. At this stage, we can offer clinical guidance but not formal recommendations. We advocate considering lipid-lowering strategies beyond statins, including PCSK9 inhibitors, for patients who require more intensive lipid control to achieve treatment targets.

肾脏病学未来展望：从广泛保护到精准治疗，多方协作共促发展

作为欧洲肾脏协会前主席和领域思想领袖，Wanner教授对肾脏病学的未来方向进行了展望。他认为，未来五年，通过广泛、通用机制提供心肾保护的疗法（即“一刀切”方案）将持续发展，例如内皮素受体拮抗剂、醛固酮合成酶抑制剂和可溶性鸟苷酸环化酶激活剂等，并有望与SGLT2抑制剂、非甾体类MRAs共同完善现有治疗体系，预计未来5~6年内这些疗法将逐步应用于临床。

同时，他提到在IgA肾病、局灶节段性肾小球硬化及其他罕见肾小球疾病的药物研发方面正取得重大进展，尤其是罕见遗传性疾病和肾小球肾炎方面。肾脏病学领域正逐渐向罕见病管理方向发展。

在协作层面，心肾保护及延缓肾脏病进展需要与糖尿病专家、内分泌专家和全科医生密切合作，因为大多数慢性肾脏病患者初期由他们负责管理，他们在患者早期管理中发挥着关键作用。而目前肾脏病医生的数量不足以应对所有慢性肾脏病患者。因此，肾脏病学领域在聚焦罕见病的同时，也在为全科医生创造更多机会，使其在更广泛的慢性肾脏病患者管理中发挥更大作用，并提高有效治疗的可及性。

关于新疗法的风险与获益平衡问题，Wanner教授表示这并非新问题。SGLT2抑制剂已临床应用约十年，全球已有数百万患者接受过该类治疗，其虽可能引发生殖器感染，但风险较低，适用于更广泛的患者群体，即总体而言，SGLT2抑制剂风险较小。因此，在慢性肾脏病中使用SGLT2抑制剂、在糖尿病中使用非甾体类MRAs均是推荐做法。此外，非甾体类MRAs非奈利酮在非糖尿病肾病中的应用正处于研究阶段，相关新数据预计将在明年格拉斯哥举行的欧洲肾脏协会大会上公布。

Nephrology On-line: As a former ERA president and thought leader, how do you envision the future direction of nephrology? Which areas—such as genetic diagnostics, inflammation resolution, or metabolic modulation—do you believe will reshape CKD management in the next decade?

Dr Wanner:Over the next five years, the development of therapies offering cardiovascular and renal protection through broad, generalized mechanisms—a "one-size-fits-all" approach—will continue. For example, agents such as endothelin receptor antagonists, aldosterone synthase inhibitors, and soluble guanylate cyclase activators are expected to complement the existing treatment landscape alongside SGLT2 inhibitors and non-steroidal MRAs. These therapies are anticipated to become available within the next five to six years.

In parallel, As you mentioned, substantial advancements are being made in drug development for IgA nephropathy, focal segmental glomerulosclerosis, and other rare glomerular diseases. In fact, it could be said that nephrology is increasingly evolving towards the management of rare diseases, particularly rare genetic disorders and glomerulonephritides. 

Cardiovascular protection and slowing the progression of kidney disease require close collaboration with diabetologists, endocrinologists, and general practitioners, who play a critical role in the early management of patients, as most CKD patients are initially under their care. The current number of nephrologists is insufficient to manage all patients with chronic kidney disease. The field of nephrology is increasingly focusing on rare diseases, while simultaneously expanding opportunities for general practitioners to play a greater role in managing the broader CKD population and improving access to effective treatments.

Regarding your question on balancing the benefit-to-risk ratio of new treatments, this is not a recent concern. SGLT2 inhibitors have been in clinical use for approximately ten years, with millions of patients worldwide having received these therapies. It is well established that SGLT2 inhibitors are associated with a low risk of genital infections; however, these agents remain appropriate for a broader patient population. The overall risk is minimal, and the use of SGLT2 inhibitors in chronic kidney disease and non-steroidal MRAs in diabetes is recommended. Additionally, finerenone, a non-steroidal MRA, is currently being investigated for use in non-diabetic kidney disease.  New data on non-steroidal MRAs in non-diabetic kidney disease are expected to be presented at the ERA Congress in Glasgow next year.