Seminars in nephrology最新文献

英文中文

Integrating Metabolomics and Transcriptomics to Characterize Differential Functional Capabilities of Kidney Proximal Tubule Cell Subtypes 整合代谢组学和转录组学来表征肾近端小管细胞亚型的不同功能能力。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-11-01 DOI: 10.1016/j.semnephrol.2025.151577

Jens Hansen , Mustafa M. Siddiq , John Cijiang He , Ravi Iyengar

The coupling between energy metabolism and transport processes is a key feature that defines the functional capability of proximal tubule cells. Recent studies using metabolomics and transcriptomics provide insights into the relationships between changes in single-cell transcriptomic profiles and energy metabolism during kidney development and in disease states. In this review, we describe insights from these studies and how mapping of metabolites to functional pathways within cells enables these insights. We also describe our analyses of fatty acid metabolism pathways from single-cell transcriptomic data obtained by the Kidney Precision Medicine Project, which indicate that proximal tubule cell subtypes can be divided into two major groups with high and low levels of mRNAs for fatty acid (beta) oxidation enzymes. On average, patients with CKD have higher levels of cells with low fatty acid oxidation capability. These cells also have lower levels of sodium transporters. Within each group of proximal tubule cell subtypes there is considerable variability between individual patients. Integrating these data with metabolomics analyses can provide insights into how the differential metabolic capabilities of proximal tubule cells are related to disease features in individual patients. Identifying such relationships can lead to development of precision medicine approaches in nephrology.

能量代谢和运输过程之间的耦合是定义近端小管细胞功能能力的关键特征。最近使用代谢组学和转录组学的研究为肾脏发育和疾病状态中单细胞转录组谱变化与能量代谢之间的关系提供了见解。在这篇综述中，我们描述了这些研究的见解，以及如何将代谢物映射到细胞内的功能途径中，从而实现这些见解。我们还描述了我们从肾脏精密医学项目获得的单细胞转录组数据中对脂肪酸代谢途径的分析，这些数据表明近端小管细胞亚型可以分为两大类，具有高水平和低水平的脂肪酸（β）氧化酶mrna。平均而言，CKD患者具有较高水平的低脂肪酸氧化能力的细胞。这些细胞的钠转运蛋白水平也较低。在每一组近端小管细胞亚型中，个体患者之间存在相当大的差异。将这些数据与代谢组学分析相结合，可以深入了解近端小管细胞的差异代谢能力如何与个体患者的疾病特征相关。确定这种关系可以导致肾病学中精确医学方法的发展。

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引用次数: 0

The Role of Mucosal Immunity: What Can We Learn From Animal and Human Studies? 粘膜免疫的作用：我们能从动物和人体研究中学到什么？

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151566

Patrick J. Gleeson MB, BAO, BCh, PhD , Renato C. Monteiro MD, PhD

Immunoglobulin A (IgA) is a key actor in the mucosal immune system, which moderates interactions between the host and environmental factors such as food antigens and commensal microorganisms. The pathogenesis of IgA nephropathy (IgAN) involves a multistep process starting with deglycosylation of mucosally derived, polymeric IgA1 (dg-IgA1) that reaches the circulation. Modified O-glycans on dg-IgA1 are targeted by IgG-autoantibodies, leading to the formation of circulating immune complexes that deposit in the glomerular mesangium. Infections of mucosal surfaces trigger flares of primary IgAN, while inflammatory bowel disease and liver cirrhosis are important causes of secondary IgAN, supporting a mucosal source of nephritogenic IgA1. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T-cell–dependent or T-cell–independent B-cell differentiation into IgA-secreting plasma cells. Herein we review the literature concerning mucosal immune function and how it is altered in this disease. We discuss recent evidence supporting a causal role of gut microbiota dysbiosis in IgAN pathogenesis.

免疫球蛋白 A（IgA）是粘膜免疫系统中的关键角色，它能调节宿主与环境因素（如食物抗原和共生微生物）之间的相互作用。IgA 肾病（IgAN）的发病机制涉及一个多步骤过程，首先是进入血液循环的粘膜衍生高分子 IgA1（dg-IgA1）发生脱糖基化。IgG 自身抗体靶向 dg-IgA1 上的修饰 O-糖，形成循环免疫复合物，沉积于肾小球系膜。粘膜表面的感染会引发原发性 IgAN 的复发，而炎症性肠病和肝硬化则是继发性 IgAN 的重要原因，这支持了肾炎 IgA1 的粘膜来源。在微生物病原体或食物抗原存在的情况下，肠道粘膜中活化的树突状细胞会诱导依赖 T 细胞或不依赖 T 细胞的 B 细胞分化为分泌 IgA 的浆细胞。在此，我们回顾了有关粘膜免疫功能及其在这种疾病中如何发生改变的文献。我们讨论了支持肠道微生物群失调在 IgAN 发病机制中起因果作用的最新证据。

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引用次数: 0

IgA Nephropathy: Epidemiology and Disease Risk Across the World IgA肾病：全球流行病学和疾病风险。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151564

Malak Ghaddar MD , Mark Canney MB, BCh, BAO, PhD , Sean J. Barbour MSc, MD

Despite decades of research, our knowledge of the global epidemiology of IgA nephropathy remains limited. Much of what we know about IgA nephropathy incidence comes from biopsy registry studies that are subject to bias related to differences in screening programs, referral patterns, and access to healthcare. Fewer epidemiologic studies used an appropriate data infrastructure that includes a well-defined source population. Nonetheless, all these studies show considerable geographic variation in disease incidence with an increase from west to east and south to north across Eurasia. This pattern is partly explained by the distribution of genetic risk alleles in individuals of European and East Asian ancestry. Although historically thought to be an indolent disease, recent long-term follow-up studies have demonstrated an exceptionally high lifetime risk of kidney failure. The International IgA Nephropathy Prediction Tool, derived and validated in multiple ethnically diverse cohorts, has improved our ability to identify patients at high risk of progression who may benefit from therapies being tested in clinical trials. The earlier identification of high-risk patients, evaluation of novel risk factors, and accurate assessment of global disease burden require high-quality regional data infrastructures and broad collaborative efforts to ensure the impact of new treatments is maximized.

尽管经过数十年的研究，我们对IgA肾病全球流行病学的了解仍然有限。我们对IgA肾病发病率的了解大多来自活检登记研究，这些研究存在与筛查方案、转诊模式和获得医疗保健的差异相关的偏倚。很少有流行病学研究使用适当的数据基础设施，包括定义明确的源人群。尽管如此，所有这些研究都表明，在欧亚大陆上，疾病发病率从西到东、从南到北都有所增加，存在相当大的地理差异。这种模式可以部分解释为遗传风险等位基因在欧洲和东亚血统个体中的分布。虽然历来被认为是一种惰性疾病，但最近的长期随访研究表明，肾衰竭的终生风险异常高。国际IgA肾病预测工具，在多个种族不同的队列中推导和验证，提高了我们识别高风险进展患者的能力，这些患者可能从临床试验中测试的治疗中受益。早期识别高风险患者、评估新的风险因素和准确评估全球疾病负担需要高质量的区域数据基础设施和广泛的协作努力，以确保新疗法的影响最大化。

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引用次数: 0

IgA Vasculitis and IgA Nephropathy: Two Sides of the Same Coin? IgA血管炎和IgA肾病：同一枚硬币的两面？

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151571

Evangéline Pillebout MD, PhD

IgA vasculitis (IgAV) is considered a systemic form of IgA nephropathy (IgAN). The two diseases share similar geographic and ethnic distribution, along with common variants in genetic association studies. The pathophysiology of IgAN and IgA vasculitis nephritis (IgAVN) can be explained by the four-hit hypothesis. Key molecules involved at each step in both diseases were evaluated as diagnostic and prognostic biomarkers with many common factors, most prominently serum galactose-deficient IgA1. On kidney biopsy, the two diseases are indistinguishable, and the established histological Oxford classification for IgAN will soon be validated for IgAVN. Chronic lesions (segmental glomerulosclerosis and tubular atrophy / interstitial fibrosis) seem more frequent in IgAN, while proliferative lesions (endocapillary hypercellularity and crescents) are more frequent in IgAVN, which could explain the worse IgAN renal prognosis. Due to characteristic skin rash, IgAVN patients are diagnosed precociously. Conversely, the frequent absence of overt clinical signs in IgAN leads to a delayed diagnostic kidney biopsy in the disease evolution, which explains the chronic pathologic lesions. From a therapeutic perspective, while impressive advances have been made in recent years for IgAN, there is a glaring lack of evidence-based guidelines for the treatment of IgAVN. Large therapeutic clinical studies are required, and future IgAN trials should include IgAVN.

IgA血管炎（IgAV）被认为是IgA肾病（IgAN）的一种系统性形式。这两种疾病具有相似的地理和种族分布，在遗传关联研究中也有共同的变异。IgAN和IgA血管炎肾炎（IgAVN）的病理生理可以用四击假说来解释。在这两种疾病的每个步骤中涉及的关键分子被评估为具有许多共同因素的诊断和预后生物标志物，最突出的是血清半乳糖缺乏IgA1。在肾脏活检中，这两种疾病是无法区分的，IgAN的组织学牛津分类将很快被证实为IgAVN。慢性病变（节段性肾小球硬化和小管萎缩/间质纤维化）似乎在IgAN中更常见，而增生性病变（毛细血管内高细胞性和新月形）在IgAVN中更常见，这可以解释IgAN肾脏预后较差的原因。由于特征性皮疹，IgAVN患者被过早诊断。相反，IgAN患者经常缺乏明显的临床体征，导致在疾病发展过程中延迟诊断肾活检，这解释了慢性病理病变。从治疗的角度来看，尽管IgAN近年来取得了令人印象深刻的进展，但IgAVN的治疗明显缺乏循证指南。需要进行大规模的治疗性临床研究，未来的IgAN试验应包括IgAVN。

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引用次数: 0

Updates on IgA Nephropathy IgA肾病的最新进展。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151574

Dana V. Rizk MD

引用次数: 0

The Pathology of IgA Nephropathy: How Can It Inform Management? IgA肾病的病理：如何为管理提供信息？

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151568

Mark Haas MD, PhD

IgA nephropathy (IgAN), the world's most common form of primary glomerulonephritis (GN), has a variable clinical and pathologic presentation. While all cases of IgAN show dominant or codominant glomerular IgA deposits, their histologic appearance can range from essentially normal to severe crescentic GN. Oxford (MEST-C) scoring is widely used to classify IgAN on kidney biopsies and has been validated to correlate with clinical presentation and as an independent predictor of kidney outcomes in multiple studies. Components of MEST-C, most notably endocapillary hypercellularity (E score) and crescents (C score), have also been shown to correlate with response to immunosuppressive therapy. Furthermore, immunohistologic evidence of complement activation by the alternative pathway and sometimes the lectin pathway correlates with histologic lesions, proteinuria, and kidney survival, suggesting the complement cascade as a potential therapeutic target. Recent clinical trials have demonstrated the potential of newer classes of immunosuppressive agents as well as complement inhibitors to reduce proteinuria, a marker associated with disease progression, in patients with IgAN. While pathologic studies of kidney biopsies have generally not been part of these trials, this review presents an algorithm by which kidney biopsy findings can be used to guide the choice of therapeutic agents in patients with IgAN.

IgA肾病（IgAN）是世界上最常见的原发性肾小球肾炎（GN），具有不同的临床和病理表现。虽然所有IgAN病例均表现为显性或共显性肾小球IgA沉积，但其组织学表现可从基本正常到严重新月形GN。牛津（MEST-C）评分被广泛用于对肾活检的IgAN进行分类，并已被证实与临床表现相关，并在多项研究中作为肾脏预后的独立预测因子。MEST-C的组成部分，最显著的是毛细血管内高细胞（E分）和新月（C分），也被证明与免疫抑制治疗的反应相关。此外，免疫组织学证据表明补体通过替代途径激活，有时凝集素途径与组织学病变、蛋白尿和肾脏存活相关，这表明补体级联是一个潜在的治疗靶点。最近的临床试验表明，新型免疫抑制剂和补体抑制剂有可能减少IgAN患者的蛋白尿（一种与疾病进展相关的标志物）。虽然肾活检的病理研究通常不是这些试验的一部分，但本综述提出了一种算法，通过该算法，肾活检结果可用于指导IgAN患者治疗药物的选择。

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引用次数: 0

Post-transplant IgA Nephropathy 移植后IgA肾病。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151570

Song C. Ong MB, BS , Bruce A. Julian MD

Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis in many countries. Most patients progress to kidney failure for which kidney transplantation is the optimal therapy. Unfortunately, IgA nephropathy commonly recurs post transplant and shortens allograft survival. Multiple recipient and donor characteristics have been associated with the risk of recurrence, although these have varied between different cohorts. The clinical expression of post-transplant IgA nephropathy is modified by immunosuppression. Biomarkers have been identified and studied in native-kidney IgA nephropathy but need validation in transplantation. Treatment of recurrent IgA nephropathy hinges on supportive measures derived largely from evidence in native-kidney IgA nephropathy. The improved understanding of the autoimmune mechanisms of disease in native-kidney IgA nephropathy has led to promising new targets for treatment, which may in turn be deployed in post-transplant IgA nephropathy.

免疫球蛋白A （IgA）肾病是许多国家最常见的肾小球肾炎。大多数患者进展为肾衰竭，肾移植是最佳的治疗方法。不幸的是，IgA肾病通常在移植后复发并缩短同种异体移植的生存期。多个受体和供体特征与复发风险相关，尽管这些特征在不同的队列中有所不同。免疫抑制可改变移植后IgA肾病的临床表达。生物标志物已经在原生肾IgA肾病中被识别和研究，但在移植中需要验证。复发性IgA肾病的治疗取决于支持措施，这些措施很大程度上来源于原生肾IgA肾病的证据。对原生肾IgA肾病自身免疫机制的进一步了解已经导致了有希望的新治疗靶点，这些靶点可能反过来用于移植后IgA肾病。

引用次数: 0

The Genetics of IgA Nephropathy: Implications for Future Therapies IgA肾病的遗传学：对未来治疗的影响。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151567

Xu-jie Zhou MD, PhD , Hong Zhang MD, PhD

IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. The etiology of IgAN, however, remains incompletely understood, and effective treatment is lacking. Although the multihit model effectively identifies key steps in IgAN development and, to date, provides the best description of IgAN pathogenesis, it remains under development to fully capture the complexity of immune system dysregulation. Large-scale genome-wide association studies have revealed clues regarding the association between IgAN and genes in both innate and adaptive immune pathways. Hence, genetic investigations may shed light on the aberrant molecular mechanisms, thereby presenting new opportunities for therapeutic advancements. This review discusses the genetic associations that have been robustly connected with IgAN, placing them within the framework of disease mechanism. Altogether, these findings highlight numerous new possibilities for the development of treatments and the road to personalized medicine.

IgA肾病（IgAN）是世界范围内最常见的原发性肾小球肾炎，具有相当大的终生肾衰竭风险。然而，IgAN的病因仍然不完全清楚，缺乏有效的治疗方法。尽管多靶点模型有效地识别了IgAN发展的关键步骤，并且迄今为止提供了对IgAN发病机制的最佳描述，但它仍在发展中，以充分捕捉免疫系统失调的复杂性。大规模全基因组关联研究揭示了IgAN与先天和适应性免疫途径中基因之间关联的线索。因此，基因研究可以揭示异常的分子机制，从而为治疗进步提供新的机会。本综述讨论了与IgAN密切相关的遗传关联，并将其置于疾病机制的框架内。总之，这些发现突出了治疗方法发展和个性化医疗之路的许多新可能性。

引用次数: 0

IgAN Across the Age Spectrum: The Pediatric Perspective 跨年龄谱IgAN：儿科视角。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151569

Licia Peruzzi MD, PhD , Rosanna Coppo MD

IgA nephropathy (IgAN) presents with different expressions and natural histories across ages. The direct comparison of incidence and progression of IgAN in children and adults is difficult due to different policies for performing kidney biopsy in different ages and countries. In the past decade the focus has been on assessing the individual risk profile at kidney biopsy or after 1 year of follow-up in children and adults. This would help avoid overtreatment and unnecessary drug exposure in benign cases of IgAN, and promptly initiate an aggressive therapy in progressive ones. This issue is particularly relevant in children. This review addresses some recent insights into the similarities and differences of IgAN across the age spectrum, with a particular focus on the prognostic predictors of progression in children and in adults, aiming at offering some critical elements useful for treatment choices for IgAN across ages.

IgA肾病（IgAN）在不同年龄表现出不同的表达和自然病史。由于不同年龄和国家对肾活检的政策不同，很难直接比较儿童和成人IgAN的发病率和进展。在过去的十年中，重点是评估肾脏活检或儿童和成人随访1年后的个体风险概况。这将有助于避免良性IgAN病例的过度治疗和不必要的药物暴露，并在进展性IgAN病例中及时启动积极治疗。这个问题与儿童特别相关。本综述探讨了IgAN在不同年龄段的异同，特别关注儿童和成人进展的预后预测因素，旨在为不同年龄段的IgAN治疗选择提供一些有用的关键因素。

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The Journey to Advocacy: Celebrating the IgA Nephropathy Foundation's 20th Anniversary 倡导之旅：庆祝IgA肾病基金会成立20周年。

IF 3.5 3区医学 Q2 UROLOGY & NEPHROLOGY

Seminars in nephrology

Pub Date : 2024-09-01 DOI: 10.1016/j.semnephrol.2025.151575

Brian Parlato BS Mech Eng, MBA

The IgA Nephropathy Foundation was established in 2004 by Bonnie and Ed Schneider, the concerned parents of a young boy diagnosed with IgA nephropathy (IgAN). At the time the Foundation was established, patients had trouble finding the most basic information about IgAN, and few nephrologists had experience with this rare disease. Celebrating its 20th anniversary this year, the Foundation has been instrumental in bringing the IgAN community together through research grants, advocating for patients and caregivers, offering patient support services, and becoming the go-to source for information and education. A big focus for the Foundation is communicating the “voice of the patient” to the medical community to help identify needs and provide insight into the lives of IgAN patients and caregivers. The Foundation is very active in getting the word out, attending the last two International Symposia on IgA Nephropathy, in Prague, Czech Republic, and Tokyo, Japan. The Foundation also sponsored the IgA Nephropathy Seminar Day at the 6th CKD Summit in Boston in spring 2024. This article chronicles some of the Foundation's key milestones, highlights patient-facing and point-of-care resources, and provides key insights into the patient experience as well as tips for how clinicians can best meet patients where they are, bridge gaps, and improve care. The unmet needs of the IgAN community continue to drive the IgA Nephropathy Foundation's purpose and steadfast commitment to finding a cure for this rare disease.

IgA肾病基金会由Bonnie和Ed Schneider夫妇于2004年成立，他们的孩子被诊断患有IgA肾病（IgAN）。在基金会成立的时候，患者很难找到关于IgAN的最基本信息，而且很少有肾病专家有这种罕见疾病的经验。今年是该基金会成立20周年，通过研究资助、为患者和护理人员倡导、提供患者支持服务以及成为信息和教育的首选来源，该基金会在将IgAN社区团结在一起方面发挥了重要作用。基金会的一大重点是向医学界传达“患者的声音”，以帮助确定需求，并深入了解IgAN患者和护理人员的生活。基金会非常积极地宣传，参加了最近在捷克共和国布拉格和日本东京举行的两届关于IgA肾病的国际研讨会。基金会还于2024年春季在波士顿举行的第六届CKD峰会上赞助了IgA肾病研讨会日。本文记录了基金会的一些重要里程碑，重点介绍了面向患者和护理点的资源，并提供了有关患者体验的关键见解，以及临床医生如何最好地满足患者的需求、弥合差距和改善护理的提示。IgAN社区未满足的需求继续推动着IgA肾病基金会的目标和坚定的承诺，即寻找治疗这种罕见疾病的方法。

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