American Journal of Pathology最新文献

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Celebrating the First 100 Years of Publishing Significant Scientific Discoveries in The American Journal of Pathology 庆祝《美国病理学杂志》发表重大科学发现100周年。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.10.011

Mark E. Sobel , Martha B. Furie

引用次数: 0

Single-Cell Advances in Investigating and Understanding Chronic Kidney Disease and Diabetic Kidney Disease 评论：研究和了解慢性肾病和糖尿病肾病的单细胞进展。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.07.007

Sagar Bhayana , Philip A. Schytz , Emma T. Bisgaard Olesen , Keng Soh , Vivek Das

Chronic kidney disease (CKD) and its subset diabetic kidney disease are progressive conditions that affect >850 million people worldwide. Diabetes, hypertension, and glomerulonephritis are the most common causes of CKD, which is associated with significant patient morbidity and an increased risk of cardiovascular events, such as heart failure, ultimately leading to premature death. Despite newly approved drugs, increasing evidence shows that patients respond to treatment differently given the complexity of disease heterogeneity and complicated pathophysiology. This review article presents an integrative approach to understanding and addressing CKD through the lens of precision medicine and therapeutics. Advancements in single-cell omics technologies and artificial intelligence can be leveraged to explore the intricate cellular mechanisms underlying CKD and diabetic kidney disease pathogenesis. Dissecting the cellular heterogeneity and identifying rare cell populations using single-cell approaches will facilitate uncovering novel therapeutic targets and biomarkers for personalized treatment strategies. Finally, we discuss the potential of artificial intelligence–driven analyses in predicting disease progression and treatment response, thereby paving the way for tailored interventions.

慢性肾脏病（CKD）及其亚型糖尿病肾病（DKD）是影响全球 8.5 亿多人的渐进性疾病。糖尿病、高血压和肾小球肾炎是导致慢性肾脏病的最常见原因，而慢性肾脏病与患者的严重发病率和心血管事件（如心力衰竭）的风险增加有关，最终导致患者过早死亡。尽管新近批准了一些药物，但越来越多的证据表明，由于疾病的异质性和病理生理学的复杂性，患者对治疗的反应各不相同。本综述论文从精准医学和治疗学的角度，介绍了一种理解和解决慢性肾功能衰竭问题的综合方法。利用单细胞全息技术和人工智能（AI）的进步，我们可以探索 CKD 和 DKD 发病机制背后错综复杂的细胞机制。通过使用单细胞方法剖析细胞异质性和识别罕见细胞群，我们将有可能发现新的治疗靶点和生物标志物，从而制定个性化治疗策略。最后，我们讨论了人工智能驱动的分析在预测疾病进展和治疗反应方面的潜力，从而为量身定制的干预措施铺平道路。

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引用次数: 0

miRNA and mRNA Signatures in Human Acute Kidney Injury Tissue 人类急性肾损伤组织中的 miRNA 和 mRNA 信号。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.08.013

Danielle Janosevic , Thomas De Luca , Ricardo Melo Ferreira , Debora L. Gisch , Ying-Hua Cheng , Takashi Hato , Jinghui Luo , Yingbao Yang , Jeffrey B. Hodgin , Carrie L. Phillips , Pierre C. Dagher , Kidney Precision Medicine Project, Michael T. Eadon

Acute kidney injury (AKI) is an important contributor to the development of chronic kidney disease (CKD). There is a need to understand molecular mediators that drive recovery and progression to CKD. In particular, the regulatory role of miRNAs in AKI is poorly understood. Herein, miRNA and mRNA sequencing were performed on biobanked human kidney tissues obtained during the routine care of subjects with a diagnosis of AKI, minimal change disease, or on nephrectomy tissue with no known kidney disease. mRNA analysis revealed that nephrectomy tissues exhibited an injury signature similar to that of AKI which was not identified in minimal change disease samples. The transcriptomic signature of human AKI was enriched in pathways involved in cell adhesion, epithelial-to-mesenchymal transition, and cell cycle arrest (eg, CDH6, ITGB6, CDKN1A). In AKI, up-regulation of miR-146a, miR-155, miR-142, and miR-122 was associated with pathways involved in immune cell recruitment, inflammation, and epithelial-to-mesenchymal transition. miR-122 and miR-146 were associated with down-regulation of DDR2 and IGFBP6, which are genes involved in the recovery and progression of kidney disease. These data provide integrated miRNA signatures that complement mRNA and other epigenetic data available in kidney atlases.

急性肾损伤（AKI）是导致慢性肾脏病（CKD）发展的重要因素。我们需要了解推动恢复和发展为慢性肾脏病的分子介质。mRNA分析表明，Ref组织表现出与AKI相似的损伤特征，但在MCD样本中没有发现。人类 AKI 的转录组特征富含参与细胞粘附、上皮细胞向间质转化和细胞周期停滞的通路（如 CDH6、ITGB6、CDKN1A）。在 AKI 中，miR-146a、miR-155、miR-142、miR-122 的上调与免疫细胞招募、炎症和上皮细胞向间质转化的通路相关。这些数据提供了综合的 miRNA 特征，补充了肾脏图谱中的 mRNA 和其他表观遗传学数据。

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引用次数: 0

A Novel Deep Learning Approach for Analyzing Glomerular Basement Membrane Lesions in a Mouse Model of X-Linked Alport Syndrome 分析 X 连锁阿尔波特综合征小鼠模型肾小球基底膜病变的新型深度学习方法。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.10.004

Kunio Kawanishi , Masaki Baba , Ryosuke Kobayashi , Ryotaro Hori , Kentaro Hashikami , Kenta Danbayashi , Takako Iwachido , Mitsuyasu Kato

Alport syndrome is a rare kidney disease typically more severe in males due to its X-linked inheritance. However, female patients with heterozygous X-linked Alport syndrome (XLAS) can develop renal failure over time, necessitating accurate pathologic assessment for effective therapy. A key pathologic finding in female patients with XLAS is the mosaic pattern of partial loss of α5 chains of type IV collagen (COL4α5). This study, using a mouse model of XLAS with a nonsense mutation (R471∗) in the Col4a5 gene, analogous to human XLAS, aimed to examine the consistency of this pattern with the glomerular basement membrane (GBM) structure. A modified periodic acid–methenamine silver staining method was developed for clearer GBM visualization. The integrated images from COL4α5-stained fluorescence, periodic acid–methenamine silver, and low-vacuum scanning electron microscopy into a single-slide section and applied supervised deep learning to predict GBM lesions. Results showed significant individual variability in urinary protein levels and histologic lesions. Pathologic parameters, including crescent formation, focal segmental glomerulosclerosis, and the COL4α5/α2 ratio, correlated with clinical parameters like urinary protein and plasma creatinine levels. Integrated low-vacuum scanning electron microscopy analysis revealed dense GBM regions corresponded to areas where COL4α5 was preserved, whereas coarse GBM (basket-weave lesions) occurred in COL4α5-deficient regions. These advanced techniques can enhance biopsy-based diagnosis of Alport syndrome and aid in developing artificial intelligence diagnostic tools for diseases involving basement membrane lesions.

阿尔波特综合征是一种罕见的肾脏疾病，由于是 X 连锁遗传，男性患者的病情通常更为严重。然而，患有杂合子X连锁阿尔波特综合征（XLAS）的女性患者随着时间的推移也会出现肾功能衰竭，因此有必要进行准确的病理评估，以便进行有效治疗。女性 XLAS 患者的一个重要病理发现是 IV 型胶原蛋白 α5 链部分缺失的镶嵌模式。本研究利用 Col4a5 基因无义突变（R471*）的 XLAS 小鼠模型（类似于人类 XLAS），旨在研究这种模式与肾小球基底膜（GBM）结构的一致性。为了更清晰地观察肾小球基底膜（GBM），研究人员开发了一种改良的周期性酸-甲酚胺银（PAMS）染色法。将COL4α5染色荧光、PAMS和低真空扫描电子显微镜（LVSEM）的图像整合到单张切片中，并应用有监督的深度学习来预测GBM病变。结果显示，尿蛋白水平和组织学病变存在明显的个体差异。病理参数，包括新月体形成、局灶节段性肾小球硬化和COL4α5/α2比值，与临床参数（如尿蛋白和血浆肌酐水平）相关。综合 LVSEM 分析显示，致密的 GBM 区域与 COL4α5 保留的区域相对应，而粗大的 GBM（篮织病变）则发生在 COL4α5 缺乏的区域。这些先进的技术可提高基于活检的阿尔波特综合征诊断水平，并有助于为涉及基底膜病变的疾病开发人工智能诊断工具。

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引用次数: 0

Single-Cell Analysis Provides New Insights into the Roles of Tertiary Lymphoid Structures and Immune Cell Infiltration in Kidney Injury and Chronic Kidney Disease 单细胞分析为了解三级淋巴结构和免疫细胞浸润在肾损伤和慢性肾病中的作用提供了新的视角。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.07.008

Takahisa Yoshikawa , Motoko Yanagita

Chronic kidney disease (CKD) is a global health concern with high morbidity and mortality. Acute kidney injury (AKI) is a pivotal risk factor for the progression of CKD, and the rate of AKI-to-CKD progression increases with aging. Intrarenal inflammation is a fundamental mechanism underlying AKI-to-CKD progression. Tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates formed in nonlymphoid organs, develop in aged injured kidneys, but not in young kidneys, with prolonged inflammation and maladaptive repair, which potentially exacerbates AKI-to-CKD progression in aged individuals. Dysregulated immune responses are involved in the pathogenesis of various kidney diseases, such as IgA nephropathy, lupus nephritis, and diabetic kidney diseases, thereby deteriorating kidney function. TLSs also develop in several kidney diseases, including transplanted kidneys and renal cell carcinoma. However, the precise immunologic mechanisms driving AKI-to-CKD progression and development of these kidney diseases remain unclear, which hinders the development of novel therapeutic approaches. This review aims to describe recent findings from single-cell analysis of cellular heterogeneity and complex interactions among immune and renal parenchymal cells, which potentially contribute to the pathogenesis of AKI-to-CKD progression and other kidney diseases, highlighting the mechanisms of formation and pathogenic roles of TLSs in aged injured kidneys.

慢性肾脏病（CKD）是全球关注的健康问题，发病率和死亡率都很高。急性肾损伤（AKI）是导致慢性肾脏病恶化的关键风险因素，随着年龄的增长，急性肾损伤导致慢性肾脏病恶化的速度也会加快。肾小球内炎症是 AKI 演变为 CKD 的基本机制。三级淋巴结构是在非淋巴器官中形成的异位淋巴聚集体，在老年损伤肾脏中出现，而在年轻肾脏中则没有，炎症持续时间长，修复不适应，这可能会加剧老年人从 AKI 到 CKD 的进展。失调的免疫反应参与了各种肾脏疾病的发病机制，如 IgA 肾病、狼疮性肾炎和糖尿病肾病，从而导致肾功能恶化。在移植肾和肾细胞癌等多种肾脏疾病中也会出现三级淋巴结构。然而，这些肾脏疾病从 AKI 到 CKD 进展和发展的确切免疫机制仍不清楚，这阻碍了新型治疗方法的开发。本综述旨在描述单细胞分析对细胞异质性和免疫细胞与肾实质细胞之间复杂相互作用的最新发现，这些发现可能是导致 AKI 至 CKD 进展和其他肾脏疾病的发病机制，并强调了三级淋巴结构在老化损伤肾脏中的形成机制和致病作用。

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引用次数: 0

Both Classical and Non-Classical Monocytes Patrol Glomerular Capillaries and Promote Acute Glomerular Inflammation 经典和非经典单核细胞都会巡逻肾小球毛细血管，并促进急性肾小球炎症。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.07.010

ZheHao Tan , Pam Hall , Matthias Mack , Sarah L. Snelgrove , A. Richard Kitching , Michael J. Hickey

Monocyte patrolling of the vasculature has been ascribed primarily to the non-classical monocyte subset. However, a recent study of the glomerular microvasculature provided evidence that both classical and non-classical monocytes undergo periods of intravascular retention and migration. Despite this, whether these subsets contribute differentially to acute glomerular inflammation is unknown. This study used glomerular multiphoton intravital microscopy to investigate the capacity of classical and non-classical monocytes to patrol the glomerular microvasculature and promote acute, neutrophil-dependent glomerular inflammation. In imaging experiments in monocyte reporter Cx3cr1^gfp/+ mice, co-staining with anti-Ly6B or anti-Ly6C revealed that both non-classical monocytes [CX3 chemokine receptor 1–green fluorescent protein positive (CX3CR1-GFP⁺)] and classical monocytes (CX3CR1-GFP⁺ and Ly6B⁺ or Ly6C⁺) underwent prolonged (>10 minutes) retention and migration in the glomerular microvasculature. On induction of acute glomerulonephritis, these behaviors were increased in classical, but not non-classical, monocytes. Using non-classical monocyte–deficient Csf1r^Cre Nr4a1^fl/fl mice, or anti-CCR2 to deplete classical monocytes, the removal of either subset reduced neutrophil retention and activation in acutely inflamed glomeruli, while the depletion of both subsets, via anti-CCR2 treatment in Csf1r^Cre Nr4a1^fl/fl mice, led to further reductions in neutrophil activity. In contrast, in a model of CD4⁺ T cell–dependent glomerulonephritis, the depletion of either monocyte subset failed to alter neutrophil responses. These findings indicate that both classical and non-classical monocytes patrol the glomerular microvasculature and promote neutrophil responses in acutely inflamed glomeruli.

在血管中巡逻的单核细胞主要是非经典单核细胞亚群。然而，最近一项对肾小球微血管的研究提供了证据，证明经典和非经典单核细胞都会经历血管内滞留和迁移期。尽管如此，这些亚群是否会对急性肾小球炎症产生不同的影响尚不清楚。本研究利用肾小球多光子显微镜研究了经典和非经典单核细胞巡视肾小球微血管和促进急性中性粒细胞依赖性肾小球炎症的能力。在单核细胞报告基因 Cx3cr1gfp/+ 小鼠的成像实验中，用抗 Ly6B 或抗 Ly6C 联合染色显示，非经典（CX3CR1-GFP+）和经典（CX3CR1-GFP+ & Ly6B+ 或 Ly6C+）单核细胞都会在肾小球微血管中进行长时间（> 10 分钟）的滞留和迁移。诱导急性肾小球肾炎会增加经典单核细胞的这些行为，但不会增加非经典单核细胞的这些行为。利用非经典单核细胞缺陷的 Csf1rCreNr4a1fl/fl 小鼠或抗-CCR2 来清除经典单核细胞，清除任何一个亚群都会减少中性粒细胞在急性炎症肾小球中的滞留和活化，而通过抗-CCR2 处理 Csf1rCreNr4a1fl/fl 小鼠来清除这两个亚群，则会进一步降低中性粒细胞的活性。相反，在 CD4+ T 细胞依赖性肾小球肾炎模型中，任一单核细胞亚群的耗竭都不能改变中性粒细胞的反应。这些研究结果表明，经典和非经典单核细胞都会巡视肾小球微血管，并能促进急性炎症肾小球的中性粒细胞反应。

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引用次数: 0

A Newly Identified Protective Role of C5a Receptor 1 in Kidney Tubules against Toxin-Induced Acute Kidney Injury 新发现的 C5aR1 在肾小管中对毒素引起的急性肾损伤的保护作用。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.10.003

Samuel Mon-Wei Yu , Emily King , Miguel Fribourg , Susan Hartzell , Liam Tsou , Logan Gee , Vivette D. D'Agati , Joshua M. Thurman , John Cijiang He , Paolo Cravedi

Acute kidney injury (AKI) remains a major reason for hospitalization with limited therapeutic options. Although complement activation is implicated in AKI, the role of C5a receptor 1 (C5aR1) in kidney tubular cells is unclear. Herein, aristolochic acid nephropathy (AAN) and folic acid nephropathy (FAN) models were used to establish the role of C5aR1 in kidney tubules during AKI in germline C5ar1^−/−, myeloid cell–specific, and kidney tubule–specific C5ar1 knockout mice. After aristolochic acid and folic acid injection, C5ar1^−/− mice had increased AKI severity and a higher degree of tubular injury. Macrophage depletion in C5ar1^−/− mice or myeloid cell–specific C5ar1 deletion did not affect the outcomes of aristolochic acid–induced AKI. RNA-sequencing data from renal tubular epithelial cells (RTECs) showed that C5ar1 deletion was associated with the down-regulation of mitochondrial metabolism and ATP production transcriptional pathways. Metabolic studies confirmed reduced mitochondrial membrane potential at baseline and increased mitochondrial oxidative stress after injury in C5ar1^−/− RTECs. Moreover, C5ar1^−/− RTECs had enhanced glycolysis, glucose uptake, and lactate production on injury, corroborated by metabolomics analysis of kidneys from AAN mice. Kidney tubule–specific C5ar1 knockout mice recapitulated exacerbated AKI observed in C5ar1^−/− mice in AAN and FAN. These data indicate that C5aR1 signaling in kidney tubules exerts renoprotective effects against toxin-induced AKI by limiting overt glycolysis and maintaining mitochondrial function, thereby revealing a novel link between the complement system and tubular cell metabolism.

急性肾损伤（AKI）仍然是住院治疗的一个主要原因，但治疗方案有限。虽然补体激活与 AKI 有关，但 C5a 受体 1（C5aR1）在肾小管细胞中的作用尚不清楚。我们利用马兜铃酸肾病（AAN）和叶酸肾病（FAN）模型，在种系C5ar1-/-小鼠、髓样细胞特异性和肾小管特异性C5ar1基因敲除小鼠中确定了AKI期间C5aR1在肾小管中的作用。注射马兜铃酸和叶酸后，C5ar1-/-小鼠的 AKI 严重程度增加，肾小管损伤程度加重。C5ar1-/-小鼠的巨噬细胞耗竭或骨髓细胞特异性C5ar1缺失不会影响AA诱导的AKI结果。RTECs的RNA测序数据显示，C5ar1缺失与线粒体代谢和ATP产生转录途径的下调有关。代谢研究证实，C5ar1-/- RTEC 的线粒体膜电位基线降低，损伤后线粒体氧化应激增加。此外，C5ar1-/- RTEC 在损伤后的糖酵解、葡萄糖摄取和乳酸生成均增强，AAN 小鼠肾脏的代谢组学分析也证实了这一点。肾小管特异性 C5ar1 基因敲除小鼠再现了在 C5ar1-/- AAN 和 FAN 小鼠中观察到的加重的 AKI。我们的数据表明，肾小管中的 C5aR1 信号通过限制明显的糖酵解和维持线粒体功能，对毒素诱导的 AKI 发挥肾保护作用，揭示了补体系统与肾小管细胞代谢之间的新联系。

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引用次数: 0

Advances in Single-Cell Sequencing and Spatial Profiling of Kidney Disease 肾脏疾病单细胞测序和空间图谱研究进展。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.10.010

Amit Verma, Parker C. Wilson

引用次数: 0

Histopathologic Analysis of Human Kidney Spatial Transcriptomics Data 基于组织病理学的人类肾脏空间转录组学数据分析：迈向精准病理学。

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/j.ajpath.2024.06.011

Pierre Isnard , Dian Li , Qiao Xuanyuan , Haojia Wu , Benjamin D. Humphreys

The application of spatial transcriptomics (ST) technologies is booming and has already yielded important insights across many different tissues and disease models. In nephrology, ST technologies have helped to decipher the cellular and molecular mechanisms in kidney diseases and have allowed the recent creation of spatially anchored human kidney atlases of healthy and diseased kidney tissues. During ST data analysis, the computationally annotated clusters are often superimposed on a histologic image without their initial identification being based on the morphologic and/or spatial analyses of the tissues and lesions. Herein, histopathologic ST data from a human kidney sample were modeled to correspond as closely as possible to the kidney biopsy sample in a health care or research context. This study shows the feasibility of a morphology-based approach to interpreting ST data, helping to improve our understanding of the lesion phenomena at work in chronic kidney disease at both the cellular and the molecular level. Finally, the newly identified pathology-based clusters could be accurately projected onto other slides from nephrectomy or needle biopsy samples. Thus, they serve as a reference for analyzing other kidney tissues, paving the way for the future of molecular microscopy and precision pathology.

空间转录组（ST）技术的应用正在蓬勃发展，已经在许多不同的组织和疾病模型中产生了重要的见解。在肾脏病学领域，空间转录组技术有助于破译肾脏疾病的细胞和分子机制，并在最近建立了健康和患病肾脏组织的空间锚定人类肾脏图谱。在 ST 数据分析过程中，计算标注的集群往往被叠加到组织学图像上，而没有根据组织和病变的形态和空间分析对其进行初步识别。在本研究中，我们对人类肾脏样本的空间转录组学数据进行了基于组织病理学的分析，尽可能贴近医疗保健或研究背景下肾脏活检的实际解读。我们的工作证明了用基于形态学的方法解读 ST 数据的可行性，有助于我们从细胞和分子两个层面加深对慢性肾脏病病变现象的理解。最后，我们的研究表明，我们新发现的基于病理学的集群可以准确地投射到来自肾切除术或针刺活检样本的其他切片上，从而作为分析其他肾组织的参考，为未来的分子显微镜和精确病理学铺平道路。

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引用次数: 0

Scientific Integrity Policy

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology

Pub Date : 2025-01-01 DOI: 10.1016/S0002-9440(24)00436-X

引用次数: 0

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