Kidney international最新文献

英文中文

Insights from the BKEVER Trial comparing everolimus versus mycophenolate mofetil for BK Polyomavirus infection in kidney transplant recipients 比较依维莫司和霉酚酸酯治疗肾移植受者 BK 多瘤病毒感染的 BKEVER 试验的启示。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.09.018

Sophie Caillard , Nicolas Meyer , Morgane Solis , Dominique Bertrand , Maite Jaureguy , Dany Anglicheau , Laure Ecotiere , Matthias Buchler , Nicolas Bouvier , Betoul Schvartz , Jean Philippe Rerolle , Anne Elisabeth Heng , Lionel Couzi , Agnes Duveau , Emmanuel Morelon , Yann LeMeur , Léonard Golbin , Eric Thervet , Ilies Benotmane , Samira Fafi-Kremer

The MTOR inhibitors have demonstrated antiviral properties, and prior non-randomized studies have suggested they may have a suppressive effect on BKPyV replication. Here, in this randomized, multicenter, controlled trial (BKEVER study), we sought to evaluate the impact of everolimus (EVR) in facilitating the clearance of BKPyV compared to simply reducing immunosuppression among kidney transplant recipients (KTRs). All together, 130 KTRs presenting with BKPyV DNAemia were randomized 1:1 into two groups. The EVR group, in which mycophenolate mofetil (MMF) was replaced by EVR along with a decrease in calcineurin inhibitor trough levels and secondly the MMF group, in which the MMF dose was decreased by half along with a similar lowering of calcineurin inhibitor levels. The primary endpoint was the proportion of patients achieving viral clearance at six months. Secondary endpoints included the kinetics of BKPyV replication over time, the incidence of BKPyV-associated nephropathy, kidney graft function, the incidence of kidney graft rejection, and medication tolerability over two years. Significantly, BKPyV clearance was achieved in 55.7% of patients in the EVR group compared to 81.3% of patients in the MMF group at six months. The reduction in BKPyV DNA load was significantly more rapid in the MMF group. Calcineurin inhibitor trough levels were within expected target ranges and did not differ meaningfully between the two groups from randomization through month six. Two grafts were lost, and four patients died. Eleven patients in the EVR group and six patients in the MMF group developed biopsy-proven BKPyV nephropathy. Thus, in KTRs with BKPyV DNAemia, replacing MMF with EVR along with lowering calcineurin inhibitor levels did not lead to more frequent or faster clearance of BKPyV.

MTOR 抑制剂具有抗病毒特性，之前的非随机研究表明它们可能对 BKPyV 复制有抑制作用。在这项随机、多中心对照试验（BKEVER 研究）中，我们试图评估依维莫司（EVR）在促进清除 BKPyV 方面的作用，与单纯减少肾移植受者（KTR）中的免疫抑制相比有何影响。130 名出现 BKPyV DNA 血症的 KTR 按 1:1 随机分为两组。第一组是EVR组，用EVR替代霉酚酸酯（MMF），同时降低钙神经蛋白抑制剂的谷值水平；第二组是MMF组，MMF剂量减半，同时降低类似的钙神经蛋白抑制剂水平。主要终点是在六个月时达到病毒清除率的患者比例。次要终点包括 BKPyV 随时间推移的复制动力学、BKPyV 相关肾病的发生率、肾移植功能、肾移植排斥反应的发生率以及两年内的药物耐受性。值得注意的是，EVR 组有 55.7% 的患者在 6 个月后清除了 BKPyV，而 MMF 组则有 81.3% 的患者清除了 BKPyV。在 MMF 组中，BKPyV DNA 负荷的减少速度明显更快。降钙素抑制剂的谷值在预期目标范围内，从随机分组到第六个月，两组之间没有明显差异。两例移植物丢失，四例患者死亡。EVR 组中的 11 名患者和 MMF 组中的 6 名患者出现了活检证实的 BKPyV 肾病。因此，在患有 BKPyV DNA 血症的 KTR 患者中，用 EVR 取代 MMF 并同时降低降钙素抑制剂的水平并不会导致 BKPyV 更频繁或更快地被清除。

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引用次数: 0

A randomized controlled trial evaluated the efficacy and safety of apixaban for prevention of recurrent thrombosis after thrombectomy of hemodialysis vascular access 一项随机对照试验评估了阿哌沙班预防血液透析血管通路血栓切除术后血栓复发的有效性和安全性。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.10.023

Tsung-Yu Ko , Chih-Cheng Wu , Mu-Yang Hsieh , Chung-Wei Yang , Chi-Hung Cheng , Chun-Kai Chen , Hsien-Li Kao

Dialysis vascular access thrombosis poses a substantial challenge for individuals undergoing hemodialysis. The efficacy and safety of apixaban, a direct oral coagulation factor Xa inhibitor, in preventing recurrent access thrombosis have yet to be explored. Here, a multicenter randomized control study (NCT04489849) enrolled hemodialysis patients to evaluate this who underwent successful endovascular thrombectomy within 48 hours. Participants were assigned to standard care or standard care plus apixaban, 2.5 mg twice daily for three months. The trial design involved open-label administration, with independent adjudication of endpoints. The primary efficacy endpoint was recurrent access thrombosis within three months after thrombectomy. A total of 186 patients with well-balanced baseline characteristics were enrolled, 93 randomized to the apixaban group and 93 to the control group. The apixaban group demonstrated a significantly lower rate of access thrombosis at three months than the control group (24.0% vs. 40.8%; hazard ratio, 0.52 [95% confidence interval 0.31–0.88]), along with a significantly better primary patency failure rate (32.2% vs. 49.5%, 0.57 [0.36–0.91]). Safety outcomes showed comparable death rates and major bleeding incidents but significantly higher incidence of minor bleeding in the apixaban group (22.6% vs. 7.5%). The effect of apixaban did not show interaction in subgroups of different access types, antiplatelet usage, severity of comorbidities, or history of thrombosis. Thus, apixaban effectively reduced the risk of recurrent thrombosis in hemodialysis vascular access post-thrombectomy. Despite a minor increase in bleeding adverse effects, the net clinical benefit favors the use of apixaban in this context.

透析血管通路血栓是血液透析患者面临的一大挑战。阿哌沙班是一种直接口服凝血因子 Xa 抑制剂，其在预防复发性通路血栓形成方面的有效性和安全性尚有待探索。在此，一项多中心随机对照研究（NCT04489849）招募了血液透析患者，对在 48 小时内成功进行血管内血栓切除术的患者进行评估。参与者被分配到标准护理或标准护理加阿哌沙班（2.5 毫克，每天两次，持续三个月）。试验设计为开放标签给药，终点独立裁定。主要疗效终点是血栓切除术后三个月内再次出现入路血栓。共有186名基线特征均衡的患者参加了试验，其中93人被随机分配到阿哌沙班组，93人被随机分配到对照组。阿哌沙班组三个月内的入路血栓形成率明显低于对照组（24.0% 对 40.8%；危险比 0.52 [95% 置信区间 0.31-0.88]），初次通畅失败率也明显高于对照组（32.2% 对 49.5%，0.57 [0.36-0.91]）。安全结果显示，阿哌沙班组的死亡率和大出血率相当，但轻微出血率明显更高（22.6% 对 7.5%）。阿哌沙班的效果在不同入路类型、抗血小板药物使用情况、合并症严重程度或血栓形成史的亚组中未显示交互作用。因此，阿哌沙班能有效降低血栓切除术后血液透析血管通路复发血栓的风险。尽管出血不良反应略有增加，但阿哌沙班的净临床获益有利于在这种情况下使用阿哌沙班。

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引用次数: 0

In situ molecular profiles of glomerular cells by integrated imaging mass spectrometry and multiplexed immunofluorescence microscopy 通过综合成像质谱和多重免疫荧光显微镜分析肾小球细胞的原位分子特征。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.11.008

Allison B. Esselman , Felipe A. Moser , Léonore E.M. Tideman , Lukasz G. Migas , Katerina V. Djambazova , Madeline E. Colley , Ellie L. Pingry , Nathan Heath Patterson , Melissa A. Farrow , Haichun Yang , Agnes B. Fogo , Mark de Caestecker , Raf Van de Plas , Jeffrey M. Spraggins

Glomeruli filter blood through the coordination of podocytes, mesangial cells, fenestrated endothelial cells, and the glomerular basement membrane. Cellular changes, such as podocyte loss, are associated with pathologies like diabetic kidney disease. However, little is known regarding the in situ molecular profiles of specific cell types and how these profiles change with disease. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is well-suited for untargeted tissue mapping of a wide range of molecular classes. Importantly, additional imaging modalities can be integrated with MALDI IMS to associate these biomolecular distributions to specific cell types. Here, we integrated workflow combining MALDI IMS and multiplexed immunofluorescence (MxIF) microscopy. High spatial resolution MALDI IMS (5 μm) was used to determine lipid distributions within human glomeruli from a normal portion of fresh-frozen kidney cancer nephrectomy tissue revealing intra-glomerular lipid heterogeneity. Mass spectrometric data were linked to specific glomerular cell types and substructures through new methods that enable MxIF microscopy to be performed on the same tissue section following MALDI IMS, without sacrificing signal quality from either modality. Machine learning approaches were combined enabling cell type segmentation and identification based on MxIF data. This was followed by mining of cell type or cluster-associated MALDI IMS signatures using classification and interpretable machine learning. This allowed automated discovery of spatially specific molecular markers for glomerular cell types and substructures as well as lipids correlated to deep and superficial glomeruli. Overall, our work establishes a toolbox for probing molecular signatures of glomerular cell types and substructures within tissue microenvironments providing a framework applicable to other kidney tissue features and organ systems.

肾小球通过荚膜细胞、间质细胞、栅栏状内皮细胞和肾小球基底膜的协调作用过滤血液。荚膜细胞脱落等细胞变化与糖尿病肾病等病变有关。然而，人们对特定细胞类型的原位分子特征以及这些特征如何随疾病发生变化知之甚少。基质辅助激光解吸电离成像质谱法（MALDI IMS）非常适合对各种分子类别进行非靶向组织绘图。重要的是，其他成像模式可与 MALDI IMS 集成，将这些生物分子分布与特定细胞类型联系起来。在这里，我们整合了 MALDI IMS 和多重免疫荧光（MxIF）显微镜的工作流程。利用高空间分辨率 MALDI IMS（5 μm）确定正常部分肾癌肾切除组织中人肾小球内的脂质分布，揭示了肾小球内脂质的异质性。通过新方法将质谱数据与特定的肾小球细胞类型和亚结构联系起来，这样就能在 MALDI IMS 之后在同一组织切片上进行 MxIF 显微镜检查，而不会牺牲两种模式的信号质量。结合机器学习方法，可根据 MxIF 数据进行细胞类型分割和识别。然后利用分类和可解释的机器学习挖掘细胞类型或集群相关的 MALDI IMS 特征。这样就能自动发现肾小球细胞类型和亚结构的空间特异性分子标记，以及与深层和浅层肾小球相关的脂质。总之，我们的工作为探测组织微环境中肾小球细胞类型和亚结构的分子特征建立了一个工具箱，提供了一个适用于其他肾组织特征和器官系统的框架。

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引用次数: 0

The Case | A rare cause of acute kidney injury and proteinuria

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.11.012

Siarhei Dzedzik , Frank Cortazar , Dominick Santoriello

引用次数: 0

The membrane transporter SLC25A48 enables transport of choline into human mitochondria 膜转运体 SLC25A48 能够将胆碱转运到人体线粒体中。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.06.022

Suraj Patil , Oleg Borisov , Nora Scherer , Christophe Wirth , Pascal Schlosser , Matthias Wuttke , Sandra Ehret , Luciana Hannibal , Kai-Uwe Eckardt , Carola Hunte , Björn Neubauer , Anna Köttgen , Michael Köttgen

Choline has important physiological functions as a precursor for essential cell components, signaling molecules, phospholipids, and the neurotransmitter acetylcholine. Choline is a water-soluble charged molecule requiring transport proteins to cross biological membranes. Although transporters continue to be identified, membrane transport of choline is incompletely understood and knowledge about choline transport into intracellular organelles such as mitochondria remains limited. Here we show that SLC25A48 imports choline into human mitochondria. Human loss-of-function mutations in SLC25A48 show impaired choline transport into mitochondria and are associated with elevated urine and plasma choline levels. Thus, our studies may have implications for understanding and treating conditions related to choline metabolism.

胆碱作为细胞基本成分、信号分子、磷脂和神经递质乙酰胆碱的前体，具有重要的生理功能。胆碱是一种水溶性带电分子，需要转运蛋白才能穿过生物膜。虽然转运蛋白不断被发现，但人们对胆碱的膜转运还不完全了解，而且对胆碱转运到线粒体等细胞内器官的了解仍然有限。在这里，我们发现 SLC25A48 能将胆碱转运到人的线粒体中。人类 SLC25A48 功能缺失突变显示胆碱向线粒体的转运受损，并与尿液和血浆胆碱水平升高有关。因此，我们的研究可能会对了解和治疗与胆碱代谢相关的疾病产生影响。

引用次数: 0

Genetic deletion of the kidney sodium/proton exchanger-3 (NHE3) does not alter calcium and phosphate balance due to compensatory responses 肾脏钠/质子交换子-3（NHE3）的基因缺失不会因代偿反应而改变钙磷平衡。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.07.013

Søren B. Poulsen , Sathish K. Murali , Linto Thomas , Adrienne Assmus , Lena L. Rosenbæk , Rikke Nielsen , Henrik Dimke , Timo Rieg , Robert A. Fenton

The sodium/proton exchanger-3 (NHE3) plays a major role in acid–base and extracellular volume regulation and is also implicated in calcium homeostasis. As calcium and phosphate balances are closely linked, we hypothesized that there was a functional link between kidney NHE3 activity, calcium, and phosphate balance. Therefore, we examined calcium and phosphate homeostasis in kidney tubule–specific NHE3 knockout mice (NHE3^loxloxPax8 mice). Compared to controls, these knockout mice were normocalcemic with no significant difference in urinary calcium excretion or parathyroid hormone levels. Thiazide-induced hypocalciuria was less pronounced in the knockout mice, in line with impaired proximal tubule calcium transport. Knockout mice had greater furosemide-induced calciuresis and distal tubule calcium transport pathways were enhanced. Despite lower levels of the sodium/phosphate cotransporters (NaPi)-2a and -2c, knockout mice had normal plasma phosphate, sodium-dependent ³²Phosphate uptake in proximal tubule membrane vesicles and urinary phosphate excretion. Intestinal phosphate uptake was unchanged. Low dietary phosphate reduced parathyroid hormone levels and increased NaPi-2a and -2c abundances in both genotypes, but NaPi-2c levels remained lower in the knockout mice. Gene expression profiling suggested proximal tubule remodeling in the knockout mice. Acutely, indirect NHE3 inhibition using the SGLT2 inhibitor empagliflozin did not affect urinary calcium and phosphate excretion. No differences in femoral bone density or architecture were detectable in the knockout mice. Thus, a role for kidney NHE3 in calcium homeostasis can be unraveled by diuretics, but NHE3 deletion in the kidneys has no major effects on overall calcium and phosphate homeostasis due, at least in part, to compensating mechanisms.

钠/质子交换子-3（NHE3）在酸碱和细胞外容量调节中发挥着重要作用，同时也与钙平衡有关。由于钙和磷酸盐平衡密切相关，我们假设肾脏 NHE3 活性、钙和磷酸盐平衡之间存在功能性联系。因此，我们研究了肾小管特异性 NHE3 基因敲除小鼠（NHE3loxloxPax8 小鼠）体内的钙磷平衡。与对照组相比，这些基因敲除小鼠血钙正常，尿钙排泄或甲状旁腺激素水平无明显差异。噻嗪类药物引起的低钙尿在基因敲除小鼠中不那么明显，这与近端肾小管钙转运受损有关。基因敲除小鼠呋塞米诱导的钙尿症更严重，远端肾小管钙转运途径得到了加强。尽管钠/磷酸盐共转运体（NaPi）-2a 和 -2c 的水平较低，但基因敲除小鼠的血浆磷酸盐、近端小管膜囊泡中的钠依赖性 32 磷酸盐摄取和尿磷酸盐排泄均正常。肠道磷酸盐摄取量没有变化。低饮食磷酸盐降低了甲状旁腺激素水平，增加了两种基因型小鼠的 NaPi-2a 和 -2c 丰度，但基因敲除小鼠的 NaPi-2c 水平仍然较低。基因表达谱分析表明，基因敲除小鼠的近端肾小管发生了重塑。使用SGLT2抑制剂empagliflozin间接抑制NHE3不会影响尿钙和磷酸盐的排泄。基因敲除小鼠的股骨骨密度和结构均未发现差异。因此，肾脏 NHE3 在钙稳态中的作用可以通过利尿剂来揭示，但肾脏中的 NHE3 基因缺失不会对总体钙和磷稳态产生重大影响，这至少部分归因于补偿机制。

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引用次数: 0

Title Page

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/S0085-2538(24)00865-2

引用次数: 0

TRAIL induces podocyte PANoptosis via death receptor 5 in diabetic kidney disease TRAIL通过死亡受体5诱导糖尿病肾病荚膜细胞泛凋亡

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.10.026

Zhimei Lv , Jinxiu Hu , Hong Su , Qun Yu , Yating Lang , Meilin Yang , Xiaoting Fan , Yue Liu , Bing Liu , Yanfang Zhao , Cheng Wang , Shangwei Lu , Ning Shen , Rong Wang

Podocytes can undergo PANoptosis (apoptosis, pyroptosis, and necroptosis). Diabetic kidney disease (DKD) is the leading cause of kidney failure, and podocyte loss is a major event leading to the progression of DKD. Here, we compared single cell RNA sequencing (scRNA-seq) data between three normal and three DKD human kidney samples and found a significant increase of TNFSF10 and TNFRSF10B expression in podocytes of patients with DKD. Tumor necrosis factor (TNF)-related apoptosis–inducing ligand (TRAIL), coded by TNFSF10, belongs to the TNF superfamily members and TNFRSF10B codes for death receptor 5 (DR5). We confirmed that expression of TRAIL and DR5 increased in podocytes of patients with DKD and correlated with the severity of DKD. In vitro, TNF-α stimulated TRAIL and DR5 expression in cultured human podocytes. Silence of TRAIL or DR5 by small interfering RNA alleviated TNF-α-stimulated podocytes PANoptosis, while overexpression of TRAIL, treatment with recombinant human TRAIL (rh-TRAIL) or the DR5 activator (Bioymifi) enhanced podocytes PANoptosis. In vivo, podocyte-specific deletion of TNFSF10 or TNFRSF10B alleviated podocyte and glomerular injury in high fat diet and streptozotocin-induced obese diabetic mice and was associated with decreased podocyte PANoptosis. Conversely, the induction of TNFSF10 overexpression specifically in podocytes exacerbated albuminuria and kidney injury in diabetic mice with increased podocyte PANoptosis. Additionally, administration of soluble DR5-Fc, an inhibitor of DR5, resulted in a marked reduction in albuminuria and glomerular injury in BTBR ob/ob mice. Our findings suggest a critical autocrine role of TRAIL/DR5 in inducing podocyte injury in DKD via activation of PANoptosis.

荚膜细胞可发生泛凋亡（凋亡、热凋亡和坏死）。糖尿病肾病（DKD）是导致肾衰竭的主要原因，而荚膜细胞丢失是导致糖尿病肾病恶化的主要原因。在这里，我们比较了三个正常人肾脏样本和三个糖尿病肾脏样本的单细胞 RNA 测序（scRNA-seq）数据，发现糖尿病肾脏病患者荚膜细胞中 TNFSF10 和 TNFRSF10B 的表达显著增加。TNFSF10编码的肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）属于TNF超家族成员，TNFRSF10B编码的是死亡受体5（DR5）。我们证实，TRAIL和DR5在DKD患者荚膜细胞中的表达增加，并与DKD的严重程度相关。在体外，TNF-α 可刺激培养的人类荚膜细胞中 TRAIL 和 DR5 的表达。通过小干扰 RNA 沉默 TRAIL 或 DR5 可减轻 TNF-α 刺激下的荚膜细胞泛凋亡，而过表达 TRAIL、使用重组人 TRAIL（rh-TRAIL）或 DR5 激活剂（Bioymifi）可增强荚膜细胞泛凋亡。在体内，荚膜特异性缺失 TNFSF10 或 TNFRSF10B 可减轻高脂饮食和链脲佐菌素诱导的肥胖糖尿病小鼠的荚膜和肾小球损伤，并与荚膜细胞泛凋亡减少有关。相反，诱导 TNFSF10 在荚膜细胞中的特异性过表达会加重糖尿病小鼠的白蛋白尿和肾损伤，同时增加荚膜细胞的 PAN 凋亡。此外，服用 DR5 抑制剂可溶性 DR5-Fc 可显著减少 BTBR ob/ob 小鼠的白蛋白尿和肾小球损伤。我们的研究结果表明，TRAIL/DR5 在通过激活 PAN 细胞凋亡诱导 DKD 中的荚膜细胞损伤方面起着关键的自分泌作用。

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引用次数: 0

Advancing anti-inflammatory therapies: leveraging glucocorticoid pathways for novel treatments 转化科学推动抗炎疗法--利用糖皮质激素途径开发新的治疗方法。

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.11.005

Valerie Etzrodt , Huihui Huang , Samir M. Parikh

引用次数: 0

Corrigendum to “KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis.” Kidney International 2024;105(3S):S71–S116

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international

Pub Date : 2025-02-01 DOI: 10.1016/j.kint.2024.10.004

引用次数: 0

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